The COVID-19 pandemic has had a widespread impact on attendance in biomedical research and health care visits.This study aimed to identify when and how American adults might feel comfortable about resuming in-person research and health care visits.Cross-sectional questionnaire data were collected from 135 adults  who were engaged in health-related research.P=.001).More than half of the respondents  felt that the COVID-19 pandemic positively affected their desire to participate in research. Although 73.6% (95/129) of respondents also indicated a willingness to attend in-person health care visits while Centers for Disease Control and Prevention (CDC) guidelines are implemented, 85.8% (109/127) indicated a willingness to attend in-person, outdoor visits, and 92.2% (118/128) reported a willingness to attend drive-through visits (with CDC guidelines implemented during both visit types). Videoconferencing was the most preferred format for intervention visits; however, adults over the age of 65 years preferred this format less than younger adults (Researchers and clinicians should continue to provide opportunities for continuing the conduction of remote-based interventions while enforcing CDC guidelines during in-person visits. Lockdown and stay-at-home orders that were enacted to contain the spread of COVID-19 ,3. ThereThis study was a cross-sectional analysis of US adults who were enrolled in biomedical research studies. An email describing this study and a link for participating in the web-based survey was sent to 250 adults who had previously completed a survey that assessed COVID-19 impacts on research participation and mental health outcomes , and addThe 87-item questionnaire, which was developed by the study team, was used to collect sociodemographic information , query respondents about the number of underlying health conditions that were suspected to increase COVID-19 severity , and askP value of <.05. Study findings were reported by using the STROBE  guidelines.Descriptive statistics were computed to describe research participation and health care engagement. In total, 3 items for querying respondents about their beliefs regarding participating in research and whether the COVID-19 pandemic has positively or negatively affected their desire to participate in research were scored on 5-point, Likert-style scales . For anaResponses were collected from 135 adults participating in biomedical research. P=.04). Moreover, a majority of respondents  indicated that they did not believe that such participation put them at greater risk of contracting COVID-19. The most preferred methods of engaging in behavioral interventions included videoconferencing (60.7%) and in-person sessions (53.3%). Regarding future research participation, respondents were most interested in engaging in clinical  and public health research  and were least interested in vaccine development research .Almost three-quarters of respondents  felt comfortable with attending in-person, indoor clinic visits, and over 85% felt comfortable with attending outdoor  and drive-through  clinic visits while adhering to Centers for Disease Control and Prevention (CDC) guidelines ; however, younger adults (aged 18-64 years) were significantly more likely to report feeling comfortable with videoconferencing platforms than adults over the age of 65 .There were no significant differences between men and women or between White participants and people of color in terms of responses for any survey items , and fewer indicated that the COVID-19 pandemic had a negative impact . Although we do not have additional data to explain this finding, it is possible that the greater news coverage of biomedical research during the pandemic has increased individuals’ appreciation for this scientific process  and incr2, 53.3%,With the ongoing pandemic, most respondents reported a willingness to attend in-person, health care–related clinic visits while adhering to CDC guidelines ; however, even more were comfortable with outdoor  and drive-through  formats. Our results also suggested that the availability of vaccines and effective COVID-19 treatments may improve individuals’ willingness to resume attending in-person clinic visits. Overall, videoconferencing was the most preferred format. Videoconferencing offers greater flexibility in scheduling compared to in-person visits, and this format can also retain the visual cues  that are lost in phone-based delivery formats . The incTaken together with other findings that support the role of telehealth approaches in health care delivery , our resThe limitations to this study included the use of a convenience sample of biomedical research participants that consisted predominately of highly educated White women with health insurance. Although this sample is generally reflective of research populations within the nutrition and obesity intervention fields ,19, this


