This study aimed to evaluate real-life data on patterns of hydroxyurea prescription/use in polycythemia vera (PV).This retrospective chart review study included PV patients who had received hydroxyurea therapy for at least 2 months after PV diagnosis. Data were collected from 10 representative academic medical centers.Of 657 patients, 50.9% were in the high-risk group (age ≥60 years and/or history of thromboembolic event). The median duration of hydroxyurea therapy was 43.40 months for all patients; 70.2% of the patients had ongoing hydroxyurea therapy at last follow-up. Hydroxyurea was discontinued in 22.4% of the patients; the most common reason was death (38.5%). The predicted time until hydroxyurea discontinuation was 187.8 months (standard error: ±21.7) for all patients. This duration was shorter in females (140.3±37.7 vs. 187.8±29.7) (p=0.08). This trend was also observed in surviving patients aged ≥50 years at hydroxyurea initiation . Among the patients who were still on hydroxyurea therapy, 40.3% had a hematocrit concentration of ≥45% at their last follow-up visit, and the rate of patients with at least one elevated blood cell count was 67.8%.Hydroxyurea prescription patterns and treatment aims are frequently not in accordance with the guideline recommendations. Its discontinuation rate is higher in females. Janus kinase2 (JAK2) gene on the 9th chromosome is found in 95%-97% of PV patients and this discovery was a milestone in its diagnosis and treatment  count of >10x109/L) after hydroxyurea therapy used for at least 3 months at a dose of ≥2 g/day, or iii) failure to reduce massive splenomegaly (>10 cm underneath the rib) by at least 50% on palpation or failure to completely improve splenomegaly-related symptoms after hydroxyurea therapy used for at least 3 months at a dose of ≥2 g/day, or iv) an absolute neutrophil count of <1x109/L or a platelet count of <100x109/L or a hemoglobin level of <10 g/dL at the lowest hydroxyurea dose required to provide complete or partial clinicohematological response as defined by the ELN ) (range or interquartile range) for numerical variables. Normality of data was tested using visual  and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). The chi-square test was used to compare independent categorical variables, whereas Student’s t-test was used to compare numerical variables. The continuation rate of hydroxyurea was calculated as a ratio and also using Kaplan-Meier analysis. Values of p<0.05 were considered as statistically significant.JAK2V617F mutation, and 8.2% had an active or a history of a thromboembolic/vascular event at diagnosis. Of the patients, 50.9% (295/579) were in the high-risk group (age ≥60 years and/or history of a thrombotic event) at diagnosis. The general characteristics of the study patients and hydroxyurea therapy are presented in Charts of 657 PV patients who were diagnosed between January 1985 and July 2017 were reviewed until April 2018. Fifty-one patients not receiving hydroxyurea and 18 patients not fulfilling the criteria of the study protocol were excluded; accordingly, data of 588 patients were included in the statistical analyses. Of the patients, 56.8% were male, 44.9% were aged ≥60 years, 89.2% of the tested cases were positive for the All PV patients (n=588) received hydroxyurea therapy, while 1.7%, 2.4%, and 3.9% of the patients respectively received standard or PEGylated recombinant interferon alpha, or anagrelide as a second cytoreductive therapy in addition to hydroxyurea therapy . It was Evaluation of the patients for whom the exact starting date of hydroxyurea treatment was known (n=496) revealed that there were 284 (57.3%) patients who were commenced on hydroxyurea therapy within the first 2 months after the diagnosis, whereas 212 (42.7%) patients started hydroxyurea later (at a median of 20.3 months [interquartile range: 7.1-49.5 months] after the diagnosis). The characteristics of the patients according to their hydroxyurea therapy schedule (i.e. upfront or later) are presented in 9/L was also associated with commencement of upfront hydroxyurea .High-risk patients were more frequently commenced on upfront therapy with hydroxyurea; the rates were 63% in the age group of ≥60 years (n=260) and 52.5% in the age group of <60 years (n=319) (p=0.019), and the rates were 72.3% in the patients with thrombotic/vascular event (n=54) and 55.6% in those without (n=523) (p=0.028). In addition, a WBC count of >15x10The median duration of hydroxyurea therapy was 43.4 months (range: 2-378 months) for all patients. The number of patients who were still on hydroxyurea therapy at their last follow-up visit accounted for 70.2% (n=413) of the study population, whereas the number of those who discontinued hydroxyurea accounted for 22.4% (n=132). Excluding 43 cases with missing data, the discontinuation rate for hydroxyurea therapy was 24.2%. The median duration of hydroxyurea therapy was 36.4 months (range: 2-378 months) for the patients who discontinued hydroxyurea therapy and 45.8 months (range: 2-323 months) for those who continued.The reported reasons for discontinuation of hydroxyurea therapy were death (38.5%), toxicity (33.3%), inappropriate disease control or disease progression (22.8%), and other/unknown (5.4%). The patients who discontinued and those who were continuing hydroxyurea treatment were compared according to their demographic/clinical variables. Gender was determined as a significant variable for discontinuation; the rate of discontinuation was significantly higher in females than in males  . LimitinAccording to the Kaplan-Meier analysis, the median time until hydroxyurea discontinuation was found as 187.8 months  for all patients. This duration was shorter in females  than in males  (p=0.08). We also limited the Kaplan-Meier analysis to surviving patients aged ≥50 years at hydroxyurea initiation in order to understand if the main reasons for hydroxyurea discontinuation were fertility/teratogenicity concerns or death. We found that the median time until hydroxyurea discontinuation was still significantly shorter in females  (p=0.03), indicating that the above-mentioned factors were not the main reasons for drug discontinuation .9/L), WBC count (>10x109/L), and at least one of these three. The rates of hydroxyurea resistance (7.9%) and intolerance (8.1%) were estimated as 16% in total.Complete blood count values during the last follow-up visits of the patients still on hydroxyurea therapy are demonstrated in While the frequencies of thrombotic/vascular events, hemorrhage, and solid tumor at diagnosis were 8.2%, 2.2%, and 1.5%, respectively, they were 4.8%, 0%, and 0.17% under hydroxyurea therapy. Secondary myeloid neoplasms (i.e. acute myeloid leukemia or myelodysplastic syndrome) and post-PV myelofibrosis during hydroxyurea treatment were reported in 3 and 7 cases, respectively. The estimated risks at 10 years were 6.2% and 8%.Hydroxyurea remains the first-line cytoreductive therapy in the treatment of patients with PV . The prePV is more prevalent in the elderly population and advanced age (≥60 years) is a significant risk factor for prognosis and survival. In our study, nearly half of the patients (44.9%) were ≥60 years. In a chart review study from Germany, 1476 PV patients were evaluated and 77.1% were found to be over the age of 60 years . In a cr9/L as the risk factors for poor prognosis. The classical risk factors for thrombotic events in PV patients include age of ≥60 years, history of thrombosis, and a hematocrit concentration of ≥45%. In addition, other risk factors still in need of validation have been reported, such as an elevated WBC count, female gender, mutant JAK2 allele burden, and classical cardiovascular risk factors [In their international study, Tefferi et al.  evaluate factors . In the JAK2 mutation is an important criterion for the diagnosis of PV. In a prospective observational study from the United States, nearly half of the patients (n=2510) were investigated for the presence of JAK2 mutation and 95.8% of these patients were found to be positive for JAK2V617F mutation [JAK2V617F mutation was positive in 89.2% of the tested patients. The mutation status was unknown in 14.9% of the patients. These cases were mostly diagnosed before discovery of the mutation. Jentsch-Ullrich et al. [JAK2 mutation was included in the diagnostic criteria in the revised 2008 WHO classification system [Analysis of the mutation . In the h et al.  reportedAlthough risk stratification of PV patients can be a guide for treatment, the patients may still be subjected to the risk of overtreatment or undertreatment . A studyPatients with PV are at higher risk of morbidity and mortality as compared with the general population. Thrombotic and hemorrhagic events are the major complications associated with mortality . Treatme9/L, WBC count of >10x109/L) in significant proportions of their patients on hydroxyurea . Similar outcomes were also obtained in the present study; hydroxyurea was discontinued in 22.4% of the patients and the main reported reasons for discontinuation were death (38.5%), toxicity (33.3%), and inappropriate disease control or progression (22.8%). Of the patients who were still on hydroxyurea therapy, 40.3% had a hematocrit concentration of ≥45%, 29.2% had a platelet count of >400×109/L, and 34.4% had a WBC count of >10x109/L.Parasuraman et al.  reportedResistance/intolerance has been reported in nearly one-fourth of the patients receiving hydroxyurea therapy ,23. HydrIn the present study, discontinuation of hydroxyurea therapy was more common in females than in males . Limiting the analysis to the patients aged ≥50 years, the drug discontinuation rate was still higher in females . For this reason, we think that the higher hydroxyurea discontinuation rate in females was not due to fertility and/or teratogenicity concerns. We assume that aesthetic concerns due to cutaneous side effects might be a potential reason for this difference.The use of hydroxyurea for the treatment of PV in routine clinical practice is not in line with the guideline recommendations in some regards. Among hydroxyurea users, a substantial proportion of patients had blood count values that remained higher than recommended in the guidelines. These findings underline the need for more emphasis on the importance of reviewing treatment algorithms in accordance with the recommendations of current guidelines and following these algorithms in clinical practice. The finding of a higher hydroxyurea discontinuation rate among women and its reasons should be further investigated.


