Values for ST2 and galectin-3 did not significantly differ by receipt of anthracycline. After further adjustment for age at breast cancer diagnosis, ethnicity, and receipt of trastuzumab, associations between receipt of anthracycline and higher NT-proBNP persisted (p < 0.001), showing that NT-proBNP may be a biomarker of cardiovascular toxicity after receipt of anthracycline-based chemotherapy. Further research to assess the clinical utility of NT-proBNP testing after receipt of anthracycline is recommended. sST2 and galectin-3 do not appear to differentiate between anthracycline recipients and non-recipients amongst breast cancer survivors.NT-proBNP, soluble ST2 (sST2), and galectin-3 are biomarkers of cardiac dysfunction that have been proposed as identifiers of patients experiencing asymptomatic cardiac dysfunction after anthracycline-based chemotherapy. This study aimed to compare the proportion of breast cancer (BC) survivors with elevated serum levels of these three putative biomarkers by prior receipt of anthracycline (yes vs. no). Five-hundred-eighty survivors of BC who had received anthracycline-based chemotherapy were matched by age and time between diagnosis and serum storage to 580 who had not. Cardiac biomarker levels were analyzed using immunoassays. Analyses were carried out using linear and logistic regression models. Anthracycline recipients had higher values of NT-proBNP than non-recipients (mean 116.0 ng/L vs. 97.0 ng/L, respectively;  Cardiovascular diseases are among the leading contributors to mortality in cancer survivors, accounting for 30–50% of all deaths in non-metastatic breast cancer (BC) survivors over the age of 65 . This apAnthracycline-induced cardiotoxicity is thought to be mediated by topoisomerase II β, interrupting mitochondrial biogenesis, generating reactive oxygen species and double-strand DNA breaks, and subsequently activating apoptosis of cardiac myocytes . This prCardiac biomarkers such as natriuretic peptides, including N-terminal prohormone brain-type natriuretic peptide (NT-proBNP), can be elevated due to cardiac stress prior to symptom onset; thus, these may be useful for risk stratification in order to help target cardiovascular interventions to those most likely to benefit. The 2016 European Society of Cardiology Guidelines recommend natriuretic peptide testing for all patients with suspected heart failure (HF) and one additional factor of heightened probability, including prior exposure to cardiotoxic medications such as anthracyclines . A recenTwo other emerging biomarkers for HF: suppressor of tumorgenicity 2 (sST2) and galectin-3, have been shown to independently correlate with the risk of hospitalization and death in patients with known HF . sST2 isThis study aimed to address a gap in knowledge by comparing levels of NT-proBNP, sST2, and galectin between breast cancer survivors previously treated with anthracycline-based chemotherapy and survivors with no prior anthracycline exposure.This retrospective cohort study compared cardiac biomarkers by prior receipt of anthracycline using stored serum from women who had a previous breast cancer diagnosis . In order to minimize confounding, each patient who had received anthracycline was matched to a non-recipient based on age and time from cancer diagnosis to blood draw. Specifically, there was a 1:1 match by age (within 5 years) and by time between breast cancer diagnosis and sample collection (within 6.5 months). This study was approved by the Mayo Clinic Institutional Review Board (IRB #1815-04).The Mayo Clinic Breast Disease Registry (MCBDR) aims to enroll all patients seen at least once at the Mayo Clinic in Rochester, Minnesota within a year of a new breast cancer diagnosis; after informed consent, participants are asked to provide serial blood and survey, as well as access to stored tumor tissue. Blood samples were obtained by venipuncture. After adequate centrifugation, serum samples were stored at −80 °C. Five-hundred-eighty-one female patients who had received anthracycline-containing chemotherapy and 581 who had not were identified from the MCBDR database. One matched pair was excluded because one of the subjects was a male patient; this resulted in 580 matched pairs for analysis, or 1160 subjects overall. Receipt of anthracycline was confirmed by MD review.NT-proBNP levels were assessed using an immuno-electrochemiluminescence assay . Soluble ST2 was determined using a high-sensitivity sandwich monoclonal immunoassay , and galectin-3 levels were assessed using an enzyme-linked fluorescent assay (BioMerieux ref. 411191). Values greater than the upper limit of detection were set to the highest value detectable; galectin-3 values greater than 100 ng/L were set to 100, and sST2 values greater than 200 ng/L were set to 200. NT-proBNP values less than 10 ng/L were set to 10, and values greater than 2000 ng/L were set to 2000.t-tests for continuous variables. Following the univariate analyses, we fitted multivariate models to assess associations between attributes and anthracycline receipt after accounting for the effects of the other attributes. Finally, we examined associations of biomarker values with age at breast cancer diagnosis and time from diagnosis to serum collection in the pooled set of anthracycline recipients and non-recipients, using Pearson correlation coefficients. Due to the inherent right skewness in the biomarker data, regression analyses were carried out using rank-transformed scores, with values for the 1160 subjects ranging from 1  to 1160 . Sensitivity analyses were run using original values, log-transformed values, and inverse normal (van der Waerden) rank scores. All statistical tests were two-sided, and all analyses were carried out using the SAS System .Data were summarized using frequencies and percentages for categorical variables, and means and standard deviations for continuous variables. Comparisons of demographic, clinical, and biomarker attributes with receipt of anthracycline were carried out using conditional logistic regression for categorical variables and linear regression models for continuous variables. For each, the attribute of interest was modeled as the outcome (y-) variable and anthracycline receipt was modeled as the exposure (x-) variable. All analyses accounted for the matched nature of the data by including a matched set ID in the model. For the logistic models, this was carried out using the standard conditional likelihood approach. For the linear regression models, set ID was included as a blocking factor. We first examined univariate associations by fitting separate regression models for each attribute, in turn. These analyses are mathematically equivalent to McNemar tests for categorical variables (when using the score test from the logistic model) and paired p < 0.001). Anthracycline recipients were much more likely to have received trastuzumab than non-recipients . Anthracycline recipients were also more likely to identify as non-Hispanic than non-recipients (p < 0.001). There were no differences in time from breast cancer to serum collection between anthracycline recipients and non-recipients.The mean age at breast cancer diagnosis for the 1160 participants  was 52.2 years (SD 9.6), 94% identified their race as White, and 92% identified their ethnicity as non-Hispanic. The stored serum used to assess cardiac biomarkers was collected on average 2.7 years after diagnosis of breast cancer (SD 1.7). Comparisons of demographic and clinical variables by receipt of anthracycline are shown in p < 0.001). Values for sST2 and galectin-3 did not significantly differ by receipt of anthracycline , while associations with sST2 and galectin-3 remained non-significant (p = 0.002).Comparisons of cardiac serum biomarkers by anthracycline receipt are shown in nificant . Sensitip = 0.05). This association attenuated to null after accounting for age at diagnosis . Correlations between higher NT-proBNP and older age at diagnosis were stronger  anthracycline recipients had higher values of NT-proBNP than non-recipients; (2) increasing time between breast cancer diagnosis and serum collection was associated with higher NT-proBNP values; and (3) sST2 and galectin-3 did not differ between anthracycline recipients and non-recipients.The role of natriuretic peptides for the detection of myocardial injury after antineoplastic therapy has been studied in a variety of patient populations and at various timepoints ,25,26,27The current results demonstrate that patients with exposure to anthracyclines have higher NT-proBNP levels than non-recipients. Ranked analysis confirmed that values for NT-proBNP in anthracycline recipients were higher than non-recipients, and that this association persisted after adjustment for age at breast cancer diagnosis, ethnicity, and receipt of trastuzumab. Furthermore, the detection of abnormal NT-proBNP levels (>125 ng/L) in almost a third of anthracycline recipients in the current study correlates well with data from children who had previously received anthracyclines . As expeThe ST2 gene is upregulated in the setting of myocardial stretch, increasing levels of soluble ST2 rapidly. However, the current study demonstrated that values of sST2 were not significantly different between the patients who received anthracyclines and those who did not. This supports that sST2 is not useful as an early biomarker of cardiac dysfunction from anthracyclines. These results are concordant with those of a study comparing sST2 in survivors of adult-onset lymphoma and childhood cancer to sST2 in healthy controls ,33.Galectin-3 is a known marker of cardiac fibrosis; higher levels of this protein have been previously shown to be associated with an increased risk of heart failure and all-cause mortality in community populations, as well as with risk of morbidity and mortality amongst patients with heart failure. The absence of a difference in galectin-3 levels between anthracycline recipients and non-recipients suggests that galectin-3 is likely not a useful biomarker of cardiotoxicity after anthracycline receipt for breast cancer.This study has several limitations including its retrospective design and single-center study population. In addition, we did not assess levels of cardiac troponin, which has previously been shown to be a promising biomarker of myocardial injury from oncologic therapy ,35,36. I


Heterologous vaccination was more effective than homologous vaccination. Calcineurin inhibitors plus mycophenolate reduced the seroconversion rate. No seroconversion was observed in belatacept patients. In mycophenolate-treated patients, IMPDH activity was a significantly better predictor of response than mycophenolate dose . Immunosuppression strongly affects vaccine response. Modifications to immunosuppression should be considered in order to facilitate this response. Erythrocyte IMPDH activity can be used to guide mycophenolate treatment.Immunosuppression increases the risk of severe coronavirus disease 2019 (COVID-19). Morbidity and mortality of this disease in kidney transplant patients are higher than in the general population. As the vaccination response of transplant patients is weak, serological monitoring was performed. In this cohort study, we analyzed the determinants of vaccination response. All patients had no history of COVID-19. With anti-spike IgG monitoring, 148 responders and 415 non-responders were identified. We compared both groups using multivariate analyses of the cohort and a sub-cohort of mycophenolic-acid-treated patients. We investigated the influence of patient characteristics, immunosuppression, and erythrocyte inosine monophosphate dehydrogenase (IMPDH) activity. In responders, the time after transplantation was longer (13.5 vs. 8.5 years), the glomerular filtration rate was higher (56.9 vs. 47.8 mL/min/1.73 m Recipients of solid organ transplants are at an increased risk of severe disease and death after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection ,2. The rMPA dosing usually follows a standard regimen adapted by individual clinical events, such as rejection on one side and gastrointestinal symptoms, hematopoietic side effects, and opportunistic infections on the other side. Because of the well-known