Pancreatic cancer usually presents late when it has spread to distant sites. In a small proportion of patients, the cancer can be removed by surgery. Surgery is usually followed by chemotherapy, as studies have shown that this improves survival. However, due to complications after surgery and a decline in fitness, some patients do not start their chemotherapy and many do not complete the planned course. The cancer returns in the majority of patients. Chemotherapy or a combination of chemotherapy and radiotherapy before surgery are being investigated to improve survival. The best treatment regime and patient selection for different treatment strategies remains to be defined and is discussed here.Pancreatic ductal adenocarcinoma (PDAC) has an aggressive tumor biology and is associated with poor survival outcomes. Most patients present with metastatic or locally advanced disease. In the 10–20% of patients with upfront resectable disease, surgery offers the only chance of cure, with the addition of adjuvant chemotherapy representing an established standard of care for improving outcomes. Despite resection followed by adjuvant chemotherapy, at best, 3-year survival reaches 63.4%. Post-operative complications and poor performance mean that around 50% of the patients do not commence adjuvant chemotherapy, and a significant proportion do not complete the intended treatment course. These factors, along with the advantages of early treatment of micrometastatic disease, the ability to downstage tumors, and the increase in R0 resection rates, have increased interest in neo-adjuvant treatment strategies. Here we review biomarkers for early diagnosis of PDAC and patient selection for a neo-adjuvant approach. We also review the current evidence for different chemotherapy regimens in this setting, as well as the role of chemoradiotherapy and immunotherapy, and we discuss ongoing trials. Pancreatic ductal adenocarcinoma (PDAC) is the 14th commonest cancer worldwide. Amongst all malignancies, PDAC accounted for 2.6% of new cancer cases and 4.7% of new cancer deaths in 2020 ,4,5.KRAS in 90% of cases, with frequent inactivation of tumor suppressor genes such as TP53, SMAD4, and CDKN2A and with complex interactions with the tumor microenvironment [Tumorigenesis in PDAC is driven by signature gene mutation of ironment . PDAC reTo date, curative resection offers the only chance of cure. However, only 10–20% of patients present with resectable disease, while the majority are diagnosed with borderline resectable, locally advanced (30%), or metastatic disease (50%) . In ordeDespite advances in surgical techniques, along with the incorporation of more active chemotherapy regimens, the 5-year survival rate for PDAC has remained poor at 9% for all disease stages combined . After cThe benefit from adjuvant chemotherapy in patients undergoing a curative treatment paradigm is undisputed. However, 50% of patients may never commence adjuvant chemotherapy due to post-operative complications or poor performance status, and a proportion of patients do not complete the intended course ,31. AddiAlthough less well studied than the adjuvant setting, emerging evidence suggests that select populations may be more likely to benefit from neo-adjuvant treatment, thereby suggesting that treatment will need to be tailored for individual patients. Additionally, given that the success of combination treatment with gemcitabine and nab-paclitaxel in the metastatic setting did not directly translate into the adjuvant setting, the question of which chemotherapy regimen is best in the neo-adjuvant setting needs to be carefully considered.Here we review the evidence for different neoadjuvant treatment regimens, including chemotherapy, chemo-radiotherapy, and immunotherapy, as well as biomarkers for early diagnosis, and we discuss which patients may benefit from neo-adjuvant treatment.There is a clear unmet need to discover biomarkers to aid the early diagnosis of PDAC, given that patients usually become symptomatic and present later in the clinical course when curative resection is no longer feasible. Additionally, any biomarker used in this context, needs to be able to reliably differentiate PDAC from both chronic pancreatitis and other benign or malignant diseases . Currentp < 0.001) [Multiple studies have evaluated the performance of CA-19.9 with other protein biomarkers. CA-19.9 was evaluated together with apolipoprotein A-IV and metalloproteinase-1 in a cohort of 182 individuals including stage