Salvage radiation therapy (SRT) can be offered to patients with relapsing glioblastoma multiforme (GBM). Here we report our experience with a schedule extending the treatment time of SRT with the aim to prolong the cytotoxic effect of ionizing radiation while minimizing the cytotoxic hazards for the surrounding brain.From 2009 until 2017, 124 of 218 patients received radical resection, adjuvant chemo-radiation with photons and temozolomide (TMZ) followed by adjuvant TMZ. Re-irradiation was performed in 26 patients due to local relapse. Treatment schedules varied. Survival and molecular markers were assessed.p=0.038). Patients who received daily fractions of 1,6 to 1,65 Gy to a total dose of >40 Gy had a median survival time of 24,6 months compared to patients treated with higher daily doses or a total dose of <40 Gy (p= 0.039), consistent with the observation that patients treated with 21–28 fractions had a median survival of 21,9 months compared to 15,8 months of patients who received 5–20 fractions (p=.0.05). Patients with Ki-67 expression of >30% seemed to perform better than patients with expression levels of ≤20% (p=0.03). MGMT methylation status, TERT promoter or ATRX mutations, overexpression of p53, p16, PD-L1, and EGFR were not prognostic.The median survival was respectively 12 months (9–14.5) of the 124 patients treated with tri-modal therapy and 19.2 months (14.9–24.6) for the 26 patients retreated with SRT (Re-irradiation of relapsing GBM is a highly valid treatment option. Our observation challenges hypofractionated stereotactic radiotherapy for retreatment and controlled trials on the fractionation dose for SRT are needed. Robust predictive molecular markers could be beneficial in the selection of patients for SRT. Glioblastoma multiforme (GBM) is an aggressive form of brain tumor. Classical local therapies such as surgery and radiotherapy have complemented with chemotherapy and electric treatment fields after initial multimodal therapy –3. The cIn the present study, we review our experience with patients treated with SRT in respect of survival and potential biological markers associated with prolonged survival.This research was a retrospective analysis of a cohort of all consecutive patients who underwent SRT at a single tertiary health care facility from January 2009 until December 2017, prior to introduction of systemic therapy of GBM patients with electric treatment fields. A total of 218 patients were diagnosed with primary GBM at the City Hospital of Dessau, Germany and 124 patients were treated with trimodal therapy consisting of radical total resection, postoperative adjuvant radiotherapy to 60 Gy with concomitant TMZ followed by adjuvant TMZ. The minimal follow-up for all patients was 2 years. All patients consigned to analysis and communication of their data in anonymized reports or publications, and the case review study was approved by the ethics’ committee  and internal review board.Surgery was planned on the basis of the preoperative magnetic imaging (MRI) studies. After trepanation and visualization of the tumor, guidance included intraoperative ultrasound, neurostimulation and fluorescence . Complet2, and all 26 patients received TMZ during primary RT. After the end of chemoradiation, adjuvant TMZ with a first course of 150 mg/m2 (days 1 to 5) followed by more courses with 200 mg/m2 (days 1 to 5) was given to all patients. Courses were repeated every 28 days to at least six cycles or until relapse was observed.Initial chemotherapy consisted of concomitant temozolomide (TMZ) during primary radiotherapy at a dose of 75mg/mPrimary chemo-radiation was performed with 6 MV photons using coplanar or non-coplanar beam geometries of dynamic or static modulated fields in the vast majority of patients. All patients received 1,8 to 2,0 Gy daily to a total dose of 59,4 to 61,4 Gy. Patients treated subsequently with SRT had a Karnofsky performance status of >70%. All patients received 3D-treatment planning on a planning computer tomography  or on a Toshiba Aquillon LB . All patients had magnetic resonance imaging studies available for target volume definition and SRT planning. The planning CT  was fused with the MRI  using the T1 imaging with Gadolinium and the T2-imaging studies to define the gross tumor volume (GTV) of the relapse . A margin of 2–4 mm surrounding the GTV was used to define the primary planning target volume disregarding the perilesional edema. However, the PTV varied according to the physician’s discretion. The PTV was often asymmetrically extended into the direction of the neighboring surface of the resection cavity to a maximum up to 6 mm, or towards parts of edematous structures or suspected areas of tumor cell infiltration. The planning was performed with ARIA version 9.0 and 11.0 after 2012 . The treatment was 3D-conformal in twelve cases and highly conformal using IMRT, VMAT or combined techniques in 14 patients. The choice for the used technique was the result of comparative planning and the dose to organs at risk in the sum plans with the primary radiotherapy defined the use of the beam geometry for SRT. The average number of fractions used was 21,3 (range: 5–28). To have a comparable number of patients in groups analyzed in respect of treatment duration, a cutoff of four treatment weeks was chosen. Fourteen patients were treated with 5–20 fractions and 12 patients with 21 to 28 fractions.EGFR gene amplification were analyzed on a subset of 22 tumor cases. The markers were chosen from a larger molecular panel including MGMT promotor methylation, IDH1/2 mutation, BRAF (V600E) mutation, 1p19q-deletion, TERT promotor mutation as well as the IHC-markers  routinely applied in our molecular GBM testing. Corresponding data are not shown. The four markers selected proved to be the most promising ones due to their high levels of variance and the limited number of cases available for analysis.Tissue samples from GBM where fixed using 4% phosphate buffered formaldehyde and embedded in paraffin according to standard procedures. H&E staining and immunohistochemistry (IHC) were performed on 3 µm paraffin sections. Expression of three protein markers  and For IHC the following antibodies were used: Ki-67 (Dako), p16  and PD-L1 . Staining was performed with the Dako Autostainer Link 48 using protocols supplied by the manufacturers: Ki-67 , p16 , PD-L1 .Staining results were examined by experienced pathologists under the microscope. Expression was quantified as the proportion of stained tumor cells in percent. The PD-L1 scoring is therefore equivalent to the tumor proportion score (TPS) applied to other tumor types . A hundrEGFR gene amplification was evaluated by FISH using the ZytoLight SPEC EGFR/CEN 7 Dual Color probe  according to the supplied protocol. EGFR amplification was scored after examination of 100 tumor cells as follows: EGFR/CEN7-ratio <2,0 (no amplification), EGFR/CEN7-Ratio ≥2,0 (amplification) (ication) , 16.Statistical analyses were done in R , 18 withThe median survival of the 124 patients treated primarily with trimodal therapy was 12 months (0.95LCL–0.95UCL: 9–14.5 months). The median survival of the patients treated with SRT was 19.2 months (0.95LCL–0.95UCL: 14.9–24.6 months) and 6,4 months (0.95LCL–0.95UCL: 4.8–8.4) after the end of the primary radiotherapy Figure 1The average age of the entire group treated with trimodal therapy was 67.4 years (range: 26–94 years). Patients who received a second series of radiotherapy after primary radiochemotherapy had an average age of 63.6 years (range: 25–81) (p>0.05). Patients offered SRT were selected on performance and the presentation of a single lesion accessible to SRT. Results of the Cox Proportional-Hazards model testing for age give a positive (0.03983) and a highly significant beta coefficient (0.0291), suggesting age as a major risk factor for shortened survival after SRT.The mean GTV was 15.0 ml (range 0.3–71.7 ml) and the mean PTV was 66.8 ml (range 2.9–185.5 ml). Larger GTV or PTV would more likely be treated with prolonged treatment courses with more than 20 fractions. Correlations between GTV and number of fractions (r = 0.35) and correlations between GTV and Re RT Dose (r = 0.15) Figure 3Patients with increasing GTV or PTV had poorer, however still similar survival rates: results of the Cox Proportional-Hazards model for GTV give a positive (0.013) but no significant beta coefficient (0.236), and the PTV gave a positive (0.001) but not significant beta coefficient (0.773).To test, whether the coverage of the GTV could impact on the survival, the ratio of PTV/GTV was analyzed. PTV/GTV ratio gave a negative (-0.0015) but not significant beta coefficient (p = 0.884). Thus, an increasing PTV/GTV ratio was not associated with enhanced survival rates.SRT was performed on an average of 338 days  after the end of chemoradiation. The Cox Proportional-Hazards model for the variable radiotherapy-free time (days) gave a negative (-0.009316) and highly significant beta coefficient (4.98e-05). Postponing SRT to 4–13 months after the end of primary radiotherapy was associated with prolonged survival (p < 0.05). Thus, survival time after initial surgery correlated with the radiotherapy-free time.Fractionation schedules used were heterogeneous. Patients were treated with daily doses of 1,6 to 1,65 Gy or with 1,8 to 2,0 Gy. For hypofractionated radiotherapy, daily doses of 3 or 6 Gy were used. Patients treated with a total number of ≤20 treatments had a median survival time of 15.8 months (0.95 LCL–0.95 UCL: 12.7–NA months), compared to patients treated with 21–28 fractions with a median survival time of 21.9 months (0.95 LCL–0.95 UCL: 13.1–33.7 months) (p = 0.051) as shown in Ki-67 expression proved highly variable among the 22 tumor cases. It ranged from about 1% to 70%. Ki-67 showed a high difference in survival distributions (p = 0.03). Survival was lower for patients with an expression of 1%–20% of Ki-67 in comparison to patients with an expression level of 30%–70% Figure 5EGFR gene amplification but did not associate with survival time.In contrast, the other two expression parameters p16 and PD-L1 did not show high difference in survival distribution between the different categories. A complete loss of p16 expression was observed in 11 cases. High expression >50% was noticed in 5 cases. PD-L1 expression proved positive in 15 tumors with scores between 1% and >50%. Eleven tumors had A variety of salvage options exists for relapsing GBM including re-operation, systemic and cytotoxic therapies or a combination of treatment modalities . The choet al. who suggest that early SRT should be beneficial preferentially in the context of previous salvage surgery , Germany; IRB, Städtisches Klinikum Dessau, Dessau, Germany. Patients agreed to handling and analysis of their anonymized or pseudonymized personal data, most of all outcome analysis within the frameworks of quality assurance of medical care as a part of hospital services.IC, YG, CR, SS, and KN designed the study. NA was in charge of the histology analysis. NA and KN were in charge of the molecular analysis. IC, KN, and NA analyzed the data. YG was in charge of the statistics. IC, YG, CR, SS, and KN wrote the paper. IC, SS, CR, and KN edited the paper. All authors contributed to the article and approved the submitted version.Author YG was employed by PathoNext GmbH.