dose-response variability of MPA, therapeutic drug monitoring (TDM) has been established, either as MPA blood level or inosine 5′-monophosphate dehydrogenase (IMPDH) monitoring ,16. We r® , Spikevax® , and Vaxzevria® ; or one injection in the case of COVID-19 Vaccine Janssen® . Combinations of different vaccines were allowed. Further inclusion criteria were an anti-spike IgG antibody test ≥28 days after the last vaccination, no clinical history of COVID-19, and a negative anti-nucleocapsid antibody test. The patients underwent negative serological tests before vaccination. Third vaccine applications led to the exclusion of patients. Positive results for anti-spike IgA only were not classified as seroconversion. The deadline for the database retrieval was 31 August 2021.We searched for all adult ≥18 years) kidney allograft recipients with a functioning graft at Charité–Universitätsmedizin Berlin using our electronic patient record system, TBase [ years kiWe used an anti-SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) to detect IgG antibodies against the S1 domain of the SARS-CoV-2 spike (S) protein in serum according to the manufacturer’s instructions (Anti-SARS-CoV-2-ELISA (IgG), EI 2606-9601 G, EUROIMMUN Medizinische Labordiagnostika AG, Lübeck, Germany). Processing and measurement were done using the fully automated Immunomat . The results were determined by comparing the obtained signals of the patient samples with the previously obtained cutoff value of the calibrator. As suggested by the manufacturer, samples with a cutoff index ≥ 1.1 were considered positive.To exclude patients who had previously acquired COVID-19, we simultaneously measured antibodies against the nucleocapsid (N protein) using an electrochemiluminescence immunoassay . The results were determined by comparing the obtained signals of the patient samples with the previously obtained cutoff value of the calibrator. As suggested by the manufacturer, samples with a cutoff index ≥ 1.0 were considered positive.g for 10 min at 20 °C, the supernatant was discarded, and the packed cells were washed with another 2.5 mL of phosphate-buffered saline and centrifuged under the same conditions. The sediment was lysed with 3 mL HPLC-water, and 1 mL aliquots were frozen at −20 °C for later use. IMPDH activity in erythrocytes was measured in the supernatant of thawed cell lysates. We used identical incubation conditions and the previously described HPLC method for mononuclear cells [Erythrocyte IMPDH activity was measured as previously described . Brieflyar cells . XanthosDescriptive analyses were performed to describe the parameters of interest using absolute and relative frequencies for categorical data and means with standard deviations or medians with ranges for continuously distributed parameters, as appropriate. The vaccination response rate was analyzed using a multilevel mixed-effects logistic regression model to account for the clustering of patients at the three sites of Charité–Universitätsmedizin Berlin. The medical therapies were divided into mutually exclusive groups. Grand mean coding was performed to analyze the association between vaccination response and therapies and to compare a single therapy with the mean vaccination response across all therapies. Reference-level coding was performed for the other categorical predictor variables. Calcineurin inhibitor (CNI) levels under treatment with tacrolimus or cyclosporine A were combined by calculating the percentage of deviation from the base 6 ng/mL for tacrolimus and 80 ng/mL for cyclosporine A.Receiver operating characteristic (ROC) analysis was used to evaluate the predictive ability of MPA dose, lymphocyte count, and IMPDH activity in relation to response to SARS-CoV-2 vaccination in patients treated with MPA. The area under the ROC curve (AUC) was compared using the statistical test proposed by DeLong et al. . ROC anaThe algorithm used to establish the cohort is shown in The responders were younger and had better graft function. The interval between transplantation and vaccination was longer in responders. The gender distribution was similar between responders and non-responders.®, and due to increasing safety concerns for the second application, an mRNA-based vaccine had been chosen. Among the non-responders, the majority received three-fold immunosuppression, whereas responders were similarly often two- and three-fold immunosuppressed.The application of two doses of BioNTech-Pfizer vaccine was dominant in our cohort. A small subset of the cohort was administered a heterologous vaccination (mRNA after vector vaccine). The patients had been administered VaxzevriaTacrolimus in combination with MPA is the most common immunosuppressive regimen. Altogether, 49.5% of patients received immunosuppressive doses of glucocorticoids .Multivariate analyses were performed to determine the influence of baseline characteristics, vaccine types, immunosuppressive combinations, eGFR, lymphocyte counts, and CNI trough levels on response to SARS-CoV-2 vaccination .Higher age increased the risk of non-response to vaccination, whereas longer time after transplantation significantly increased the serological response rate. The selection of vaccine(s) influenced the success of vaccination. In our cohort, we found the highest immunogenicity with heterologous vaccine combinations. Immunosuppressive combinations containing MPA  significantly decreased the odds of serological response after SARS-CoV-2 vaccination. In contrast, the absence of MPA or replacement of MPA with other immunosuppressants increased the probability of response. A higher eGFR, higher lymphocyte count, and lower CNI trough levels were also associated with higher response rates. However, steroids did not have convincing effects on humoral immune reactions after vaccination.For a detailed analysis of the determinants of vaccination response in patients receiving MPA, we analyzed a sub-cohort of 492 patients with MPA .As before, younger age and a longer interval between transplantation and vaccination increased the probability of response in this subgroup. In addition, male gender had a positive impact on the response rate. The inclusion of MPA dose and IMPDH activity measurements in the analysis led to the loss of significance of the vaccine(s), most of the immunosuppressive combinations (except MPA + Tac + steroid), and lymphocyte counts with respect to the serological response rate. Higher eGFR and lower CNI trough levels moderately improved the humoral response to vaccination. Markers of MPA exposure, i.e., a lower MPA dose and lower erythrocyte IMPDH activity, were associated with significantly increased response rates.p = 0.015). ROC analyses were performed to compare the influence of MPA dose and IMPDH activity on the prediction of response to SARS-CoV-2 vaccination , and IMPDH monitoring was incomplete (348 of 492 patients).After 31 August 2021 , several patients were vaccinated a third time  or even a fourth time . The former did not significantly improve the response rate and therefore has not been included in this analysis. The results of the latter are still not available (short followup).In summary, elderly patients with low GFR are at high risk of non-response to standard SARS-CoV-2 vaccination. Strong immunosuppression or overimmunosuppression should be avoided to ensure successful vaccination. MPA and belatacept are highly potent in preventing humoral immune responses to vaccination. Heterologous vaccination strategies elicited the highest response rates in our cohort. Tailoring MPA-based immunosuppression using IMPDH monitoring may be a promising strategy for successful vaccination against SARS-CoV-2 after kidney transplantation. Another strategy might be the complete peri-vaccination cessation of MPA, as already done in non-renal patients  and planOur data suggest a risk-based stratification to obtain a sufficient immune response to SARS-CoV-2 vaccination and an effective immunosuppression in KTPs:First, given the observed lack of response in patients treated with belatacept, the drug should not be initiated unless patients are immunized against SARS-CoV-2.Second, in patients already treated with belatacept, a temporary switch to another immunosuppressive strategy before the first vaccination attempt is warranted. If this is impossible, a passive vaccination strategy might be advisable.Third, in patients treated with dual immunosuppression , an attempt to achieve a vaccination response without prior modification of immunosuppression is warranted.Fourth, in patients treated with MPA, dose reduction and the best available TDM appear to be important for optimizing the vaccination response. In addition, given the association of dose reductions or discontinuation of mycophenolate with an increased risk of acute rejection and inferior patient and graft survival , a preci


Reverse total shoulder arthroplasty (rTSA) is effective and increasingly utilized for the management of proximal humerus fracture (PHF). However, the optimal patient-reported outcome metrics (PROMs) for the evaluation of patient outcomes after this surgery are unclear. We investigated the correlation among global, upper extremity-specific, and shoulder-specific PROMs in patients undergoing rTSA for PHF as well as the responsiveness of these PROMs as assessed by floor and ceiling effects. We hypothesized that patients’ post-operative outcome would be best reflected by a combination of these metrics.Thirty patients with a history of rTSA for ipsilateral PHF filled out the following outcomes questionnaires at a minimum of 3 years post-op: EQ-5D, EQ-5D VAS, PROMIS physical function, DASH, SSV, SPADI, and ASES. Correlation between metrics was assessed using the Spearman correlation coefficient. Responsiveness was assessed by comparing the proportion of patients reaching floor or ceiling values using McNemar’s test.Global health metrics  were strongly correlated with the upper extremity-specific metric (DASH). Shoulder-specific outcomes  were moderately correlated with both the global metrics and DASH. There was no significant difference between PROMs with regards to floor and ceiling effects.The DASH score has been shown to be valid and responsive for shoulder interventions, and our data demonstrate that it correlates strongly with overall quality of life. Shoulder-specific metrics are valid and responsive for shoulder interventions but correlate less with global quality of life. An optimal PROM strategy in rTSA for PHF might involve both DASH and a shoulder-specific score. Based on our assessment of floor and ceiling effects, none of these metrics should be excluded for poor responsiveness. Fractures of the proximal humerus account for nearly 6 % of fractures in the adult population and the frequency of this injury is expected to increase with aging of the US population . Non-opePatient-reported outcome metrics (PROMs) attempt to capture the biopsychosocial impact of disease on patients’ lives  and are The objectives of this study were (1) to assess correlations among global health, upper extremity-specific, and shoulder-specific functional outcome measures for rTSA performed for proximal humerus fractures at minimum 3-year follow-up, and (2) to compare the responsiveness of global health, upper extremity-specific, and shoulder-specific functional outcome measures by assessing floor and ceiling effects.The study was designed following the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) guidelines for studies on measurement properties and specifically those guidelines regarding construct validity and responsiveness . The stu After obtaining approval from the Institutional Review Board, a retrospective analysis was performed of all patients who underwent rTSA for proximal humerus fractures at two American College of Surgeons Level I trauma centers from January 2003 to June 2017. Using our institutions’ Research Patient Data Registry (RPDR), patients were identified using the International Classification of Disease (ICD-9 and ICD-10) codes for the diagnosis of proximal humerus fracture and Current Procedural Terminology (CPT) code for shoulder arthroplasty. Five hundred seventy-six patients were identified from the initial