I–II and III–IV PDAC patients, patients with pancreatitis, and healthy controls. Sensitivity reached a value of 86%, specificity was 90%, while sensitivity was 71% for CA-19.9 alone . Moreove< 0.001) .KRAS mutation. In early stage PDAC, ctDNA was only detected in 30–65% of patients [KRAS mutation, ctDNA has also been detected in up to 20% of cases with chronic pancreatitis and 17% of non-malignant pancreatic masses [With improvements in precision medicine, the use of blood and other body fluids as liquid biopsy tools for diagnosis, genotyping, prognostication, response assessment, and surveillance has gained increasing interest in oncology. In this regard, circulating tumor DNA (ctDNA) can act as a genomic surrogate for tumor and has been investigated as an early diagnostic biomarker for PDAC, given that >90% of tumors harbor a patients ,43,44,45patients . Howeverc masses . TherefoExosomes, which contain proteins and enzymes, constitute a class of extracellular vehicles defined as membrane-bound nanovesicles of endocytic origin, with a diameter of 40–150 nm. Increasing evidence suggests that exosomes are associated with cancer and accelerate PDAC cell proliferation, migration, and invasion. Unlike ctDNA, exosomes do not depend on the occurrence of apoptosis or necrosis to be detectable and have a much longer half-life . MoreoveSome microRNAs (miRNAs) were reported to be over-expressed in the plasma of patients with early-stage PDAC compared with normal controls and may therefore help with early diagnosis. For example, miR-16 showed a 92% sensitivity and 95.6% specificity for the determination of early PDAC cases. In addition to miR-16, compared with controls, miR-155, miR-181a, miR-181b and miR-210 were also found to be overexpressed in PDAC patients. MiR-19a-3p was shown to be overexpressed in PDAC with a potential to be used as an early non-invasive diagnostic biomarker but also as a prognostic biomarker. Another study reported the role of miR-29a, miR29b, miR-103, and miR-320 as early diagnostic predictors of PDAC when upregulated .CHI3L2 and CD44) were associated with poor survival after PDAC resection. Prognostic biomarkers may be useful in selecting patients at high-risk of relapse after surgery for a neo-adjuvant chemotherapy strategy in an attempt to treat micro-metastatic disease early [In patients with resectable PDAC, high pre-operative C-reactive protein-to-albumin ratio was reported as an independent predictor of poor survival after resection of the primary tumor . Similarse early . HoweverIn borderline-resectable patients receiving neo-adjuvant chemotherapy, the expression of marginal zone B and B1-cell-specific protein (MZB1) was detected in the tumor stroma. MZB1 was associated with higher accumulation of CD8+ tumor-infiltrating lymphocytes induced by chemotherapy. Patients with higher accumulation of CD8+ cells after chemotherapy had better prognosis after neo-adjuvant treatment and resection . SimilarSo far, none of these candidate biomarkers have been approved for clinical practice. Indeed, results obtained in small investigational cohorts need to be validated in larger studies. However, this is often challenging due to the long follow-up times required and the need to recruit a large number of patients for conclusive results. Additionally, PDAC is a heterogeneous disease with different tumor clones that may contribute to inter-patient variability in the expression of tissue and circulating biomarkers .It has been suggested that the simple dichotomy of resectable vs. borderline resectable disease can be overcome by biological classification of favorable or unfavorable disease according to biomarker status. Indeed, a recent study that conducted multi-omics profiling of resectable PDAC revealed molecular subtypes with distinct tumor biology . TherefoSome centers consider nearly all patients who appear to have resectable PDAC as having borderline resectable disease, given the inaccuracy of imaging and the very high rates of a positive margin after surgery and its association with poor OS. Older trials and meta-analysis included patients staged with substandard imaging modalities or sub-optimal chemotherapy schedules . Modern chemotherapy  allows significant shrinkage and conversion surgery in about 60% of patients with borderline resectable PDAC ,58, so iRadiological modalities, surgical exploration, metabolic and functional imaging, and plasma biomarkers have been explored as predictors of resectability. Disease is usually split between resectable and borderline resectable/unresectable cases. With conventional imaging (CT), the distinction between these two categories is associated with a high sensitivity but reduced