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The aims of the study were to assess the clinical and histopathological characteristics of a comprehensive cohort of women with vulvovaginal melanoma (VVM) treated at our institution and to study the treatment response of checkpoint inhibitors in this patient cohort.This is a retrospective study of women with invasive VVM treated at the Princess Margaret Cancer Centre in Toronto, Ontario, Canada, over a period of 15 years. Clinical and histopathological characteristics, treatment, as well as treatment-related outcome were analyzed in 32 women. Treatment response was evaluated retrospectively using the “response criteria for use in trials testing immunotherapeutics” (iRECIST). The objective response rate was defined as the proportion of patients with complete or partial response based on the best overall response.p = .023). Grade 3/4 adverse events were observed in 3 (13.0%) of the 23 patients.At a median follow-up of 37.8 months (5.8–110.4), 26 women (81.3%) had disease progression and 16 (50%) died. Thirteen patients with locally unresectable or metastatic melanoma were treated with immune checkpoint inhibitors. Ten additional cases were identified from previously published reports. The best objective response rate for immune checkpoint inhibitors was 30.4% (95% CI = 11.6%–49.2%) and the clinical benefit rate was 52.2% (95% CI = 31.8%–72.6%). The clinical benefit rate was significantly better for programmed cell death protein 1 inhibitors (or a combination) compared with ipilimumab alone (Fisher exact, Women with VVM constitute a high-risk group with poor overall prognosis. Immune checkpoint inhibitors are effective in the treatment of metastatic melanoma in this patient cohort. Trials with the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitor ipilimumab and the programmed cell death protein 1 (PD-1) inhibitors nivolumab and pembrolizumab have shown profound improvements of survival in patients with unresectable or metastatic melanoma.The aims of this study are to describe clinical characteristics of a comprehensive cohort of women with VVM treated at our institution and to assess the treatment response of immune checkpoint inhibitors in this patient cohort.12 Demographic data, Eastern Cooperative Oncology Group performance (ECOG) score, histopathology, type of surgery, lymph node assessment, adjuvant treatment, recurrence, treatment details for recurrent disease, and vital status were extracted from the electronic patient records. Programmed death-ligand 1 was not routinely tested in our patient cohort. Selection for immunotherapy was based on availability. Treatment response was evaluated retrospectively using the “response criteria for use in trials testing immunotherapeutics” (iRECIST).13 The objective response rate (ORR) was defined as the proportion of patients with complete (iCR) or partial response (iPR) based on the best overall response (iBOR).13 The clinical benefit rate (CBR) was defined as the proportion of patients with iCR, iPR, or stable disease (iSD). An iSD was assigned if no disease progression occurred for at least 2 months. Adverse events were categorized using the common terminology criteria for adverse events version 5.0.14 The treatment response of immune checkpoint inhibitors was analyzed in our cohort. In addition, treatment response from previously published case series and case reports was identified from PubMed using the search terms “ipilimumab,” “nivolumab,” or “pembrolizumab” in combination with “vulva” or “vagina,” and a separate analysis was performed for our cohort and the combined cohort. Reports without information on treatment response were not included.This is a retrospective single-center cohort study of women with invasive melanoma of the vulva or vagina treated at the Princess Margaret Cancer Centre in Toronto, Ontario, Canada. The study protocol was approved by the institutional review ethics board (UHN 19-5620). All women with histologically confirmed invasive vulvar or vaginal melanoma diagnosed over a period of 15 years (2004–2018) were included and all cases were reviewed by an expert pathologist at the time of initial presentation; women with melanoma in situ without invasive components were not included. Vulvar melanomas were staged according to the AJCC staging classification in the eighth edition, and vaginal melanomas were classified as local, regional, or distant.t test, Mann-Whitney test, or Wilcoxon test, as appropriate. Categorical data were compared using the Fisher exact test. Progression-free survival (PFS) and overall survival (OS) for the comprehensive cohort were calculated from the date of diagnosis to date of progression or death (PFS) and date of diagnosis to date of death (OS). Progression-free survival and OS for the subgroup analysis of immune checkpoint inhibitors were calculated from the date of treatment initiation to the date of progression or death, respectively. The Kaplan-Meier method with log-rank test was used to analyze PFS and OS. The 2- and 5-year survival rates were calculated using the Kaplan-Meier method. Statistical analysis was performed using SPSS Version 26, IBM, Armonk. A p value of less than .05 was considered statistically significant, all tests were 2-sided.Descriptive statistics was used to report demographic data. Continuous variables were compared using the Student I.W.-W. is supported by a grant from the Austrian Science Fund (Project Number J 4382-B) to fund her fellowship at the Division of Dermatology, Department of Medicine, University of Toronto, Ontario, Canada. No external funding was used in the preparation of this manuscript.n = 28) and vaginal (n = 4) melanoma were treated at our institution over a period of 15 years and included in our study. Demographic and clinical characteristics are shown in Table In total, 32 women with invasive vulvar : adjuvant interferon α in 3 and nivolumab in 2 patients, and their outcome is reported hereinafter.p = .126).At a median follow-up of 37.8 months (5.8–110.4), 26 (81.3%) women had disease progression and 16 (50%) died. The median PFS was 17.7 months (95% CI = 5.5–29.8 months), and the 2- and 5-year PFS rates were 35.4% and 23.2%, respectively. The median OS was 59.1 months (95% CI = 23.6–94.5 months), and the 2- and 5-year OS rates were 71.1% and 45.6%, respectively. The 2-year PFS rate by the AJCC stage in vulvar melanoma was as follows: stage I, 100%; stage II, 35.9%; stage III, 42.4%; stage IV, 33.3%; and in the 4 patients with regional vaginal melanoma, 0% (Fifteen (51.7%) of the 29 nonmetastatic patients at diagnosis developed distant metastases with a median time to metastatic disease of 39.5 months (95% CI = 0–84.2 months). Two patients received adjuvant nivolumab: 1 patient with vaginal melanoma developed brain metastases during adjuvant treatment with nivolumab. She was treated with stereotactic radiation and switched to pembrolizumab. The best overall response was iSD, but she ultimately progressed and died of melanoma , and the CBR was 61.5% (95% CI = 35.1%–88.0%). The median PFS was 4.0 months (95% CI = 2.3–5.7 months), and the median OS was 17.0 months (95% CI = 12.7–21.3 months). Ipilimumab was given in 8 patients; the ORR was 12.5% (95% CI = 0%–35.4%), and the CBR was 25.0% (95% CI = 0%–55.0%). Programmed cell death protein 1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors were given in 9 patients; the ORR was 33.3% (95% CI = 2.5%–64.1%), and the CBR was 66.7% (95% CI = 35.9%–97.5%).20; 10 patients with metastatic or unresectable VVM were included , and the CBR was 52.2% (95% CI = 31.8%–72.6%). The median PFS was 4.0 months (95% CI = 2.7–5.3 months), and the median OS was 17.0 months (95% CI = 12.7–21.3 months). The ORR for ipilimumab alone was 8.3% (95% CI = 0%–24%) compared with 37.5%  for PD-1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors. The CBR was 16.7% (95% CI = 0%–37.8%) for ipilimumab compared with 62.5%  for PD-1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors. The median PFS for ipilimumab alone was 3.0 months (95% CI = 2.6–3.4 months) compared with 9.0 months  for PD-1 inhibitors or the combination of CTLA-4 and PD-1 inhibitors. Severe adverse events (grade 3/4) were observed in 2 (15.4%) of the 13 patients in our cohort and 3 (13.0%) of the 23 patients in the total cohort.In addition, 13 patients with VVM receiving immune checkpoint inhibitors were identified from previously published cases in the literatureIn this study, we report the clinical characteristics of VVM and the treatment response to immune checkpoint inhibitors in a comprehensive cohort.21 More than 80% of our cohort had disease recurrence or progression with a 2- and 5-year PFS rate of 35.4% and 23.2%, respectively. More than 50% of the women, who were free of distant metastases at diagnosis, developed metastatic disease. Therefore, women with VVM represent a high-risk group.Most women were diagnosed in advanced disease stages with poor prognostic indicators. Half of the nonmetastatic patients undergoing surgical lymph node assessment had lymph node metastases, and most our patients had a high mitotic count, both of which were recently shown to be important independent predictors for survival in women with VVMs.4 cKIT mutations were observed 14% and NRAS mutations in 13%; 2 patients were found to have a mutation in SF3B1, a mutation that was recently found to be more prevalent in VVMs and may be associated with worse outcome.22Consistent with previous reports and unlike in cutaneous melanomas, only a small proportion of patients had BRAF mutations, limiting the treatment options with BRAF/MEK inhibitors.23 and CA209-03824; 1 phase II trial: CheckMate 06925; and 3 phase III trials: CheckMate 066,26 CheckMate 037,27 and CheckMate 06710).The introduction of immune checkpoint inhibitors has led to an enormous progress in melanoma treatment and checkpoint inhibitors are now United States Food and Drug Administration and European Medicines Agency approved in the adjuvant and metastatic setting. The mechanism of action of CTLA-4 and PD-1 inhibitors is shown in Figure 10 but comparable with 40.9% for nivolumab10 and 33.0% for pembrolizumab . Severe adverse events were observed in 15.4% of our cohort, which is comparable with the rate observed in mucosal melanomas.10For PD-1 or a combination of PD-1 and CTLA-4 inhibitors, the ORR was 37.5% and the CBR was 62.5% with a median PFS of 9.0 months. This is again lower compared with the ORR of 60.4% reported for a combination of nivolumab and ipilimumabThis study investigates a large series of well-described cases of vulvar and vaginal melanoma diagnosed and treated at a comprehensive cancer center. We report clinical characteristics, outcome and treatment response with immune checkpoint inhibitors. The study is, however, limited by its retrospective design. Furthermore, including case reports into the analysis of treatment response adds the risk of publication bias. We have therefore analyzed our own series including all patients with VVM treated at our institution separately, and no distortion of the response rates was observed when adding the additional 10 cases previously published in the literature.Women with VVM constitute a high-risk group with poor overall prognosis. Immune checkpoint inhibitors are effective with a complete or partial response being observed in approximately one third of women with locally unresectable or metastatic VVM. Programmed cell death protein 1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors were associated with a significantly higher CBR and a trend toward longer progression-free survival compared with CTLA-4 inhibitors alone.