screen. Inclusion criteria were patients 18 years of age or older who underwent rTSA for a proximal humerus fracture between January 1, 2003 and August 1, 2018 and had a minimum of 3 years postoperative follow-up. Exclusion criteria included diagnoses other than proximal humerus fracture, procedures other than rTSA, surgeries performed at an outside institution, and patients without documented postoperative follow-up.We excluded 264 patients for a diagnosis other than proximal humerus fracture, 74 patients who did not undergo rTSA, and 14 patients who had rTSA for fracture performed at an outside institution. The remaining 224 patients were contacted by telephone at a minimum of 3 years following rTSA for our outcome measures; 71 patients were further excluded for inadequate follow-up, of which 26 were deceased and 55 were unavailable. Furthermore, 113 patients were excluded for an incomplete set of outcome measures at a minimum of 3 years following rTSA, 112 because they were not sent all of the functional outcomes surveys due to their inclusion in different research protocols, and 1 who was contacted for all scores but returned EQ-5D, PROMIS, and DASH but not ASES, SPADI, or SSV. The final cohort included 30 patients (30 shoulders) with proximal humerus fractures treated with rTSA with a complete set of functional outcome measures at least 3 years of follow-up.The outcome measures in this study included global health outcome measures, an upper extremity-specific outcome measure, and shoulder-specific outcome measures. Global health outcome measures included the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Physical Score Short Form 10b, EuroQol Five-Dimension Score (EQ-5D), and EuroQol Visual Analogue Scale (EQ-VAS). The upper extremity-specific outcome measure was the Disabilities of the Arm, Shoulder and Hand (DASH) score. Shoulder-specific outcome measures included the Shoulder Subjective Value (SSV), American Shoulder and Elbow Surgeons (ASES), and Shoulder Pain and Disability Index (SPADI). All outcome measures were collected through review of the medical records and telephone contact at a minimum of 3 years following rTSA.The PROMIS Physical Function instrument is a 10-item questionnaire that evaluates physical, mental, and social aspects of health, and all items are evaluated on a 5-point Likert scale , 21.The EQ-5D is a health-related quality of life measure with 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression  There arThe DASH score is a 30-item upper-extremity-specific outcome measure which is intended to measure shoulder, elbow, hand, and wrist function in one combined metric . It doesThe SSV is an entirely subjective shoulder-specific measure where the patient is asked to rate their shoulder on a scale from 0 to 100 with some version of the following question: “What is the overall percent value of your shoulder if a completely normal shoulder represents 100 %?”  The SSV The ASES is a shoulder-specific score which consists of 10 functional questions and a pain VAS score . The totThe SPADI is a self-assessment of symptoms and function of the shoulder designed for any disorder of the shoulder joint . It consPatient demographics were collected through our institutional RPDR and review of the electronic medical records, including age, sex, hand dominance, body mass index (BMI), Charlson Comorbidity Index (CCI), diabetes mellitus, depression, osteoporosis, smoking status at presentation, and employment status. Injury-related variables included fracture type, presence of ipsilateral upper extremity fracture, open fracture, and associated nerve injury. Treatment-related variables included initial treatment (acute rTSA versus nonoperative treatment), tuberosity repair, complications, and reoperation. The operative techniques and rehabilitation protocols were at the discretion of the treating surgeon.Descriptive statistics were calculated for the study cohort. Measurement of correlations between outcome measures were performed using the Spearman correlation coefficient. To study floor and ceiling effects, the proportion of patients reporting the minimum and maximum scores of each outcome measure, respectively, were determined. Paired comparisons of the proportion of patients at the floor and ceiling of outcome measures were performed using McNemar’s test. The standard significance criterion of α = 0.05 was employed. A convenience sample was used.Our study cohort comprised 30 patients treated with rTSA following proximal humerus fracture. The average age of our cohort was 70.2 years at the time of surgery, and 87 % were female. Ten (33 %) of patients had diabetes mellitus, 6 (20 %) had depression, 6 (20 %) had osteoporosis, and 1 (3 %) smoked at the time of surgery. The dominant upper extremity was affected in 18 (60 %) of patients, and 6 (20 %) of patients were actively employed. The tuberosity was repaired during rTSA in 20 (67 %) of patients (Table Twenty-three out of 30 (77 %) patients were treated with rTSA acutely, and 7 (23 %) were treated with rTSA after failed initial nonoperative treatment. Complications occurred in four patients and included instability, infection, heterotopic ossification, and periprosthetic fracture. Two patients (7 %) underwent reoperation, which included component revision for instability and irrigation and debridement with liner exchange for infection. The median clinical follow-up after rTSA was 17.5 months (IQR 10.5 to 30.1 months). The median time to telephone assessment of functional outcome measures was 5.2 years .Global health, upper extremity-specific outcome measure, and shoulder-specific outcome measures were collected for the cohort at minimum 3-year follow-up after rTSA for fracture Table .Table 2ρ = -0.85, p < 0.0001) and EQ-5D and DASH  were highly correlated. EQ-VAS and DASH  were moderately correlated.Global health and upper extremity-specific outcome measures were compared Fig. . PROMIS ρ = 0.58, p = 0.0007), PROMIS and SPADI , and PROMIS and ASES  were moderately correlated. EQ-5D and SSV , EQ-5D and SPADI , and EQ-5D and ASES  were moderately correlated. EQ-VAS and SSV  were moderately correlated, but EQ-VAS and SPADI  and EQ-VAS and ASES  were not significantly correlated.Global health and shoulder-specific outcome measures were compared Fig. . PROMIS ρ = -0.67, p < 0.0001), DASH and SPADI , and DASH and ASES  were moderately correlated.Upper extremity-specific and shoulder-specific outcome measures were compared Fig. . DASH anρ = 0.73, p < 0.0001) were strongly correlated, whereas PROMIS and EQ-VAS  and EQ-5D and EQ-VAS  were moderately correlated. Among shoulder-specific outcome measures, SSV and SPADI , SPADI and ASES , and SSV and ASES  were moderately correlated.Among global health outcome measures, PROMIS and EQ-5D  and EQ-5D and SPADI (p = 0.3).McNemar’s tests did not demonstrate a significant difference between the proportion of patients at the ceilings of EQ-5D and SSV  and DASH was stronger than that between global outcomes and shoulder-specific measures . This likely reflects the fact that the DASH is a comprehensive evaluation of upper-extremity function that captures the effect of an upper-extremity intervention  on a patient’s overall quality of life. As such, it can be interpreted as a proxy for the effect of an upper extremity intervention on global HRQoL, while simultaneously focusing on the upper extremity and thereby being more sensitive to treatment effect than truly global metrics like the EQ-5D. This hypothesized increased sensitivity is borne out by the fact that the data in this study was used in a separate project, not yet published, to compare outcomes between those undergoing rTSA for fracture acutely versus in a delayed manner for mal- or non-union. While there was a significant difference in DASH scores; EQ-5D and PROMIS did not detect this group difference.Shoulder-specific outcomes scores  correlated only moderately with DASH scores and global metrics. These scores focus explicitly on shoulder function, and while they may be responsive to shoulder interventions, are less reflective of overall quality of life. These findings suggest that the optimal selection of outcomes scores in evaluating rTSA for fracture may include DASH score, which offers upper-extremity focus while correlating well with global HRQoL, plus a shoulder-specific score to optimize responsiveness to this shoulder intervention. Our findings also support the use of the PROMIS instrument as an easy-to-use alternative to the well-established but lengthier DASH questionnaire. Since we found significant correlation among shoulder-specific outcome measures , we recommend collecting only one shoulder-specific score to avoid redundancy. Our study supports the construct validity of the Subjective Shoulder Score as an easily obtained metric that reflects patient quality of life as it relates to the shoulder. The SSV correlated more closely (though still just moderately) with DASH, PROMIS, and EQ-5D than ASES or SPADI and involves only one simple question. Therefore, for researchers who feel collecting the DASH metric in addition to a shoulder-specific score may add undue burden, the SSV might be a reasonable alternative. While collecting both DASH and a shoulder-specific metric seems to be a good combination following rTSA for fracture, this raises the question of whether two PROMs may introduce survey fatigue, particularly as the DASH contains 30 questions and is therefore one of the longer survey metrics available. A meta-analysis of survey burden in PROMs by Rolstad et al. demonstrated that increased survey length correlates with decreased response rate. However, there was no particular survey length at which responses dropped off and the willingness of patients to complete longer surveys varied between conditions . As suchIn addition to investigating the correlation between outcomes scores in patients undergoing rTSA for fracture, our study sought to assess whether the responsiveness of these scores were affected by floor or ceiling effects. The floor or ceiling effect describes the circumstance in which patient outcome scores cluster at the minimum or maximum value for a given metric, thus rendering the outcome measure unable to detect differences between these patients . At leasr = 0.75) [r = 0.91) [r=-0.059) [There are numerous additional outcomes metrics available for the study of shoulder interventions which were not included in our study. Perhaps the most widely used instrument in the proximal humerus fracture literature is the Constant-Murley score. We elected not to collect this score and feel it is not the metric of choice in studies of rTSA after fracture for multiple reasons. First, it contains a physical exam component which includes range of motion and power. This introduces the risk of bias by the examiner, may be inappropriate to combine with patient-reported domains, and is conflated by normal age-related declines in shoulder strength . Second, = 0.75) . These d = 0.91)  and mode=-0.059) , suggestLimitations of this study include the fact that several widely utilized PROMs were not included due to concern for patient survey fatigue. We did not collect the questionnaires at multiple pre-determined time points and thus were unable to compare the proportion of patients reaching clinically important differences, which would have better allowed us to assess the responsiveness of the scores over time. Finally, the patient population was on the smaller side of the acceptable range recommended by COSMIN guidelines.PROMs allow the patient’s subjective experience to be reflected in surgical outcomes, but there has been little consistency in the literature as to which PROMs should be used to track outcomes after rTSA for fracture. Our results suggest that use of a global health or upper extremity-specific score, such as PROMIS physical function or DASH, in conjunction with a shoulder-specific metric, such as SSV, SPADI, or ASES, may strike an optimal balance. The PROMIS physical function score and SSV are appealing instruments, because they correlate well with other relevant metrics and are more easily administered. There was no significant difference in floor or ceiling effects between any of the metrics in our study.


Anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancers (NSCLCs) have favorable and impressive response to ALK tyrosine kinase inhibitors (TKIs). However, ALK rearrangement had approximately 90 distinct fusion partners. Patients with different ALK fusions might have distinct responses to different-generation ALK-TKIs. In this case report, we identified a novel non-reciprocal ALK fusion: ALK-grancalcin (GCA) (A19: intragenic) and EML4-ALK (E20: A20) by next-generation sequencing (NGS) in a male lung adenocarcinoma patient who was staged as IIIB-N2 after surgery. After a multidisciplinary discussion, the patient received alectinib adjuvant targeted therapy and postoperative radiotherapy (PORT). He is currently in good condition, and disease-free survival (DFS) has been 20 months so far, which has been longer than the median survival time of IIIB NSCLC patients. Our study extended the spectrum of ALK fusion partners in ALK + NSCLC, and we reported a new ALK fusion: ALK-GCA and EML4-ALK and its sensitivity to alectinib firstly in lung cancer. It is vital for clinicians to detect fusion mutations of patients and report timely the newfound fusions and their response to guide treatment. ALK+NSCLC in the metastatic setting  , 5%–7% oDespite favorable results, ALK-rearranged NSCLC is a heterogeneous disease. Patients with different ALK fusions have distinct responses to ALK-TKIs . Apart fin situ hybridization (FISH)  scan revealed a lung mass with a diameter of about 5.1 cm in the left lower lobe and 7–10 rib fracture in January 2020 Figure 1n (FISH)  and confn (FISH) , the genJournal of Thoracic Oncology by Yongchang Zhang et al., as harboring concurrent ALK fusions with at least one 3′-ALK fusion and one 5′-ALK when compared to 3′-ALK alone fusion. We showed a schematic diagram of non-reciprocal ALK translocation in The non-reciprocal ALK translocation was defined firstly in Furthermore, despite surgery, the 5-year survival rates of stage III NSCLC are low and most patients mainly die from metastatic disease , 14. ThuWe identified a novel non-reciprocal ALK rearrangement, ALK-GCA (A19: intragenic) and EML4-ALK (E20: A20), by using powerful NGS, expanding the spectrum of ALK fusion in ALK+ NSCLC. In addition, this non-reciprocal fusion may be sensitive to alectinib treatment.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Institutional Review Board of West China Hospital, Sichuan University. The patients/participants provided their written informed consent to participate in this study.XZ and QW wrote the original draft and prepared the figures and reviewed the literature. DP and LY collected the data and edited the manuscript. WW Pathologic data collection and analysis. DZ supervised, provided the resource, and reviewed the article. FX conceived the idea and reviewed the article. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (81573024) which will pay for open-access publication fees.The 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Since the beginning of the Covid-19 pandemic, the scientific community has explored determinants of Covid 19 disease severity. However, the majority of studies are based on in-hospital patients with high risk of collider- or selection bias. The present investigation details risk factors associated with overall mortality, hospitalization and intensive care unit (ICU) admission in Covid-19 infections, with complete population coverage and high-resolution data on patient characteristics and comorbid conditions This population-based observational study comprises all residents 18 years and older in Stockholm Region—1.8 million inhabitants—using the real-time Covid-19 monitoring framework. The observation period lasted between March 1 to December 31, 2020. Hazard ratios (HR) for risk factors of Covid-19 disease severity were assessed using Cox proportional hazard models. In total, 3322 deaths, 11,508 hospitalizations and 1423 ICU-admissions related to Covid-19 occurred during the study period. Kidney failure, diabetes and obesity increased risk of mortality and so did heart failure and ischemic heart disease. However, atrial fibrillation and hypertension did not. Risk of hospitalization follow a similar pattern, whereas admission to intensive care differs; triage processes where clearly present as certain co-morbid conditions were associated with lower ICU admission. Observed differences in risk of mortality and hospitalization among patients with Covid 19 raise important questions about potentially protective comedication which will be further addressed using the real-time Covid-19 monitoring framework.The online version contains supplementary material available at 10.1007/s10654-021-00840-7. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus disease 2019 (Covid-19). Since 31 December 2019 until today (31 December 2020) over 100 million cases and over 2.4 million deaths have been reported [Studies of risk factors for adverse Covid-19 outcomes, for patients already infected are plentiful and have focused on hypertension, obesity, diabetes and cardiovascular comorbidity –4. A sysexposure for SARS-CoV-2; examples are obesity and smoking, associated with lower socioeconomic status [Further, multiple investigations use severity of disease and intensive care unit (ICU) admission as an outcome . This isc status  and overIn this population-wide study comprising all inhabitants 18 years and older in the Stockholm Region, we aimed at investigating risk factors for severe Covid-19 while addressing the above-mentioned issues. We primarily investigated factors of risk for overall mortality and hospitalization; secondarily, we analyzed risk factors for ICU admission with Covid-19. Uniquely, this study uses information from the real-time Covid-19 monitoring framework in Region Stockholm.This was a population-based observational study comprising all residents 18 years and older in Region Stockholm.Region Stockholm manages a central healthcare utilization data warehouse . This includes comprehensive information from inpatient, hospital outpatient, and primary care, including information on healthcare utilization, consultations and diagnoses at an individual level. VAL also contains demographic information on patient age, sex, migration status, death and information from the Population Register  as well The primary study population consisted of all individuals 18 years and older, residing in Stockholm county on March 1, 2020 based on data from the Population Register . In a seThe primary outcome was mortality with confirmed Covid-19 infection. The secondary outcome was hospitalization with confirmed Covid-19 infection. The tertiary outcome was admission to intensive care (ICU) with confirmed Covid-19 infection.The observation period was March 1, 2020 to December 31, 2020. Follow-up began on March 1, 2020 and ended at loss to follow-up (emigration from the Stockholm Region), end of study , death (not for the primary outcome), or the outcomes.Comorbidities considered as potential risk factors in the study were extracted from VAL using ICD-10 codes recorded up to five years prior to the start of the study period . Codes recorded in inpatient, hospital outpatient, and primary care (in any diagnosis position) were included. The ICD-10 codes used to define potential risk factors are presented in Supplementary Table S1. The selection of risk factors in this study is based on the comorbidities presented in previous publications (mentioned in the introduction) as well as indications of high prevalence comorbidities observed during surveillance of the epidemiological data among hospitalized Covid-19 cases within the Stockholm Region.www.dagitty.net. The bias-minimized models are presented in Supplementary Table S2.In order to identify bias-minimized models, causal diagrams were established for each potential risk factor  using th, 50th and 90th percentiles of the age distribution. Other covariates included in the models were guided by the causal diagrams (Supplementary Table S2). Socioeconomic status was included as a stratification variable, i.e., we allowed for different baseline hazards within each stratum. Two models were fitted for each risk factor/outcome pair; one where we assume additive effects of age and the risk factor within each sex and one where we allowed for an interaction to obtain age-specific estimates within each sex. Estimates from the first model is illustrated in the rows named Total in Figs. Associations between each potential risk factor and the different outcomes were assessed using Cox proportional hazards models. All models included a sex by other covariates interactions to obtain sex specific estimates and age was modeled using restricted cubic splines with knots at the 10The study was approved by the Swedish Ethical Review Authority . All data were analyzed in a pseudonymized format and confidentiality was maintained at all times.In total 3,322 cases of Covid-19 deaths occurred during the study period with the vast majority of deaths occurring among those 80 years of age and older (68.4%) . Similar patterns were observed for heart failure and IHD where older individuals had a higher risk of being hospitalized than younger individual . For obesity, diabetes type II and kidney failure we observed the opposite pattern with an increased risk for younger to be admitted to hospital hospitalized compared to older individuals . Data did support a three-way interaction (p < 0.001) between sex, age and obesity where younger women in particular had a higher risk  than younger men  of being hospitalized.All risk factors were associated with hospitalization with Covid-19 .Hypertension, obesity and diabetes type II were all associated with a higher risk of ICU admission with Covid-19 in both men and women Below is the link to the electronic supplementary material.