The study estimates the prevalence of probable psychiatric disorder in the working population, determines the proportion of people presenting a probable psychiatric disorder among people exposed to work-related psychosocial risk factors (PSRFs), and identifies which PSRF has the strongest association with having a probable psychiatric disorder.A cross-sectional study conducted in March 2018 involved a representative sample of the French working population. The General Health Questionnaire 28 (GHQ-28) was used to estimate the prevalence of probable psychiatric disorder and 44 items were gathered from theoretical models of PSRFs. We used multiple logistic regression to estimate the association of each PSRF with having a probable psychiatric disorder, adjusted on individual, health, and job confounders.This study involved 3200 French participants. The proportion of probable psychiatric disorder was 22.2% . Ten PSRFs were significantly associated with it. The strongest association was for having problems handling professional and personal responsibilities (reported by 15% of the study population) , with 45% pathological GHQ-28 scores  for people exposed to this PSRF versus 18% non-exposed. The next strongest association was lack of support of colleagues (reported by 28%) . The third strongest association was feeling sometimes afraid when doing the job (reported by 63%) .Our study identified 10 PSRFs associated with psychiatric disorder, with substantial exposure rate among the population. The results of our research could help develop recommendations to improve work environment. Treatable common psychiatric disorders affected 17.3% of people in European Union in 2018. Anxiety disorders (5.4%) and depressive disorders (4.5%) were the most prevalent  was computed to identify the modality with a significantly higher proportion of GHQ-28 score ≥ 24. This modality is the one with the higher Pearson residual for GHQ score ≥ 24.To investigate the association between each PSRF and probable psychiatric disorder, we modeled the binary outcome GHQ-28 score ≥24 as a logistic regression of some PSRFs, adjusted for possible confounders found in the literature: age, sex, chronic medical condition, working on the weekend, staggered work hours, working at night, previous experience with unemployment, work duration per week, and commuting duration ,19. To sBecause sex was previously identified as a confounding factor for psychiatric disorder, we calculated the interactions between sex and the 11 PSRFs selected by the fast-backward procedure and included in the model . We alsoAmong the 40514 eligible people from the “IPSOS Access Panel” invited by e-mail to participate in the study, 10660 agreed and 3487 were included . BecauseFor the whole sample , the meaThe distribution of scores for the GHQ28 is represented in In contrast, “I have problems handling personal and professional responsibilities” was the least reported PSRF (15.4% of the whole sample). However, for this PSRF, the absolute difference between the prevalence of probable psychiatric disorder among exposed (44.6%) and non-exposed (18.1%) individuals was the largest among the 44 PSRFs. The second largest absolute difference in proportion of cases between exposed and non-exposed individuals (21.3 points) was for “My work environment is unpleasant” (22.4% of the sample) and “sometimes I feel afraid when I do my job” (27.8% of the sample). The proportion of probable psychiatric disorder among people reporting an unpleasant work environment was 38.7% and only 17.4% among those who reported a pleasant environment. The proportion of probable psychiatric disorder among people who declared feeling sometimes afraid when they did their job was 37.6% versus 16.3% for those not exposed. The third largest absolute difference (20.3 points) between the proportion of probable psychiatric disorder among exposed and non-exposed individuals was “My job does not makes me feel useful nor gives me self-esteem” (20.7% of the sample) and “I don’t get well along with my hierarchy” (18.7% of the sample). In all, 38.3% of people reporting not feeling useful were probable psychiatric disorder and only 18% among non-exposed individuals. Overall, 39.1% were probable psychiatric disorder among people reporting not getting along with their hierarchy, and only 18.8% among non-exposed individuals.The fast-backward procedure identified 11 PSRFs to be included in the model  and the For the interactions between sex and the 11 PSRFs, none was significant . For theThis study allowed us to estimate the prevalence of probable psychiatric disorder (GHQ-28 score exceeding the threshold 24) in the working population in France: 22.2% . This prevalence was congruent with 17.2% of participants having taken psychotropic medication during the 12 last months (antidepressants or anxiolytics) . As a coOur study found that probable psychiatric disorder were more numerous among women than men and those with a long commute time, working more than 50 hours a week and earning less than 15 000 euros per year , which iIn our study, the proportion of probable psychiatric disorder was higher among people exposed to all PSRFs as compared with those non-exposed, except for two PSRFs: being required to constantly adapt to new things and placed in contact with customers/clients/users. This finding could probably be explained by the unclear meaning of these sentences are ambiguous: it can be positive and negative to be placed in contact with customers for instance.The imbalance of work and personal life embodied the strongest association with psychiatric disorder . These results are consistent with the literature from several developed countries about work–family conflicts –26. InteSocial support in the workplace was associated with having a probable psychiatric disorder  as well as communication , which confirms the model of Theorell and Karasek Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: This is a very interesting manuscript, very well written, and bringing original evidence.This is indeed the first epidemiological French study made on a representative sample of the working population. Representativeness was achieved by using quota sampling. The methodology is very sound and follows international standards. The authors conducted a STROBE-compliant cross-sectional study of a representative sample of the French workers, allowing to estimate the prevalence of probable psychiatric disorders in this population and among workers exposed to work-related psychosocial risk factors.I have few comments:- It is surprising to include individuals aged 18 to 80 years, in a study on active workers in a country where the age of retirement is around 60 to 62 years old. Moreover, the study excluded retired people. Nearly 5% of the study sample is aged more than 60. Can you clarify this point please ?- In this study, 42.6% of participants had a work duration of more than 39h a week, while the legal work duration is 35h a week. Who's is concerned by this ? Workers, independent, managers ?- One major result is that the imbalance of work and personal life embodied the most strongest association with psychiatric disorder. This is a clearly very relevant result even from clinical point of view, as it is frequently observed in workers suffering from burnout.Reviewer #2: This is a very interesting study about the estimation of the prevalence of probable psychiatric disorders in the working population, and the assessment of the proportion of people presenting a probable psychiatric disorder among people exposed to work-related psychosocial risk factors. A strength of the study is that it is conducted in a large sample representative of the French population.Only few points should be clarified.First, authors should define patients exposed vs unexposed regarding the psychosocial risk factors (PSRF). I think that a patient who is exposed to one PSRF given is a patient with a score of 1 regarding this PSRF in the list of 44 questions. But, authors should write it clearly.Second, I do not understand well this sentence: “These two PSRFs were the most reported, with 75.7% and 70.5% of the sample reporting having a job that required constantly adapting to new things and 70.5% reporting often being in contact with customers/clients/users.” This sentence should be re written.Except these two points, this manuscript is very clear with a consistent statistical analysis.Moreover, results are very interesting.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  1 May 2020Responses to the reviewers:We thank all reviewers for their careful reading. Their comments greatly helped us improve our work. Please find in blue our comments and in green the modification of the manuscript. Reviewer #1: This is a very interesting manuscript, very well written, and bringing original evidence.This is indeed the first epidemiological French study made on a representative sample of the working population. Representativeness was achieved by using quota sampling. The methodology is very sound and follows international standards. The authors conducted a STROBE-compliant cross-sectional study of a representative sample of the French workers, allowing to estimate the prevalence of probable psychiatric disorders in this population and among workers exposed to work-related psychosocial risk factors.We thank Reviewer 1 for the positive comments and encouragements. I have few comments:- It is surprising to include individuals aged 18 to 80 years, in a study on active workers in a country where the age of retirement is around 60 to 62 years old. Moreover, the study excluded retired people. Nearly 5% of the study sample is aged more than 60. Can you clarify this point please ?The eligibility criteria were: - Individuals aged 18 to 80 years AND- Having a job Exclusion criteria: - Students- Unemployed individuals- Housewives/husband- Retired peoplehttps://www.insee.fr/fr/statistiques/3646000?sommaire=3646226). A report of the French National Institute for Statistical and Economical Studies from 2018, showed that 5% of people aged [65-74] have an occupation . Top managers but also self-employed and farmers are overrepresented. Four profiles are described: employees with low education with part-time job, people with high education living in big cities, shopkeepers and farmers.  which is consistent with the national statistics.- In this study, 42.6% of participants had a work duration of more than 39h a week, while the legal work duration is 35h a week. Who's is concerned by this ? Workers, independent, managers ?https://www.insee.fr/fr/statistiques/3676634?sommaire=3696937)We performed supplementary statistics on this population of workers who reported working more than 39h per week in the table hereunder. Our results are consistent with the report of the French National Institute for Statistical and Economical Studies from 2017 with a mean work duration of 50.5 hours a week for self-employed and 39.1 hours a week for employees. (Please see figure 5 in  Work duration ≥ 39 hours / week (n=1423) Work duration < 39 hours / week (n=1777)Sex  Male 62.9 42.9 Female 37.1 57.1Age, years 42.0 (10.7) 40.9 (11.4)Number of children  None 50.1 54.5 1 23.4 20.5 2 21.2 18.9 3 4.6 4.9 > 4 0.6 1.2Highest educational degree  baccalaureate degree 18.2 23.6 Baccalaureate degree 19.2 23.5 Baccalaureate degree +2 years 24.6 23.9 Baccalaureate degree ≥ 3 years 38.0 28.9Annual household income (euros)  < 15 000 7.8 13.7 15–24 000 17.4 22.8 24–36 000 25.1 27.0 > 36 000 37.7 23.0 No information 11.9 13.5Occupational status  Independent worker 16.2 7.4 Employees 83.8 92.6Size of company (no. of employees)  < 10 21.6 22.3 10–49 20.0 24.5 50–99 9.7 11.2 100–499 19.3 21.3 > 499 17.1 16.0 No information 12.3 4.7Activity sector  Industry 11.1 14.0 Building 15.2 8.3 Trading 12.1 11.7 Transport 5.5 5.6 Insurance and real estate 3.6 3.2 Education, health and social work 19.5 26.4 Other services 33.1 30.9Duration of job  < 6 months 3.7 7.0 6 months–5 years 33.2 33.9 6–10 years 21.6 21.8 > 10 years 41.5 37.3Commuting duration  < 30 min 55.6 61.6 30 min–1hr 21.4 22.2 > 1hr 23.0 16.2- One major result is that the imbalance of work and personal life embodied the most strongest association with psychiatric disorder. This is a clearly very relevant result even from clinical point of view, as it is frequently observed in workers suffering from burnout.We agree with the reviewer that the imbalance of work and personal life is a major result of the study that echoed clinical practice. In this study we choose to focus on mental disorders and not on burn-out which is not part of the current mental disorder classification (neither the DSM-5 nor the ICM-10), as mentioned in the discussion.  **********************Reviewer #2: This is a very interesting study about the estimation of the prevalence of probable psychiatric disorders in the working population, and the assessment of the proportion of people presenting a probable psychiatric disorder among people exposed to work-related psychosocial risk factors. A strength of the study is that it is conducted in a large sample representative of the French population. Only few points should be clarified.We thank the reviewer for acknowledging our work with positive comments.First, authors should define patients exposed vs unexposed regarding the psychosocial risk factors (PSRF). I think that a patient who is exposed to one PSRF given is a patient with a score of 1 regarding this PSRF in the list of 44 questions. But, authors should write it clearly.We add a sentence in the method section (paragraph 2) Measurement of psychosocial risk factors PSRF): “Therefore, participants with a score of 1 to a given PSRF are called “participants exposed” to this PSRF in the results section.”Second, I do not understand well this sentence: “These two PSRFs were the most reported, with 75.7% and 70.5% of the sample reporting having a job that required constantly adapting to new things and 70.5% reporting often being in contact with customers/clients/users.” This sentence should be re written.We corrected the sentence as followed : “These two PSRFs were the most reported, with 75.7% of the sample reporting having a job that required constantly adapting to new things and 70.5% reporting often being in contact with customers/clients/users. “Except these two points, this manuscript is very clear with a consistent statistical analysis.Moreover, results are very interesting.Response to the editor: - We formated the manuscript according to Plos One standard. - We decided to make the the data set available (open access) as supporting information.- We add the specific sentence to the conflict of interest statement.AttachmentResponse to reviewers.docxSubmitted filename: Click here for additional data file. 6 May 2020Work-related psychosocial risk factors and psychiatric disorders: A cross-sectional study in the French working population.PONE-D-20-02569R1Dear Dr. Chevance,We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact With kind regards,Raoul Belzeaux, M.D.Academic EditorPLOS ONEAdditional Editor Comments :Reviewers' comments: 12 May 2020PONE-D-20-02569R1 Work-related psychosocial risk factors and psychiatric disorders: A cross-sectional study in the French working population. Dear Dr. Chevance:I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. 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A major challenge in the follow-up of patients treated with stereotactic radiosurgery (SRS) for brain metastases (BM) is to distinguish pseudoprogression (PP) from tumor recurrence (TR). The aim of the study was to develop a clinical risk assessment score.n = 53, 15%) or PP . Differences between the 2 groups were analyzed and used to develop a risk assessment score (the Bergen Criteria).Follow-up images of 87 of 97 consecutive patients treated with SRS for 348 BM were analyzed. Of these, 100 (28.7%) BM in 48 (53.9%) patients responded with either TR (P = .001), target cover ratio ≥98% (P = .048), BM volume ≤2 cm3 (P = .054), and primary lung cancer vs. other cancer types (P = .084). Based on the presence (0) or absence (1) of these 5 characteristics, the Bergen Criteria was established. A total score <2 points was associated with 100% PP, 2 points with 57% PP and 43% TR, 3 points with 57% TR and 43% PP, whereas >3 points were associated with 84% TR and 16% PP, P < .001.Factors associated with a higher incidence of PP vs. TR were as follows: prior radiation with whole brain radiotherapy or SRS (Based on 5 characteristics at the time of SRS the Bergen Criteria could robustly differentiate between PP vs. TR following SRS. The score is user-friendly and provides a useful tool to guide the decision making whether to retreat or observe at appropriate follow-up intervals. Treatment data predict the risk of pseudoprogression vs. recurrence post-SRS.The Bergen Criteria robustly assesses the risk of pseudoprogression vs. recurrence.A key task in the follow-up of patients with brain metastases (BM) treated with stereotactic radiosurgery (SRS) is to differentiate pseudoprogression (PP) from recurrence, for which treatment and prognosis are different. Nearly 1/3 of BM treated with SRS will display increased contrast enhancement on standard magnetic resonance imaging; either temporarily due to successful SRS or progressively due to failed SRS. Previous studies have focused on sophisticated imaging techniques to distinguish radiation induced changes from recurring tumors. The present study is the first to evaluate clinical data to predict the risk of developing PP vs. recurrence. Known predictors for successful SRS  intuitively predict higher risk of PP vs. recurrence. Based on the presence or absence of these 4 predictors the Bergen Criteria was established. It estimates with high accuracy the likelihood of PP vs. recurrence, is user-friendly and cost-free. Further validation of the Bergen Criteria is warranted.2 (3 and influx of inflammatory cells.5 These changes lead to increased T1-contrast enhancement on magnetic resonance imaging (MRI) mimicking TR, but subside spontaneously without change in treatment.6 Ambiguous MRI changes during follow-up are often managed by conducting an additional, early MRI follow-up to see if the changes stabilize or subside8 and/or to add additional imaging techniques9 to try to differentiate between the two. MRI perfusion11 may show high intratumoral blood perfusion in TR and Positron Emission Tomography (PET)12–14 may show increased uptake of glucose or amino acids in TR compared with PP, respectively, but differentiation can still be difficult. In some cases a biopsy15 or resection of the lesion will provide a definite diagnosis but involves the risks associated with a surgical procedure. Moreover, a wait and see strategy may lead to delayed treatment in cases with TR, whereas immediate treatment may turn out to be unnecessary if PP and even harmful if the lesion is reirradiated.16A major challenge in the management of patients with brain metastases (BM) treated with stereotactic radiosurgery (SRS) is to distinguish radiation necrosis or pseudoprogression (PP) from tumor recurrence (TR) for which treatment and prognosis are different2 . TR is d18 radiosensitive,19 previously irradiated20 and treated with optimal dosimetry.21 Thus, we wanted to investigate whether baseline tumor- and treatment-related data that are readily available in a clinical setting could predict the likelihood of PP vs. TR (when follow-up MRI shows increased contrast enhancement) and whether these data could be integrated into a clinical risk assessment score. To achieve this, we investigated the predictive value of various baseline characteristics at SRS to assess the likelihood of PP vs. TR.It is well documented that the chance of successful SRS is higher if the BM are small,22 Treatment and follow-up MRI of 97 consecutive patients treated for a total of 406 BM with Gamma Knife Perfexion at Haukeland University Hospital between 2009 and 2011 were prospectively collected and analyzed. Two hundred and twenty-five BM were treated initially (iSRS), 160 BM at subsequent GKS (sSRS) as distant failures, and 21 BM were treated with repeat-SRS due local failure (LF) following iSRS. In the present study, we included all BM that either pseudoprogressed (47 BM) or recurred (53 BM), Volumetric tumor change was a secondary end point in a prospective study evaluating quality of life changes following Gamma Knife Surgery (GKS) for BM.Ethical approval was obtained from the Regional Ethical Committee for Medical Research  and written informed consent was obtained from all patients.n = 340), and 16–18 Gy if prior radiation, large total tumor volume (>10–15 cm3) and/or close proximity to critical structures (n = 50). For 16 (4%) BM the prescription dose was ≤15 Gy due to prior SRS (n = 9), prior whole brain radiotherapy (WBRT) (n = 3), large tumor volume (n = 2), or tumor location (n = 2).BM were treated with a prescribed dose of 20–25 Gy (The BM volumes on MRI T1-contrast enhanced imaging (MRI-T1-C) were measured utilizing the GammaPlan software  at GKS and during follow-up at 1 and 3 months, then every third month post-GKS until September 30, 2019 or death. Follow-up images were available for 348 (85.7%) out of 406 BM in 87 (89.7%) of the 97 patients . Two patients (2.1%) are still alive in September 2019.The volume changes over time on MRI-T1-C from SRS until LF leading to new treatment  or until last follow-up/death was used to define PP from TR. Local failures that were retreated with a second course of SRS were evaluated as separate lesions/treatments and volume changes from re-SRS were recorded.n = 238, 68%), transient increase in volume defined as PP , delayed growth defined as TR , or no response with continuous growth  . Only 2 (2%) of the BM were resected after SRS yielding biopsy material. All BM followed 1 of 4 principal response patterns: either continuous reduction in size  out of the 87 patients with follow-up images of at least 1 BM that either pseudoprogressed (47 BM) and/or recurred (53 BM), n = 21 patients [43.8%]), melanoma (n = 7 [14.6%]), renal (n = 5 [10.4%]), breast (n = 4 [8.3%]), colorectal cancer , or unknown (n = 2 [4.2%]).The primary cancer site was lung (Twelve (25%) of the 48 patients that had previously been irradiated with WBRT. Thirty of the included BM (30%) occurred in the 12 patients with prior WBRT. None of the patients in this cohort were treated with immune checkpoint inhibitors at the time of SRS.n = 14 BM) and later re-SRS (n = 14 BM) for the same BM due to recurrence. Post-re-SRS 12 of the 14 BM subsequently pseudoprogressed and 2 re-recurred. The remaining 37 (77.1%) patients only underwent iSRS for 72 BM; 12 patients had at least 1 BM that pseudoprogressed, 20 patients had at least 1 BM that recurred, and 5 patients had a mixture of PP and TR.Eleven (22.9%) of the 48 patients underwent iSRS (All 47 BM responding with PP were compared with the 53 BM responding with TR. Baseline tumor- and treatment-related characteristics found to be associated with development of PP compared with TR were used to design a risk assessment score to estimate the likelihood of PP vs. TR (the Bergen Criteria). The score was refined by choosing predictive factor splits for maximizing practical use.t-test for continuous variables  and Pearson’s χ 2 test for categorical variables . For variables found to be significantly associated with PP vs. TR we used Pearson’s χ 2 test to refine the score: prior SRS (yes or no), prior WBRT (yes or no), BM volume ≤2 cm3 (yes or no), target cover ratio ≥98% (yes or no), primary lung cancer (yes or no), and to assess the predictive value of the Bergen Criteria. Overall survival (OS) was analyzed by the Kaplan–Meier method. Date for end-of-follow-up was September 30, 2019.To analyze differences between BM responding with PP vs. recurring BM we used Student’s 3) and treated with high target cover ratio (mean target cover ratio ≥ 98%) at SRS. On the other hand, BM with an unfavorable outcome were large (mean volume ≥3.5 cm3) and less optimally covered at SRS (mean target cover ratio <98%). We found significant differences when comparing BM in the PP group with the TR group: First, they were significantly smaller  and more completely covered with the prescribed dose . These differences at baseline were used to predict the likelihood that increased MRI-T1-C enhancement following SRS was due to PP or recurrence.The BM in the 4 response groups described above differed significantly in volume, prescribed dose, and target cover ratio at SRS . There w3 as cutoff. It corresponds to a tumor diameter of 1.5 cm that can be easily assessed on MRI. We found that BM less than 2 cm3 were more likely to develop PP than larger BM. Of the 47 BM displaying PP, 32 (68.1%) vs. 15 (31.9%) were ≤2 cm3, or less than 1.5 cm in diameter vs. >2 cm3 . Similar numbers for recurring BM were 26 (49.1%) vs. 27 (50.9%), For practical reasons we used 2 cmP = .048, χ 2 = 3.9, df = 1, and Cramer’s V: 0.198, BM responding with PP had significantly more often a higher coverage with the prescribed dose at SRS compared with recurring BM. Using 98% as cutoff we found a significantly higher incidence of PP vs. recurrence if the target cover ratio was ≥98%. Of 46 BM displaying PP, 37 (78.7%) vs. 10 (21.3%) had a target cover ratio of ≥98% vs. <98% and for recurring BM 32 (60.4%) vs. 21 (39.6%), P = .001, χ 2 = 13.7, df = 2, and Cramer’s V: 0.370). In the PP group, 10 BM (21.3%) were previously treated with SRS, 17 (36.2%) with WBRT whereas 20 (42.6%) were not previously irradiated. On the contrary, in the TR group, only 1 BM (1.9%) was previously treated with SRS, 13 (24.5%) with WBRT, and 39 (73.6%) were not previously irradiated, Prior IR was a strong predictor of PP vs. TR . The primary cancer site was lung for 24 (57.1%) of the 47 BM in the PP group and 18 (34.0%) of the 53 BM in the TR group, We found that BM in the PP group more often originated from primary lung cancer than from other primaries compared with BM in the TR group . PP occurred within 6 months of SRS for 37 (78.7%) of 47 BM and more than 6 months post-SRS for 10 (21.3%). Similar numbers for TR are 31 (58.5%) and 22 (41.5%) of 53 BM, respectively .The mean time from SRS