Autologous hematopoietic stem cell transplantation (auto-HSCT) has become an effective treatment for a wide range of hematologic and non-hematologic diseases. Patients undergoing HSCT might require multiple platelets and red blood cell (RBC) transfusions during aplasia phase until engraftment, which could profoundly affect patients’ conditions. Identification of risk factors associated with blood product requirements could help in decreasing transfusion-related complications. We evaluated the association of disease type, pre-transplant hemoglobin level, and pre-transplant platelet count with RBC/platelet transfusion requirement after auto-HSCT.In this retrospective study, 324 patients diagnosed with multiple myeloma (MM), Hodgkin disease (HD), and non-Hodgkin lymphoma (NHL) and underwent auto-HSCT were included. The associations of disease type, pre-transplant hemoglobin level, and platelet count with post-transplant packed cell and single-/random-donor platelet transfusions were evaluated.Our study results illustrated that the higher pre-transplant hemoglobin level significantly decreased the post-HSCT requirement for packed cell , while the pre-transplant platelet showed no significant relationship with platelet requirement after HSCT. HD was associated with increment in packed cell  and single donor platelet  requirement after transplant. The trends showed that a higher platelet level led to a lower need for platelet transfusion.Pre-transplant hemoglobin level could be valuable markers for predicting post-HSCT RBC requirements and might be beneficial for better management of transfusion requirements to minimize the transfusion-related complications. Patients with HD seem to be more prone to blood product requirements post-transplant. Autologous hematopoietic stem cell transplantation (auto-HSCT) is the most common type of HSCT  for the treatment of hematologic malignancies -3. PlateA standard threshold for the use of prophylactic platelet transfusion has been determined as platelet counts fall below 20 109/L after transplantation . PlatelePacked cells are transfused based on patients' hemoglobin (Hb) level as well as other clinical criteria. When a patient has a Hb level of 6 g/dL or less, there is an indication for transfusion, which continues until the patient reaches a stable hemoglobin level of 10 g/dL or more without bleeding -11. PackHence, reducing packed cell units could decrease patients' exposure to allogeneic blood products . DespiteIn this study, we aimed to analyze the effect of disease type, pre-transplantation hemoglobin level, and platelet count on platelet and RBC packed cell transfusion requirements. We hypothesized that low pre-transplantation hemoglobin level and platelet count as well as underlying disease could be risk factors for higher blood components transfusion requirements after autologous-HSCT.Patient selection: This retrospective study was carried out on 324 patients who underwent autologous-HSCT at Taleghani Hospital, Tehran, Iran, between March 2011 and March 2018. The required data were collected by reviewing the patients’ clinical records. Patients diagnosed with hematological disorders, including Hodgkin disease (HD), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM) were included in this study. The patients with insufficient documentation, patients who were under treatment, or had been treated before (irrelevant treatments), those who had relapsed following chemotherapy, and undiagnosed patients were excluded from the study. Disease type , pre-transplant platelet count, and hemoglobin level were evaluated as risk factors. The study was approved by Shahid Beheshti University of Medical Sciences Ethics Committee with the code of IR.SBMU.REC.1398.149, and all patients provided a written informed consent.Stem cell Transplantation procedure: Stem cell mobilization was induced by administering 5-10 μg/kg of G-CSF to patients for 4-5 days. Afterwards, peripheral HSCs were harvested using Spectra Optia  and the number of CD34+ and CD3+ cells were counted by flow cytometry  on day five after G-CSF treatment using PE-conjugated human anti-CD34  and FITC-conjugated human anti-CD3 . All multiple myeloma patients received standard myeloablative conditioning (MAC) regimen consist of Melphalan 200 mg/m2 intravenously (IV) once a day for patients younger than 65 years old and 140 mg/m2 (IV) once a day for patients older than 65 years old plus Bortezomib 1.3 mg/m2 IV in day -2 to +1 (The transplantation day was considered as day zero). Conditioning regiment for HD and NHL patients included CCNU 200 mg/m2 (IV) in day -4, Etoposide 300 mg/m2 (IV) once a day in days -3 and -2, Cytarabine 300 mg/m2 (IV) twice a day in days -3 and -2, and Melphalan 140 mg/m2 one dose in day -1. All patients received ciprofloxacin for bacterial prophylaxis, fluconazole, or itraconazole for fungal prophylaxis and acyclovir for viral prophylaxis. Transfusion procedure: All patients received random and single donor platelet concentrations and packed red cells that were ABO compatible, according to IBTO (Iranian Blood Transfusion Organization) guidelines. All transfusion units were leukocyte-reduced (<106 leukocytes). Hemoglobin level and platelet counts were measured every morning from the admission to discharge day using Sysmex XE-2100 automated blood cell counter . Single and random donor platelet transfusions were administered one week after stem cell transfusion until the platelet count became higher than 20×109/L. Patients received RBC packed cells to maintain hemoglobin levels above 9 gm/dL. Statistical analysis: The variables in this study, including packed red cells and single and random donor platelet transfusions were discrete variables. A regression model was employed to evaluate the effect of disease type, pre-transplant hemoglobin level, and platelet count on packed cell and platelet transfusion requirements after transplantation. In these models, the overdispersion assumption was assessed for the selection of the proper model. Due to the existence of overdispersion for all variables, the Negative Binomial regression model was chosen. The analysis was performed with SPSS (Version 22.0). P-values less than 0.05 were assumed statistically significant.In the present study, 324 patients with MM, HD, and NHL received autologous-HSCT in the Bone Marrow Transplantation ward at Taleghani Hospital, Tehran, Iran. The effects of disease type, pre-transplant hemoglobin level, and platelet count on transfusion requirements were assessed in these patients. The descriptive statistics of the variables for each disease as well as the clinical data of the patients are illustrated in  The mean platelet transfusion for HD was 1.95, and 124 patients had red packed cell transfusion. The mean pre-transplant platelet count was 112865 in HD patients. In these patients, the minimum and maximum pre-transplant hemoglobin levels were 2 and 11.5, in the order given. In this study, we applied the Negative Binomial regression model to investigate the effects of outcome variables on transfusion requirements after transplantation. The results of this model for the effects of pre-transplant hemoglobin level and disease type on packed red cell transfusion requirements are shown in The results in At the same time, the results pointed out that the mean estimated transfusion units in NHL patients, holding the hemoglobin level constant, were 1.3 times higher than MM patients, and it was not statistically significant. In the current study, we assessed the effects of disease type, hemoglobin concentration, and platelet count before autologous HSCT on the blood product transfusions requirement (Packed red cells and platelet) post-HSCT. We found that the low pre-transplant hemoglobin level is a risk factor for the RBC transfusion requirement after HSCT. Besides, the underlying disease is another risk factor for both RBC and platelet requirements. The patients with multiple myeloma need the lowest and HD patients requiring the most RBC and platelet transfusion among the three studied diseases. Patients undergoing HSCT need the support of blood transfusions and blood products until the engraftment time of red blood cells and platelets. Understanding the effective factors in determining the time and need for transfusion could reduce the incidence of life-threatening reactions due to over-transfusion. Since no prospective study has been conducted on the transfusion of red blood cells in patients undergoing HSCT, the American Association of Blood Banks (AABB) guidelines are mostly employed for the transfusion of red blood cells in patients undergoing HSCT. According to AABB, the blood transfusion is applied for hemoglobin level 7-8 g/dl in stable patients unless they have symptomatic anemia .Comprehending the effects of prognostic factors in determining the time and need for blood product transfusion will be helpful in the establishment of supportive treatment for patients along with the prevention of life-threatening side effects of alloimmunization. In the current study, we found that the pre-transplant hemoglobin level and the underlying disease have significant effects on the RBC transfusion requirement. Our results indicated that the mean transfusions of concentrated RBC in MM patients were lower than both HD and NHL patients. Hence, MM patients need the lowest RBC transfusion, while HD and NHL might be risk factors for high RBC transfusion requirement. It was also determined that by increasing the concentration of hemoglobin in 3 groups of patients, the mean transfusions would decrease. The drugs for malignancies often reduce production and increase the destruction of many cells, which their functionality is essential for bleeding prevention. Besides, a low platelet count often leads to hemorrhagic disorders. Hence, platelet transfusion is a significant approach for cancer management and balancing the clotting system in patients with blood disorders and cancers. However, platelet transfusion is associated with unfavorable side effects such as alloimmunization, platelet resistance, septicemia, shock, and even death, recognizing the indication of SD/RD platelet transfusions in patients after transplant who need intensive care is necessary , 16.In a Trial of Poor Performance Status Patients , those patients undergoing chemotherapy or hematopoietic stem cell transplantation were divided into two therapeutic and prophylactic groups regarding the platelet transfusion requirements. Platelet transfusion in the prophylactic group was conducted on the first day that platelet count dropped below 10 × 109/L, whereas in the therapeutic group, platelet concentrations started to be transfused upon observing the first clinical symptoms. The results revealed that the lower platelet was employed in a therapeutic group compared to the prophylactic group, although bleeding in these patients started early and lasted longer .It should be noted that in TOPPS trial, 70% of the patients who underwent the autologous transplant had a lower risk of bleeding compared to allogeneic transplants. Moreover, they showed that therapeutic platelet transfusion could increase the risk of bleeding compared to prophylactic platelet transfusion in thrombocytopenic patients because of chemotherapy or HSCT. Simultaneously, therapeutic platelet transfusion could lead to a reduction in the number of platelets administered, which decreased the risk of alloimmunization . In another similar trial conducted by Wandt et al. on patients who had autologous HSCT and the ones with acute myeloid leukemia (AML), it was established that bleeding in the therapeutic group was greater than the prophylactic group. Furthermore, in the therapeutic group, six patients had cranial bleeding, while bleeding was not observed in the prophylactic group. In this study, like TOPPS trial, a significant decrease in platelet transfusion of the therapeutic group was observed . AccordiAnother aim of this research was to determine the influential factors in predicting the time and PLT/RD and PLT/SD transfusion requirement after autologous HSCT. Our results demonstrated that patients with HD needed more SD and RD platelet transfusions that might be due to a more intensive chemotherapy regimen before transplantation. Therefore, in this group of patients, prophylactic platelet transfusion could be more beneficial. The results showed that the estimated mean of SD platelet count in HD patients is greater than MM patients. It seems that HD patients who received more intensive chemotherapy regimens or radiation therapy prior to transplantation might have more damaged bone marrow microenvironment. Damage in the bone marrow microenvironment could probably lead to thrombocytopenia, potentially reducing the speed of platelet engraftment , 20.The results of the trend showed that by increasing the pre-transplant platelet, SDP transfusion requirements decreased with the same rate for all three disease types. Comparing the SD and RD platelets identified that none of the variables under study had any significant effect on the RD platelet transfusion requirement, and all three types had the same level of requirement for RD platelet transfusions. Therefore, the underlying disease seems to be more important as a risk factor for post-HSCT platelet transfusion requirements compared to the pre-transplant platelet count. It is noteworthy that the requirement to blood products in HSCT patients depends on numerous factors such as age, sex, comorbidities, and previous treatments. Therefore, the patients who were under treatment, or had been treated before with irrelevant drugs, those who had relapsed following chemotherapy, and undiagnosed patients were excluded from the study. However, all the influencing factors were not excluded in the analysis and is suggested to be considered in the future investigations.Conclusively, we found that patients with Hodgkin disease are more susceptible to RBC and platelet transfusions. Disregarding of the disease, pre-transplant low hemoglobin level is a risk factor for post-HSCT RBC transfusion requirement. The role of underlying disease on post-HSCT platelet requirement seems to be more important than the pre-transplant platelet count. When all is said and done, we assert that factors such as pre-transplant hemoglobin concentration, disease type and probably platelet count should be considered as influential factors involved in predicting the post-transplant blood transfusion and blood product requirement, so that the incidence of undesirable and life-threatening side effects could be prevented.