until increased contrast enhancement on MRI was detected was significantly shorter for PP than TR, 5.1 months  vs. 8.4 months , respectively, P = .897) nor the steroid dose used at baseline  was significantly associated with development of PP  vs. TR .Neither the use of steroids at SRS  primary lung cancer vs. other primaries. Based on the presence (0) or not (1) of these 5 parameters, the Bergen Criteria for risk assessment of PP vs. TR was established (Factors associated with a higher incidence of PP vs. TR used were as follows (1) prior SRS, (2) prior WBRT, (3) target cover ratio ≥98%, (4) BM volume ≤2 cmablished . The totablished .2 = 24.6, df = 3, P < .001, and Cramer’s V = 0.496).A score of <2 point was associated with a 100% likelihood of PP, 2 points with 57% risk of PP vs. a 43% risk of TR, 3 points with a 57% risk of TR vs. 43% risk of PP whereas >3 points were associated with 84% likelihood for TR vs. 16% for PP (χ n = 6), lung cancer (n = 3), or unknown primary (n = 2) belonged to the TR group vs. 71% (n = 10) of the 15 BM origination from other primaries . All 7 BM with Bergen Criteria >3 and contrast enhancement occurring >6 months after SRS belonged to the TR group vs. 14 of the 18 BM occurring ≤6 months after SRS.All BM with Bergen Criteria score >3 originating from primary CRC (P < .001).The Bergen Criteria is applicable also when excluding the 13 retreated BM. For the 87 BM that were not retreated Bergen Criteria 0–1 were associated with 100% PP and Bergen Criteria of 2, 3, and 4–5 with 52%, 42%, and 12% PP, respectively, 2: 20.5, df: 3, P < .001).The mean scores for the Bergen Criteria for the 4 response patterns, continuous reduction in size, PP, delayed growth (TR), and continuous growth, are 2.7 , 2.3 , 3.2 , and 3.1 , respectively % were asymptomatic, and 4 (8.5%) were managed with a short course of dexamethasone treatment.Twenty-nine (52.7%) out of 53 TRs were treated conservatively with observation, 18 (32.7%) were retreated with SRS, 2 (3.6%) were resected with biopsy confirmed TR, and 4 (7.3%) were treated with WBRT.P < .001. The median OS for the last group was only 4.5 months (95% CI 3.8–5.1) compared with 11.7 months (95% CI 6.6–16.8) for the 21 TR only patients, 10.9 months (95% CI 3.9–17.9) for the 12 PP only patients, and 15.4 months (95% CI 12.4–18.5) for the mixed response group, respectively. The OS for the 10 patients without MRI follow-up was 0.83 months (95% CI 0.4–1.2), The OS for patients with TR, PP, or both was significantly longer than for the 49 patients with MRI follow-up that experience neither TR nor PP, 23 One could argue that PP is due to successful or even “overtreatment” with SRS while TR reflects failed SRS. Utilizing treatment data is a novel way of distinguishing PP from TR. From our data we found 4 distinct baseline characteristics at SRS distinguishing BM responding with PP from recurring BM. They were more often previously irradiated, significantly better covered with the prescribed dose at SRS, smaller and more often originating from primary lung cancer. Using this information we were able to create a simple score which robustly distinguished PP and TR in a large number of patients. All BM in our study responding either with PP or TR with a score less than 2 belonged to the PP group. For the BM with a score more than 3, 84% belonged to the TR group. The Bergen Criteria is based on easily accessible tumor- and treatment-related characteristics available in the patient’s medical record and does not require special training or additional advanced imaging techniques. Furthermore, the Bergen Criteria is based purely on known predictors2 for successful SRS and is therefore intuitive. We know when we treat a large radioresistant brain metastasis with an incomplete target cover ratio that the chance of success is lower than if we treat a small, previously irradiated radiosensitive brain metastasis with optimal target cover ratio. The Bergen Criteria works as follows. If a brain metastasis ≤2 cm3 originating from lung cancer that was irradiated with WBRT prior to SRS starts to enlarge on MRI-T1-C, we can be 100% certain that this is due to PP if the brain metastasis was completely covered with the prescribed dose (Bergen Criteria score 0). Similarly, if a brain metastasis >2 cm3 at SRS originating from melanoma and not previously irradiated starts to enlarge following SRS, we can be 84% confident that the BM are recurring if the BM were not fully covered at SRS (Bergen Criteria score 5). The likelihood might further be estimated to 100% if the primary cancer is CRC, unknown or lung or the contrast enhancement is detected more than 6 months post-SRS, but this needs to be confirmed in a larger cohort of patients.Differentiating TR from PP is a daily clinical challenge and of utmost importance to avoid both unnecessary treatments and treatment delays. More than 50% of the patients in our material experienced either TR or PP of at least one of their BM, which is in line with previous studies.24 before initiating treatment. If the tumor size is comparable on contrast enhanced T1- and T2-weighted MRI images, this is most likely to represent the true tumor size and hence TR. If however, the BM are smaller on the T2- than T1-contrast series, the difference in size on the T1 vs. T2 is most likely due to changes in the normal brain–blood circulation surrounding the tumor and hence reflect PP. MRI perfusion and PET may be of value as reduced blood flow and uptake of glucose or amino acids strengthens the suspicion of PP vs. TR. Advanced imaging methods and biopsies evaluate the tumor at the time of progression or PP. However, the Bergen Criteria can estimate the chance of success based on treatment-related factors alone and thus adds value to the existing methods by combining information at the time of SRS with information at the time the BM volume starts to increase on MRI-T1-C post-SRS.The Bergen Criteria can classify all BM enlarging following SRS either as most likely due to PP or most likely due to TR. Depending on the total score the risk of TR varies from 0% to 84% and the risk of PP from 16% to 100%. If TR is most likely it may be an advantage to confirm whether an enlarging tumor on MRI-T1-C follow-up is due to PP or TR with additional imaging such as the T1/T2 mismatch23 PP is often asymptomatic (>90% in our study) and symptoms usually respond to treatment with a short course of steroids. In rare cases, surgery may be necessary to relieve symptoms. Nevertheless, surgery has an inherent risk of complications, thus a wait and see strategy is preferred if one suspects PP.2 We suggest that the Bergen Criteria may be used to tailor appropriate follow-up intervals. If a BM enlarges on MRI-T1-C following SRS with a Bergen Criteria score <2, the patient may continue with standard 3 months follow-up intervals due to a high likelihood of PP. Conversely, a Bergen Criteria score >3 calls for an early MRI follow-up or immediate retreatment. If the score is 2 or 3, the patient may be followed at intermediate intervals (6–8 weeks) or the patient should be offered additional imaging with perfusion MRI or PET.PP is considered a good prognostic sign.25 and when high-dose SRS is used alone or repeated for the same brain metastasis. Thus, the total accumulated dose to the tumor and normal brain is clearly related to the development of PP. In the present study, the likelihood of PP increased if the brain metastasis was completely covered with the prescribed dose independent of the dose itself. This implies that the minimum dose to the tumor margins, rather than the maximum (or prescribed) dose, may be the most important dosimetric factor for successful SRS and thereby risk of TR vs. PP. Radiation damage to the tumor induces an inflammatory response which seems to play a role in the development of PP. The more complete the target cover ratio is at SRS, the more tumor cell death is induced by radiation which again might induce a stronger antitumor immune response than if the target coverage ratio is lower.Radiation is the main cause of PP in BM patients. For a brain metastasis to achieve a Bergen Criteria score <2 it must have been previously irradiated either with SRS, WBRT, or both. There are few reports on PP following WBRT alone. PP seems to occur when WBRT is combined with SRS5 Of note, none of the patients in the cohort used to derive the Bergen Criteria were treated with immunotherapy. With their increasingly common use in a wide variety of malignancies, there may be some differences in the PP and TR percentages, depending on whether or not these drugs are being employed as systemic therapy. A retrospective study showed that immunotherapy in combination with SRS increased the local control rate and risk of radiation necrosis (RN) when immunotherapy was administered during or after SRS compared with when it was administered before SRS.26 Recent reviews found inconclusive differences in LC rates and risk of RN when they compared combined SRS and immunotherapy with SRS alone.28 Nevertheless, due to the potential synergistic effect of SRS in combination with checkpoint inhibitors, the predictive value of the Bergen Criteria needs to be confirmed in a cohort receiving a combination of these 2 treatments.PP is often observed in patients treated with immunotherapy.Tumor size is the main limitation for SRS. Smaller BM respond better to SRS and therefore also more often respond with PP than larger BM. However, BM from different primaries represent different diseases. Lung cancer BM are radiosensitive and respond well to SRS with a corresponding high rate of PP compared with BM from other primary cancer sites. Moreover, lung cancer patients have a high-risk developing BM and are thus routinely screened for BM. Consequently, BM in lung cancer patients are likely to be detected when they are smaller compared with BM in patients with more radioresistant primaries.The significantly longer survival observed for patients experiencing TR, PP, or both compared with patients that do not suggests that the Bergen Criteria may be valid also for long-term survivors. However, as only 2 of 97 patients have more than 5 years OS in the present study, longer-term data on large datasets will need to be scrutinized to see if the Bergen Criteria are as infallible in patients who are in long-term follow-up as they appear to be in the short-term follow-up cohorts.The strength of the study is the prospective design, the national referral area and the high compliance rate with complete MRI follow-up until death for more than 95% of the patients. Still, the relatively low number of BM included is a limitation. Secondly, the Bergen Criteria is derived in a cohort treated with SRS before the introduction of immunotherapy. This is a potential shortcoming that requires cautioning for those who might employ the Bergen Criteria in her/his own clinic to predict the future for individual patients. Thirdly, temporary volume increase on MRI-T1-C was used as definition for PP in the present study and delayed growth as definition for TR; without histological confirmation except for 2 cases with TR. Nevertheless, the volumetric curves used represent the final outcome for all BM as all patients are followed for more than 5 years or until death. Importantly, none of the BM responding with temporary volume increase (PP) recurred at a later stage. Finally, in the present study, BM are used as the observation unit and thus assessed as independent of the patient even though some patients had more than 1 BM and a dependency between BM in the same patient therefore is likely. Independent assessment of observations of BM in the same patient may lead to excessive statistical significance. Moreover, a prognostic index will always be adjusted to the material from which it has been developed with an excessively good predictability.The Bergen Criteria is user-friendly, intuitive, and cost-free. It estimates with high accuracy the likelihood of PP, a sign of successful treatment, vs. the risk of failed treatment based on 4 simple and readily available treatment characteristics. The Bergen Criteria may be of help when deciding whether to retreat or observe, informing patient and choosing an appropriate follow-up interval. Ultimately, it may lead to reduced use of expensive PET/specialized MRI sequences and reduce the number of treatment delays and unnecessary surgeries. Larger studies are however needed to validate our results. The Bergen Criteria may be extended to additional data sources, which may lead to a refined score for subtypes of BM from different primary cancers.This study was supported by postdoctoral grant from Helse Vest (RHF) Regionalt samarbeidsorgan .Conflict of interest statement. None declared.Portions of this work were presented in abstract form at the SNO meeting in New Orleans in November 2018, the ISRS  meeting in Rio in June 2019, and the SNO Inaugural Conference on Brain Metastases in New York in August 2019.Experimental design: BSS, GOS; implementation of the data: BSS, GOS, PØE, P-HP, JIH; analysis and interpretation of the data: BSS, GOS, PØE, P-HP, JIH, GEE, JK.


Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease (ILD) with limited therapeutic options and poor prognosis. The averConsecutive patients with a confirmed specialist multidisciplinary team diagnosis of IPF based on consensus guidelines least twCT scans were assessed for MLN independently for each cohort by experienced radiologists blinded to the study outcomes . CTs were reviewed for MLN in accordance with the International Association for the Study of Lung Cancer classifications, with sig®-SPSS® version 26.0.IBMSurvival analysis was computed using Kaplan-Meier and Cox proportional-hazard models to determine any association between a) the rate of progression of mediastinal lymphadenopathy on a linear scale (mm/year) b) rate of progression of mediastinal lymphadenopathy stratified as ≥1 mm/year or <1 mm/year - a value which would be the smallest reliable measurable interval change. Survival analysis was conducted from time of the follow-up CT to death or censor. Multivariable survival analysis was adjusted for; age, antifibrotic therapy (ever vs. never taken), and either FVC% predicted or DLCO% predicted. P values of <0.05 were deemed significant. Statistical analysis was conducted using 51 patients were included in cohort 1 and 92 patients in cohort 2. The mean (standard deviation) CT imaging interval was 2.17 years (1.6) and 1.40 years (0.7) in cohort 1 and 2 respectively. The inter-radiologist agreement for presence on MLN in cohort 1 was 86% Kappa 0.681 Standard error 0.078 p<0.001.There was no significant difference observed between patients in cohorts 1 and 2 for either; sex , FVC% predicted (87% vs. 79% p=0.07), DLCO% predicted (52% vs. 54% p=0.33), or smoking history (59% vs. 58% p=0.44). Patients in cohort 1 were significantly older (72.5 years vs. 63.9 years p<0.001) and fewer had ever taken antifibrotic therapy (56% vs. 77% p=0.01). Concomitant historic diagnosis of left ventricular dysfunction was present in 5 patients in cohort 1 and 6 patients in cohort 2.Progressors’ those with significant MLN and a ≥1 mm/year increase in nodal size, and ‘Non progressors’ those with either significant MLN with a <1 mm/year increase in nodal size, or no significant MLN on either scan. Using this stratification within the DLCO% multivariate model identified ‘Progressors’ to have a significantly increased mortality risk in both cohorts 1 and 2; Hazard ratio (HR) 4.71 p=0.003 and HR 3.30 p=0.007 respectively (Significant MLN was identified in 71% (cohort 1) and 84% (cohort 2) of patients at baseline. The incidence of significant MLN increased at follow-up CT and was identified in 88% (cohort 1) and 91% (cohort 2) of patients on either CT scan. At follow-up CT the size of the largest node increased in approximately 50% of patients (55% [cohort 1] and 57% [cohort 2]). The mean unidirectional rate of temporal progression of adenopathy was 1.83 mm/year (cohort 1) and 1.43 mm/year (cohort 2). In univariable analysis the rate of temporal progression of adenopathy (mm/year) trended toward increased mortality risk in both cohorts . Howeverectively . In thisDespite the observed association between presence of MLN on Chest CTs in IPF patients and increased mortality risk, it remains uncertain whether the development, and the progression in size, of MLN is the driver of, or a reaction to, disease progression.. Proposed mechanisms underlying lymphadenopathy in lung fibrosis include an early response to lung injury facilitating recruitment of inflammatory and fibrotic cells to fibroblastic foci, 14 or sThis study is, to our knowledge, the first to assess the impact of temporal progression of MLN on survival in IPF. The strength of our study is the replication of the novel association between temporal progression of MLN and increased mortality risk in two independent cohorts of IPF patients. However, there are a number of methodological limitations including the retrospective analysis, relatively small sample size, and varying intervals of the CT scans performed as part of standard care. Further although CTs were screened for malignancy, it is also important to highlight occult malignancy as a potential confounderIn summary we identify in two independent cohorts of IPF patients that temporal progression of mediastinal lymphadenopathy is frequent and confers an additive and independent increase in mortality risk.


Introduction: Hydatid cyst (HC) of lung is a frequently encountered entity in Pakistan. The clinical and radiological manifestations of HC in lung depend on the integrity of the cyst. Patients may remain asymptomatic for years in cases of simple HC or may present with a wide variety of complications when it ruptures. The aim of this study was to compare management outcomes in simple and complex HCs.Methods: This prospective, observational study was conducted from February 2019 until May 2020. Patients were divided into two groups: simple HC (Group A) and complex HC (Group B). Preoperative complications, surgical procedures, postoperative complications, duration of hospital stay, duration of chest tube placement and need for readmission were noted and compared between the two groups. All data was processed through the Statistical Package for the Social Sciences (SPSS) Statistics version 22 .Results: Sixty-two patients were included out of which Group A had 28 (45.2%) patients and Group B had 34 (54.8%) patients. There were 39 (62.9%) males and 23 (37.1%) females. The mean age was 31.11 ± 11.02 years. Preoperative complications in Group B included empyema seen in 10 (28.5%) patients, rupture of cyst into bronchus in 8 (23.5%), biliopleural fistula in 4 (11.7%), hydropneumothorax in 2 (5.8%), bronchopleural fistula in 1 (2.9%), airway compromise in 1 (2.9%) and pneumonia in 1 (2.9%) patient. Group B required longer days of chest tube placement, longer intensive care unit stay and longer hospital stay (p<0.001). The frequency of postoperative intervention was more in group B (p<0.05), therefore requiring readmission.Conclusion: Surgery has favorable outcomes in the management of HC of lung. Complications associated with complex HC not only requires preoperative intervention like chest tubes but can also lead to life-threatening complications. There is also a frequent need for additional procedures during surgery in cases with complex HC along with greater risk of postoperative complications. All these are associated with prolonged hospital stay, readmissions and greater morbidity. Hence, early diagnosis and referral is needed to avoid these preventable complications associated with cyst rupture. Echinococcus granulosus[ [Hydatid disease is a zoonotic infection caused by the parasite ranulosus,2. It isranulosus,4. A larranulosus. In the nulosus[ . Human inulosus[ ,6.In this disease, liver is the most common organ involved (63%) followed by lungs 25%). A hydat5%. A hydIn Pakistan, hydatid disease is one of the most important neglected tropical diseases. According to a report, 270 million people (58%) of the total population are at risk of hydatid disease in Central Asia, including Pakistan . TherefoThis prospective, observational study was conducted in the Department of Thoracic Surgery, Jinnah Postgraduate Medical Center, Karachi, from February 2019 till May 2020. Informed consent from patients was obtained and the study was approved by the Institutional Review Board .All patients above 12 years of age presenting with clinical and radiological signs of HC of lung were included. Patients unfit for surgery or in whom spontaneous resolution occurred after rupture were excluded. Diagnosis was made with history, clinical examination, positive serum echinococcal antibody along with findings on chest X-ray and CT scan of the chest and abdomen. We did not refute diagnosis solely on the basis of a negative serum echinococcal antibody. Patients were divided into two groups. Group A included simple HC and group B included complex HC. Simple HC is defined as a well-defined cyst in the pulmonary field without signs of rupture. Complex HC is defined as the cyst that has ruptured into the bronchus or pleural cavity with or without infection . RadioloAll patients were treated surgically after informed consent by a single thoracic surgeon in our setup. All patients were operated on single lung ventilation with double-lumen endotracheal tubes. Standard posterolateral thoracotomy incision was utilized. In Group A, the surgical wound and pleural cavity were packed with wet packs soaked either in 10% povidone-iodine solution or 10% hypertonic saline to prevent contamination. Cystostomy, removal of the germinal layer and bronchial leak closure were performed in all cases. Capitonnage was done to obliterate the cavity using polyglactin (Vicryl®) 3/0 sutures. Complete closure of the cystic space was not carried out in severely infected cases.2O and secured. A single 32-Fr chest tube was placed before the closure of chest.Additional surgical procedures required were noted. Decortication was performed for entrapped lungs due to empyema, and phrenotomy and repair were done for transdiaphragmatic communication of the hepatic cyst into the pleural cavity. Non-anatomic lung resection was done when there was unsalvageable parenchymal destruction or involvement of almost the whole lobe by the cyst. At the end of the procedure, air leaks were checked under normal saline with positive pressure ventilation of 30-40 cm HAll patients received perioperative broad-spectrum antibiotics prophylactically with adequate postoperative analgesia and chest physiotherapy. The chest tube was removed when no air leak was evident, when drainage was less than 100 ml per day and radiologically the lung was expanded. Prolonged air leak was defined as postoperative air leak persisting for greater than seven days. A persistent air leak for more than 14 days was labeled as bronchopleural fistula (BPF). After discharge, the follow-up regimen consisted of chest X-ray on the seventh day and then biweekly for one month. Postoperatively all patients were given albendazole therapy for three months with a dose of 10 mg/kg/day.Clinical information, preoperative complications, preoperative interventions, operative procedures, postoperative complications, duration of air leak, duration of intensive care unit (ICU) stay, duration of hospital stay and readmission were recorded in a predesigned pro forma. All data was processed through the Statistical Package for the Social Sciences (SPSS) Statistics version 22 . Descriptive statistics were presented as means and standard deviations (SDs). Categorical variables