Previously, it was reported that multiple patients had hemolytic anemia associated with cimetidine administration, while only one patient who had received intravenous cimetidine was serologically diagnosed with drug-induced immune hemolytic anemia (DIIHA) caused by cimetidine-dependent antibodies. However, the ability of oral cimetidine intake to induce the production of antibodies has not been examined. In this study, we report a 44-year-old male patient in whom oral cimetidine administration resulted in cimetidine-dependent antibodies and drug-independent non-specific antibodies, leading to the development of DIIHA. Serological tests showed that the results of direct antiglobulin test (DAT) for anti-IgG (3+) and anti-C3d (1+) were positive. The IgM and IgG cimetidine-dependent antibodies  were detected in the plasma incubated with O-type RBCs and 1 mg/mL cimetidine or the plasma incubated with cimetidine-coated RBCs. IgG-type drug-independent non-specific antibodies were detected in blood samples collected at days 13, 34, 41, and 82 post-drug intake. This is the first study to report that oral administration of cimetidine can elicit the production of cimetidine-dependent antibodies, leading to DIIHA, and the production of drug-independent non-specific antibodies, resulting in hemolytic anemia independent of cimetidine. Presence of pathogenic antibodies were detectable longer than 41 days. This suggests that patients with DIIHA caused by cimetidine need to be given necessary medical monitoring within 41 days after cimetidine intake. More than 140 drugs are associated with drug-induced immune hemolytic anemia (DIIHA) . The pat2 receptors on parietal cells in the gastric wall and consequently inhibits gastric acid secretion. Hence, cimetidine has been widely used for treating gastric and duodenal ulcers and reflux esophagitis, as well as for preventing stress ulcers. Based on the immunomodulatory effect of cimetidine, it has been used in the treatment of warts, ulceration, and mastocytosis in dermatology  related to cimetidine have been reported –23. HoweHere, we report that a 44-year-old male patient developed severe hemolytic anemia after oral administration of cimetidine. Cimetidine-dependent antibodies were detected by incubating the patient's plasma with O-type RBCs and 1 mg/mL cimetidine or incubating the patient's plasma with cimetidine-coated RBCs at 37°C, with the highest titer reaching 4,096. Drug-independent non-specific antibodies (the highest titer reached 32) were also detected. This is the second case study to serologically diagnose DIIHA caused by cimetidine-dependent antibodies. Additionally, this is the first study to report that oral cimetidine can elicit the production of cimetidine-dependent antibodies and cause DIIHA. The findings of this study indicated that the oral administration of cimetidine can also induce the production of drug-independent non-specific antibodies, which caused positive DAT results and IHA for a prolonged period in the absence of cimetidine.A 44-year-old male who suffered from an episode of gout (metabolic arthritis) consumed the following non-prescription drugs: diclofenac sodium sustained-release capsule (50 mg) and cimetidine capsule (200 mg). The joint pain was alleviated after medication but the patient exhibited fatigue and anorexia. Three days after drug intake, fatigue exacerbated, urine turned yellowish-brown, and the skin and sclera exhibited yellowish color. Four days after drug intake, the subject was admitted to the Dongguan Tungwah Hospital. The clinical characteristics of the patient were as follows: blood type, A/RhCcDee; glucose-6-phosphate dehydrogenase (G6PD) activity, physiological levels; expression of CD55 and CD59 on RBCs, physiological levels; thalassemia gene screening and acid hemolysis test results, no abnormalities; sucrose hemolysis test and urine hemosiderin test results, positive; bone marrow cytology, extremely active hyperplasia; paroxysmal nocturnal hemoglobinuria (PNH) clone, not detected. Color ultrasound examination revealed diffuse fatty change in the liver. The detailed results of cell and biochemical tests of blood samples collected at days 4, 6, 13, 16, 34, 41, and 82 post-drug intake are listed in Five days after drug intake, the patient began to undergo continuous renal replacement therapy (CRRT). Six days after drug intake, the patient was transfused with washed RBCs (WRBCs) prepared from 600 mL of A/RhCcDee whole blood. Seven days after drug intake, the patient was transfused with WRBCs prepared from 300 mL of A/RhCcDee whole blood. Eight days after drug intake, the patient underwent exchange transfusion: 2,000 mL of A-type fresh frozen plasma was used as the replacement fluid for therapeutic plasma exchange (TPE) and the same amount of RBCs was replaced with leukocyte-reduced RBCs (LRBCs) prepared from 1,200 mL of A/RhCcDee whole blood. Fourteen days after drug intake, CRRT was stopped and prednisone (50 mg) was prescribed daily for 5 consecutive days. The patient was prescribed prednisone for 7 more days after discharge. Sixteen days after discharge , oral prednisone (20 mg) was administered daily for seven consecutive days. Twenty-three days after discharge , the subject resumed routine life and work.The patient had a history of gout for 3 years and was prescribed intermittent oral diclofenac sodium for pain relief. Additionally, the patient had no history of anemia or other chronic diseases and had not previously undergone blood transfusion. Furthermore, the patient took oral diclofenac sodium (50 mg) for pain relief due to a gout attack 10 months ago. At the same time, the patient also took one cimetidine capsule (200 mg) without any adverse reactions. The medical records of the patient did not indicate intravenous administration of cimetidine. According to the patient's statement, this was the second time cimetidine had been administered before admission.The patient was diagnosed with acute liver and kidney damage. Five days after drug intake, the patient underwent CRRT. During CRRT, WRBCs prepared from 900 ml of whole blood were transfused, and a blood exchange transfusion was given. Because the patient's liver and kidney functions have been significantly improved, CRRT was terminated on the 14th day after drug intake. After that, the patient returned to normal life and work after two courses of oral prednisone treatment. However, the patient's blood cells and biochemical indicators did not completely restore to normal levels until the 82nd day after drug intake.The timeline of the patient's overall disease course and treatment process is shown in The venous blood samples were collected on days 6, 13, 34, 41, and 82 post-drug intake. Serological analysis including DAT for anti-IgG and for anti-C3d, acid elution test, irregular RBC antibody screening with saline in a tube and indirect antiglobulin test (IAT) in Coombs card were conducted on the patient's blood samples. As described by Leger et al. , DiclofeThe DAT results for anti-IgG and anti-C3d were positive for all the venous blood samples collected on days 6, 13, 34, and 41 post-drug intake. However, on day 82 post-drug intake, the DAT results for IgG were positive while anti-C3d was negative. The results of irregular RBC antibody screening showed that IgG-type drug-independent non-specific antibodies were detected in the patient's plasma obtained from the blood samples collected on days 13, 34, 41, and 82 post-drug intake, and the acid eluent obtained from the blood samples collected on days 34, 41, and 82 post-drug intake. The detailed results of DAT and irregular RBC antibody screening are shown in To test for drug-dependent antibodies we tested: (1) diclofenac sodium solution incubated with O-type WRBCs and the patient's plasma at 37°C for 1 h, (2) diclofenac sodium solution incubated with O-type WRBCs and the patient's red blood cell acid eluent at 37°C for 1 h, and (3) the patient's plasma or the acid eluent was incubated with diclofenac sodium-coated RBCs at 37°C for 1 h. No diclofenac-dependent antibodies were detected in all blood samples of the patient. However, when cimetidine solution was incubated with O-type WRBCs and the patient's plasma at 37°C for 1 h, or the patient's plasma was incubated with cimetidine-coated RBCs at 37°C for 1 h, cimetidine-dependent antibodies were detected in all blood samples of the patient. Antibodies titers detected by the two methods were the same. Further experiments indicated that the cimetidine-dependent antibodies comprised IgM and IgG. Based on the above test results, the patient was diagnosed with DIIHA caused by cimetidine. Cimetidine powder was used to prepare aqueous solutions at multiple concentrations. Then, cimetidine solutions were incubated with O-type RBCs at 37°C or room temperature for 1 h to prepare cimetidine-coated RBCs. Additionally, O-type RBCs were incubated with cimetidine injection at multiple concentrations at 37°C or room temperature for 1 h to prepare cimetidine-coated RBCs; some RBCs hemolyzed . All unhThe male patient had no history of anemia and blood transfusion but was diagnosed with severe hyperbilirubinemia and hemolytic anemia within 4 days of oral administration of diclofenac sodium (50 mg) and cimetidine (200 mg) along with hepatic and renal damages. Although the color ultrasound examination revealed a diffuse fatty change in the liver, the patient had no history of hepatic insufficiency or jaundice. Drugs can potentially aggravate liver damage and hyperbilirubinemia and upregulate the levels of liver enzymes. However, drug-induced liver damage does not rapidly develop into hemolytic anemia. G6PD deficiency can induce acute hemolysis by oxidizing food or drugs –29. A fiThe results of DAT for anti-IgG and anti-C3d of the patient after oral administration of diclofenac sodium and cimetidine were all positive. These results were partially consistent with the serological characteristics of autoimmune hemolytic anemia (AIHA) –37 and DWe collected the remaining two drug capsules from the patient to prepare drug solutions and drug-coated RBCs. Drug-coated RBCs or RBCs incubated with the drug solution were used to detect the presence of diclofenac-dependent or cimetidine-dependent antibodies in the plasma. The antibody may be directed against the non-target drug component in the powder in the capsule instead of the target drug. To rule this out, a drug solution was also prepared using cimetidine solution used for injections. The cimetidine-dependent antibodies were detected in the plasma. In contrast, diclofenac-dependent antibodies were not detected in the plasma. After the cessation of cimetidine, the patient received CRRT, blood transfusion, exchange blood, and prednisone treatment. Based on alanine transaminase  and creatinine , the hepatic and renal functions were significantly improved 13 and 16 days after cimetidine intake. The hemoglobin levels began to increase 16 days after cimetidine intake without blood transfusion. These clinical manifestations and serological findings indicated that the cimetidine-dependent antibodies produced by the patient after oral administration of cimetidine caused DIIHA. As the patient exhibited a diffuse fatty change in the liver, liver compensatory function was reduced. Additionally, hemolysis further aggravated liver damage and consequently resulted in hyperbilirubinemia and elevated liver enzymes. The patient had no history of kidney disease. Thus, renal damage may be due to hemolysis.Several studies have reported cases of cimetidine-induced immunohemolytic anemia. However, only one patient was serologically confirmed to be a case of DIIHA caused by cimetidine-dependent antibodies . The abiDrug-induced antibodies include drug-dependent antibodies and drug-independent antibodies , 25. AmoThe direct agglutination titer of the plasma  and uncoated O-type RBCs in the presence of 1 mg/mL cimetidine solution was 256, while added to the Coombs card as 2,048. The direct agglutination test of the 2ME-treated plasma yielded negative results. The agglutination titer added to the Coombs card was 1,024. This indicated that the cimetidine-dependent antibodies comprised both IgM and IgG components. The cimetidine-coated RBCs prepared by incubating 30 or 20 mg/mL cimetidine solution with RBCs at room temperature for 1 h had a high sensitivity for detecting cimetidine-dependent antibodies. The Ig types and titers of cimetidine-dependent antibodies detected in the plasma were consistent with the results of examining cimetidine-dependent antibodies in the presence of cimetidine solution. Therefore, we recommend that 20–30 mg/mL cimetidine solution incubated with RBCs at room temperature is ideal for preparing cimetidine-coated RBCs for the detection of cimetidine-dependent antibodies.This study also used Coombs card to detect drug-independent non-specific antibodies. The titers of drug-independent non-specific antibodies in plasma samples collected on days 13, 34, 41, and 82 post-drug intake were 1, 32, 16, and 8, respectively. However, drug-independent antibodies were not detected using the saline tube test. The serological properties of drug-independent non-specific antibodies were similar to those of non-specific warm auto-antibodies. We speculate that the patient who developed IHA after receiving cimetidine treatment reported by Rotoli et al.  could beCurrently, there are not effective therapeutic strategies for DIIHA. The discontinuation of related drugs is essential to avoid further hemolysis . In thisDrugs administered intravenously can bind to RBCs. And in the reported cases, there is more DIIHA related to intravenous administration than DIIHA related to oral administration –12. HoweThis study reported the second case of DIIHA caused by cimetidine-dependent antibodies, which was confirmed using serological methods. Additionally, this is the first study to report that oral cimetidine can elicit the production of cimetidine-dependent antibodies and cause DIIHA. Cimetidine-dependent antibodies can be detected using RBCs incubated with cimetidine solution or cimetidine-coated RBCs. We recommended incubating O-type RBCs with 20–30 mg/mL cimetidine solution at room temperature for 1 h to prepare cimetidine-coated RBCs for the detection of cimetidine-dependent antibodies. The findings of this study indicated that the oral administration of cimetidine can also induce the production of drug-independent non-specific antibodies, which led to positive DAT results and IHA independent of cimetidine that persisted for a prolonged period. Patients with DIIHA induced by cimetidine may necessitate clinical management plans including longer monitoring and appropriate tests even after cessation of cimetidine administration.The patient was shocked when he was told that he had developed cimetidine-related antibodies and that the oral administration of cimetidine caused severe hemolytic anemia. The patient said he would listen to the doctor's advice that he would no longer receive cimetidine administration in any way. Doctor's explanations have relieved him from psychological burden by the long-term damage of DIIHA.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Ethics Committee of Dongguan Tungwah Hospital. The patients/participants provided their written informed consent to participate in this study. The patient signed the informed consent and agreed to publish the findings about his case.YJW, YW, and YLJ contributed to the conception and design of the study, data analysis, and manuscript draft preparation. YJW, YHL, and JJL prepared the draft and final manuscripts. DSW monitored the patient and conducted the treatment. YJW, YW, YLJ, GPG, and BCC performed the immunohematological test. All authors contributed to the study design, result interpretation, and preparation of the manuscript.This study was supported by two Key Project of Social and Scientific Development of Dongguan in 2019 (201950715046181 and 201950715007214).The 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Anti-EGFR Targeted agents were found to be capable of modulating the antitumor immunity in head and neck cancer and become more and more frequently used in the treatment of nasopharyngeal carcinoma(NPC). We aimed to explore whether adding concurrent chemotherapy influences the survival outcome of patients with stage II-IVb NPC treated with concurrent anti-EGFR agents and intensity-modulated radiation therapy (IMRT) and explore other prognostic factors for the patients.A total of 656 stage II-IVb NPC patients treated with concurrent anti-EGFR agents plus IMRT between January 2011 and November 2015 were enrolled. Firstly, from these patients, a well-balanced cohort of 302 patients who received concurrent chemotherapy was created by matching potential prognostic factors. Furthermore, for all 656 stage II-IVb NPC patients, univariate and multivariate analyses of overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS) were conducted to identify prognostic factors and to confirm the findings from the matching cohort.Compared with concurrent anti-EGFR agents alone, combining concurrent cisplatin and anti-EGFR agents significantly improved the OS  and PFS  of NPC patients with more severe hematologic toxicity and mucositis. The independent prognostic factors identified by multivariate analysis of OS and PFS included concurrent chemotherapy, epstein-barr virus(EBV) status and clinical stage. Patients treated without induction chemotherapy (IC) may achieve more benefits from the addition of concurrent chemotherapy to concurrent anti-EGFR agents.For stage II-IVb NPC patients treated with concurrent anti-EGFR agents, the addition of concurrent chemotherapy can significantly improve the survival outcome. Nasopharyngeal carcinoma (NPC) is an endemic disease in various regions, especially in southern China, where undifferentiated nasopharyngeal carcinoma occurs most frequently . In receAlthough radiotherapy techniques, such as IMRT and a combination of chemotherapy, have been developed, distant metastasis and local or regional recurrence can still cause treatment failure. Approximately 20% of patients develop distant metastasis or locoregional recurrence . In addiEpidermal growth factor receptor (EGFR), representing a promising new therapeutic target in cancer, is highly expressed in most human epithelial carcinomas and is expressed in 89%-100% of the samples collected from NPC patients , 7. ReseCurrently, concurrent cisplatin-based chemotherapy and anti-EGFR agents are both common therapies for stage II-IVb NPC patients treated with radiation therapy. However, no large cohort study focusing on the prognostic factors of stage II-IVb NPC patients treated with anti-EGFR agents and IMRT, especially studies investigating whether adding extra concurrent chemotherapy to concurrent anti-EGFR therapy can significantly improve the survival of patients or not.Therefore, in the present study, we investigated the role of additional concurrent chemotherapy by comparing Target-RT and Target-RT plus concurrent cisplatin-based chemotherapy (CDDP) in terms of efficacy and safety directly so that we could explore whether extra concurrent chemotherapy is essential or not. In addition, we analyzed the prognostic factors of stage II-IVb nasopharyngeal carcinoma patients treated at the Sun Yat-sen University Cancer Center with concurrent anti-EGFR targeted therapy to confirm the findings from the matching cohort.Patients enrolled in this study were selected from newly diagnosed stage II-IVb NPC patients at Sun Yat-sen University Cancer Center. The stage of the patients was assessed according to the American Joint Committee on Cancer–Union for International Cancer Control 7th edition stage-classification system . The incThe exclusion criteria were as follows: (1). Patients without complete clinical data, such as baseline body mass index (BMI), pretreatment plasma EBV DNA (EBV), C-reactive protein (CRP) and lactic dehydrogenase (LDH). (2). Patients who did not complete the planned dose of radiation therapy (RT). (3). Patients treated with adjuvant chemotherapy, noncisplatin-based concurrent chemotherapy or concurrent chemotherapy with more than one kind of drugs. (4) Patients diagnosed with a previous malignancy or other concomitant malignant disease. The patients were treated with IMRT according to the National Comprehensive Cancer Network (NCCN) guidelines, CSCO guidelines and treatment policies for NPC at Sun Yat-sen University Cancer Center , 16. TheInduction chemotherapy(IC) is playing an increasingly important role in the treatment of stage II-IVb nasopharyngeal carcinoma in the IMRT era, since it helps improve distant control and subsequent survival , 17. For. Using propensity scores to adjust for potentially significant factors, we created a well-balanced cohort by matching each patient treated with IMRT plus concurrent NTZ or CTX with a patient who received IMRT plus CDDP and concurrent NTZ or CTX. The variables available for propensity score matching included age (continuous variable), sex , T stage (T3–4 versus T1–2), N stage (N2–3 versus N0–1), clinical stage (stage IV versus stage II-III), baseline pretreatment serum lactate dehydrogenase (LDH) level (continuous variable), pretreatment C-reactive