were presented as frequencies and percentages. Chi- square test and independent t test were used to find association between categorical data and continuous data wherever appropriate. A p value ≤0.05 was taken as statistically significant.A total of 62 patients were included in this study; 23 37.1%) were females and 39 (62.9%) were males. The mean age was 31.11 ± 11.02 years. Majority of the patients were from Sindh, 34 (54.8%); followed by Baluchistan, 18 (29.0%); Afghanistan, 7 (11.3%) and Punjab, 3 (4.8%). History of animal contact was positive among 38 (61.3%) patients. Group A included 28 (45.2%) patients with simple HC and Group B included 34 (54.8%) patients with complex HC. The size of cyst in Group A ranged from 3 to 10 cm with a mean of 6.46 ± 1.8 cm. Chest pain was the most frequently observed symptom in both the groups. Fever, productive cough, dyspnea, hemoptysis and expectoration of germinal membrane were statistically significant among patients in Group B (p<0.001). A comparison of clinical manifestations among Groups A and B is given in Table % were feIntrathoracic locations of HC were right lung 33 (53.2%), left lung 20 (32.2%) and bilateral 9 (14.5%). HC was most frequently observed in the lower lobe among 44 (70.9%) of patients. The extra-thoracic location of the cyst was noted in the liver in 37 (59.7%) patients. Peritoneum was also involved in 10 (16.1%) patients. History, chest X-ray and contrast CT scan helped to reach correct diagnosis in all the cases. Echinococcal antibody was positive among 40 (64.5%) patients. There was no significant correlation between the echinococcal antibody and type of cyst. Among Group B, the most frequent preoperative complication was empyema in 10 (28.57%), followed by rupture into bronchus in 8 (23.52%), biliopleural fistula in 4 (11.76%), hydropneumothorax in 2 (5.8%), bronchopleural fistula in 1 (2.94%), airway compromise in 1 (2.94%) and pneumonia in 1 (2.94%).Preoperative interventions performed prior to definite surgery in cases with complex HCs were tube thoracostomy in 23 (67.6%) patients and bronchoscopy in 2 (5.88%) patients. Two diagnostic needle thoracentesis were performed in another center prior to referral. One of the patients required endotracheal intubation and ventilator support for massive air leak post-tube thoracostomy and had to undergo emergency surgery. One of the patients required emergency bronchoscopy for airway compromise due to the rupture of HC into bronchus. All other patients were operated electively. Patients of liver dome cyst with transdiaphragmatic extension into the thorax were operated in the same setting for liver cyst. Patients who had HC in the liver without thoracic communication were referred to a general surgeon for staged surgery. Additional surgical procedure required other than cystostomy along with bronchial leak closure and capitonnage were decortications , phrenotomy with diaphragmatic repair  and lung resection . A comparison of frequencies of postoperative complications among two groups is given in Table  Patients in Group B required longer days of chest tube placement, longer ICU stay and longer hospital stay when compared to Group A showing statistical significance (p<0.001). The frequency of postoperative intervention was higher in Group B (p<0.05). In Group A, 2 (7.1%) patients required readmission whereas in Group B, 12 35.3%) patients needed readmission. The need for readmission was higher in Group B (p<0.05). A comparison of postoperative ICU stay, chest tube duration, duration of hospital stay and frequencies of postoperative intervention among two groups is summarized in Table 5.3% patiOne patient in Group A required tube thoracostomy for pneumothorax postoperatively. Both groups responded well to surgical management with no mortality.To our knowledge, our hospital is the only tertiary care referral center providing Thoracic Surgery facility in the region, and most of our patients were referred from different areas of rural Sindh. We also received patients from Baluchistan and neighboring Afghanistan in significant numbers, which indicates the prevalence of the disease in these endemic areas. Clinical presentation depends on whether the cyst is intact or ruptured ,11. RuptThere should be a high clinical suspicion when a patient from an endemic area presents with a well-defined rounded homogeneous opacity in the pulmonary field ,14. DiagOnce the diagnosis is made, the best management option is surgery ,15. OperThe basis of the surgical therapy is removal of the entire parasite, prevention of contamination, maximum preservation of pulmonary parenchyma, identification and closure of bronchial leaks and obliteration of the remaining cavity . More raStudies have been conducted to compare perioperative morbidity and complications between open approach and video-assisted thoracoscopic surgery (VATS) with or without mini thoracotomy ,20. We oSome authors have not used lobectomies in large series studies and have proposed lung resections to be unnecessary for HC . In our 20. Postoperative BPF were managed with prolonged tube thoracostomy attached to the Heimlich valve until lung expansion. Postoperative atelectasis responded well to chest physiotherapy. Wound infection was managed locally with wound care. Postoperative empyema was managed with either chest tube or needle thoracentesis. Both groups responded well to surgical management without mortality. We observed greater morbidity associated with complex HC that was also the observation in the study by Aribas et al. [Postoperatively, the duration of ICU stay, duration of chest tube placement and hospital stay duration were longer in Group B (p<0.001). The need of readmission and interventions for postoperative complications were also higher in Group B (p<0.05). Postoperative prolonged air leak was managed with chest tube under negative suctioning of 15-20 cm Hs et al. .Surgery has a favorable outcome in the management of HC of lung. Early diagnosis and surgery helps to prevent complications associated with the cyst rupture. Complications associated with complex HC not only require preoperative intervention like chest tubes but can also lead to life-threatening complications requiring emergency procedures like bronchoscopy and thoracotomy. There is also a frequent need for additional procedures during surgery in cases with complex HC along with greater risk of postoperative complications. All these are associated with prolonged hospital stay, readmissions and greater morbidity that add to the treatment costs of a patient from a resource-constraint area like Pakistan.


Studies have shown disparate results on the consequences of morphine use in ST-segment elevation myocardial infarction (STEMI). No study has evaluated alternative treatments that could be at least non-inferior to morphine without its potentially damaging consequences for myocardial function and platelet reactivity. The aim of this study was to evaluate whether nitrous oxide/oxygen plus intravenous acetaminophen (NOO-A) is non-inferior to morphine to control chest pain in STEMI patients.This multicenter, open-label, cluster-randomized, controlled, non-inferiority study compared NOO-A with morphine in 684 prehospital patients with ongoing suspected STEMI of < 12 h duration and a pain rating score ≥ 4. The primary endpoint was the proportion of patients achieving pain relief (numeric rating score ≤ 3) after 30 min. Secondary safety endpoints included serious adverse events and death at 30 days.The median baseline pain score was 7.0 in both groups. The primary endpoint occurred in 51.7% of the NOO-A group and 73.6% of the morphine group . At 30 days, the rate of serious adverse events was 16.0 and 18.8% in the NOO-A and morphine groups respectively (p = NS). The rate of death was 1.8% (NOO-A group) and 3.8% (morphine group) (p = NS).Analgesia provided by NOO-A was inferior to morphine at 30 min in patients with acute STEMI in the prehospital setting. Rates of serious adverse events did not differ between groups.NCT02198378.ClinicalTrials.gov:  The most frequent expected adverse event was vomiting (5.0% with NOO-A and 4.7% with morphine).Table  (absolutThe percentage of patients with an unexpected (not predefined) adverse event within 30 min of starting analgesia was 6.2% with NOO-A and 3.5% with morphine, the most frequent being ventricular fibrillation (1.2% with NOO-A and 0.9% with morphine). The rate of adverse events that led to treatment interruption within the first 30 min was 7.1% with NOO-A and 1.2% with morphine, the most frequent being vomiting (2.9% with NOO-A and 0.3% with morphine).P = 0.3). The most frequent were ventricular tachycardia (3.8%), ventricular fibrillation (1.9%), cardiogenic shock (1.8%), and heart failure (1.1%). Most cases of ventricular tachycardia (21 out of 26) were observed in the NOO-A group.The incidence of serious adverse event in the 30 days following inclusion was 18.8% with NOO-A and 16.0% with morphine  NOO-A was actually inferior to intravenous morphine for the reduction of pain at 30 min in patients with STEMI; 2) there were no more adverse events in the morphine group. Controlling pain at the acute phase of STEMI is challenging. Morphine has been used for years and the issues of its efficacy and its safety have been regularly raised , 23. It Overall, the rate of adverse events was not significantly different between the NOO-A and the morphine groups. The number of deaths was numerically higher in the morphine group (3.8% vs 1.8% at 1 month). This statistically non-significant higher death rate in the morphine group should not be an argument to renounce to this potent analgesic in STEMI patients. However, this observation adds to the uncertainties surrounding the safety of morphine in ACS even if recent studies have not shown an increase in mortality in patients treated with morphine .NOO-A was inferior to morphine analgesia at 30 min in patients with acute STEMI in the prehospital setting. Rates of adverse events were not significantly different between the two treatment groups. Because morphine appears to be such a potent agent of pain control in STEMI, a randomised study specifically addressing its safety is warranted.Additional file 1:Appendix 1. SCADOL II Investigators list. Appendix 2. CONSORT 2010 checklist of information to include when reporting a randomised trial. Appendix 3. Definition of secondary outcomes. Appendix Table 1. Characteristics of Patients in the Intention-To-Treat Population. Appendix Table 2. Characteristics of Patients Who Died Within 30 Days.