protein (continuous variable), pretreatment body mass index (BMI) (continuous variable), pretreatment plasma EBV DNA copies (≥4000 versus <4000), IC status (patients receiving IC versus patients not receiving IC) and target-RT agents (NTX versus CTX) selected based on a previous study  Staging System for nasopharyngeal carcinoma. Among the entire group of 656 patients, 481 patients received IMRT plus concurrent NTZ or CTX and CDDP, while 175 patients did not receive CDDP us study –22. The us study . BMI was. Using pAfter treatment, patients were monitored through phone and outpatient clinic follow-up visits. The eligible patients were followed up every 3 months for the first 3 years and then every 6 months until the fifth year. The intervals between follow-ups gradually increased to 12 months after 5 years. The location and timing of tumor recurrence and metastasis were documented. The primary endpoint of the study was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LRRFS). All intervals were calculated from the date of the end of radiation therapy. OS was defined as the time until death from any cause. PFS was defined as the time until the date of death from any cause or treatment failure caused by locoregional recurrence or distant metastasis of NPC, whichever occurred first. DMFS was defined as the time until the first distant metastasis. LRRFS was defined as the time until the first recurrence in the cervical and/or nasopharyngeal region after radiotherapy.We first conducted a comparison between the IMRT plus CTX/NTZ and IMRT plus CTX/NTZ and concurrent cisplatin-based chemotherapy arms in terms of efficacy and safety in the well-balanced cohort of 302 patients. In addition, we conducted univariate and multivariate analyses based on all 656 cases. All analyses were performed using SPSS version 25.0 software, and a 2-tailed P value of less than 0.05 was considered statistically significant. The clinical characteristics of the cohort are described in The potentially significant variables available for the univariate analysis included age, sex, T stage, N stage, clinical stage, baseline pretreatment serum LDH level, pretreatment CRP level, pretreatment BMI, pretreatment plasma EBV DNA copies, IC status, target-RT agents and CDDP status (the addition of CDDP or not). A multivariable Cox regression method was used to adjust for various covariates to identify independent prognostic factors for the survival outcome. The factors in the univariate analysis that were potentially significant (p<0.10) for OS, PFS, DMFS, or LRRFS were included in the multivariate Cox proportional hazards model of OS, PFS, DMFS, or LRRFS. Subgroup analysis was also performed to compare the efficacy of adding CDDP in different subgroups.. All of the patients received cetuximab (CTX) or nimotuzumab (NTX), and most patients (96.0%) received CTX or NTX every week for 5–8 cycles concurrent with radiation therapy. Both the Target-RT group and CDDP plus Target-RT group comprised 151 patients. The baseline characteristics of the patients are summarized in The well balanced cohort of 302 patients who received anti-EGFR therapy with complete clinical data were included . All of . All of In the Target-RT group, the median age of the patients was 50 years (range 18–74), and 80.1% of the patients were male. A total of 27.2% of patients suffered from stage IV NPC, and the pretreatment plasma EBV DNA copies of 67 (44.4%) patients were present at greater than 4000 copies/mL. NTX (nimotuzumab) was more frequently used  than CTZ (cetuximab) .In the CDDP plus Target-RT group, patients receiving cisplatin at either 40 mg/m2 weekly or 100 mg/m2 every 3 weeks are acceptable –26, whilThe last follow-up visit was in October 2020 with a median follow-up period of 67.5 months : 66.1–68.9 months). For the entire patient population, 38 deaths (27 in the Target-RT group and 11 in the CDDP plus Target-RT group) were reported. A total of 83 progressive cases were reported, of which 50 were in the Target-RT group and 33 were in the CDDP plus Target-RT group.The survival outcomes were described in versus 19.8% P<0.001), especially leukopenia , although the P value of the χ2 test for thrombocytopenia, neutropenia and anemia was not significant. In addition, more grade 3-4 mucositis was found in the Target-RT plus CDDP group compared with the group treated without concurrent chemotherapy (28.5% versus 13.2% P=0.001).The χ2 test, corrected χ2 test or Fisher’s exact test was applied to analyze the differences in acute toxicities caused by the treatment. The acute toxicities in the NPC patients are summarized in The results of univariate analysis are summarized in Based on univariate analysis results, we performed multivariate analysis and the results are summarized in According to the multivariate analysis, the treatment status of patients receiving concurrent chemotherapy was a significant prognostic factor for OS and PFS . Adding concurrent chemotherapy was also found to be a favorable prognostic factor for LRRFS. Moreover, pretreatment plasma EBV DNA copies and AJCC clinical stage were prognostic factors for PFS, OS, LRRFS, and DMFS , predicting the poor survival outcome of patients with high pretreatment plasma EBV DNA copies and advanced clinical stage NPC.Based on the results shown in We found that subgroup analysis of OS showed a significant interaction between induction chemotherapy and the efficacy of CDDP (P for interaction: 0.048). These results demonstrate that for patients without induction chemotherapy, the addition of CDDP can provide more survival benefits; however, the addition of CDDP can improve OS outcome in both subgroups regardless of induction chemotherapy (P=0.019 in the subgroup without IC and P=0.046 in the subgroup with IC). In addition, we found that different pretreatment LDH levels may affect the efficacy of extra CDDP. This finding indicates that patients with higher pretreatment LDH level may gain more benefits by adding concurrent chemotherapy; however, the P value of the interaction was not significant .Concurrent cisplatin-based chemotherapy and anti-EGFR agents are both common therapies for stage II-IVb NPC patients treated with radiation therapy. Large retrospective studies have demonstrated that for NPC patients, anti-EGFR therapy has similar benefits as chemotherapy but with less severe toxicity, such as hematologic toxicities and gastrointestinal reactions . In addiIn the subgroup analysis of OS, induction chemotherapy was found to significantly influence the efficacy of adding concurrent chemotherapy . These results demonstrate that patients treated without induction chemotherapy may achieve more survival benefits by adding concurrent chemotherapy. However, we also found that regardless of whether they receive induction chemotherapy, combining CDDP with Target-RT can significantly improve the survival outcome of NPC patients . These results demonstrate the powerful efficacy and the necessity of adding extraconcurrent chemotherapy to anti-EGFR therapy. In addition, patients with a high level of high pretreatment LDH may gain more benefits from adding concurrent chemotherapy; however, the P value for interaction was not significant . These results demonstrate the potential predictive value of pretreatment LDH for the selection of suitable patients to receive concurrent chemotherapy, and this topic is worthy of further study. In addition, the subgroup analysis of age shows that even for elderly patients over 65 years old (P=0.036 in OS), adding concurrent chemotherapy can achieve better survival outcomes, which indicates that age is not a suitable criterion for the selection of appropriate patients adding extra concurrent chemotherapy to Target-RT. In conclusion, the subgroup analysis of OS suggested that the benefit of CDDP was not limited to a particular subgroup of patients and confirmed the necessity of adding CDDP to Target-RT. Previous study have demonstrated that concurrent chemotherapy may benefit elder patients , 30, whiWhen it comes to the side effects of additional CDDP, our research also evaluated the toxicity of different treatment regimens. Consistent with previous research , 5, we oBased on the serious side effects of concurrent chemotherapy and the fewer side effects caused by anti-EGFR target therapy, identifying patients who are suitable for omitting concurrent chemotherapy has become an emerging question that is worthy of exploration. Based on the subgroup analysis of OS, we found that pretreatment LDH status may influence the survival benefit of additional CDDP(P for interaction: 0.069). However, we also found that both patients with low or high LDH level may receive better OS outcome in Target-RT plus CDDP group when compared to Target-RT group, although the P-value in the low LDH level group was 0.511. How to identify patients who are suitable for omitting concurrent chemotherapy should be studied further in larger cohort of study.One limitation of our study is that our study was a single-center retrospective study in a high-NPC prevalence area. Additionally, although we eliminated some biases by multivariate analysis with an adjusted Cox proportional hazards model and propensity score matching, the presence of other confounding factors in our study was unclear. Additional multicenter prospective investigations are warranted to evaluate the efficacy and safety of adding concurrent chemotherapy to concurrent anti-EGFR agents for NPC patients.In summary, the addition of concurrent chemotherapy can significantly improve the survival outcome of stage II-IVb nasopharyngeal carcinoma patients treated with concurrent anti-EGFR agents.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Clinical Research Committee of Sun Yat-Sen University Cancer Center. Written informed consent to participate in this study was provided by the participants or the participants’ legal guardian/next of kin if the participant was under legal age of adults.ZK-Y and RY participated in study design. ZK-Y, XY-C, and SH-L were responsible for the analysis of data. ZK-Y and YP-L were responsible for drafting the manuscript. PY-H put forward the concepts of the study. All the authors revised the manuscript. All the authors approved the final manuscript.This work was supported by the Program of Sun Yat-Sen University for Clinical Research 5010 Program (No.2018015), the National Natural Science Foundation of China (No.81874134).The 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 reviewers CW and QZ have declared a shared parent affiliation with the authors at the time of review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.