specificity  . StagingFunctional metabolic imaging such as FDG-PET has been shown to be a useful measure of radiological response as well as for initial staging. In a subset of 194 undergoing total neo-adjuvant therapy for borderline resectable or locally advanced PDAC, three factors were independently associated with survival: extended chemotherapy duration (≥6 cycles), optimal post-chemotherapy CA-19.9 response, and a major pathological response. Major pathologic response was defined as complete pathological response or near complete response according to the College of American Pathology criteria. In a subset of patients with interval metabolic (PET) imaging after initial chemotherapy, complete metabolic response highly correlated with major pathological response . In a syThe UK National Institute for Health and Care Excellence (NICE) has recommended the use of PET-CT in the routine staging of patients with resectable PDAC . DespiteFinally, endoscopic ultrasound (EUS) is another valuable modality for the staging of PDAC. Multiple studies comparing EUS with other imaging modalities for initial diagnosis and staging of pancreatic cancer concluded that EUS might be more accurate for smaller tumors, local T and N staging, and predicting vascular invasion. The development of modern CT has markedly improved sensitivity for the detection of smaller tumors and the presence of vascular invasion, apart from dictating resectability . HoweverIn conclusion, in the presence of a pancreatic mass suspected as being a PDAC, a CT scan and EUS (for tissue confirmation) are appropriate steps to assess disease extent and resectability. Biomarkers and clinical status  may assist in prognostication. With pre-operative therapy, imaging may not reliably show whether viable tumor continues to persist (fibrosis); however, imaging can help identify disease progression, including the development of distant metastases, which would preclude surgery. It is also important to consider patient-related factors such as performance status and change in CA-19.9 levels as markers of response to neo-adjuvant therapy and likely benefit from attempted surgical resection. Minimal radiological progression or a stable disease picture may not per se represent a criterion to refuse surgical exploration. In some cases of PDAC where the resectability status is less clear, the addition of PET and/or laparoscopy may help determine whether neo-adjuvant treatment is preferable over upfront surgery.The addition of radiotherapy to chemotherapy has been explored in the neo-adjuvant setting in an attempt to improve R0 resection rates and ultimately survival outcomes in both resectable and borderline resectable disease, and key studies are summarized in In recent years, evidence has become increasingly available suggesting a survival benefit for neo-adjuvant chemo(radio)therapy in resectable PDAC and borderline resectable PDAC. A large population-based study from the Surveillance, Epidemiology, and End Results (SEER) database, including nearly 4000 patients, showed a statistically significant prolongation in OS for resectable PDAC patients receiving neo-adjuvant radiotherapy (23 months) compared with those receiving adjuvant radiotherapy (17 months) or no radiotherapy (12 months) . More rep = 0.009), locoregional failure-free interval , and R0 resections  were all superior with pre-operative chemoradiotherapy. Regarding the safety profile, the proportion of patients experiencing G3–G4 adverse events was similar between treatment arms (p = 0.096). Moreover, the compliance of intended pre-operative chemoradiotherapy  was better than that of intended post-operative chemotherapy in the immediate surgery group , and pre-operative chemoradiotherapy had a higher chance of being completed (89% vs. 58%). Borderline resectable PDAC seems to benefit more from pre-operative chemoradiotherapy, based on a predefined subgroup analysis, although an interaction test of hazard rates between both groups was not significant. While the results of this study clearly support a neo-adjuvant treatment strategy, unanswered questions remain. It is still unclear whether the optimal chemoradiotherapy strategy is gemcitabine-based treatment. Additionally, the amount that the chemoradiotherapy contributed to the favorable outcome is unclear, as these patients also received 2 cycles of chemotherapy with gemcitabine neo-adjuvantly.The long-term results of the PREOPANC-1 trial, which is the first multicenter, randomized phase III trial investigating pre-operative chemoradiotherapy in PDAC, have been reported at the American Society of Clinical Oncology (ASCO) 2021 Meeting ,73. In tBased on the effectiveness displayed in the advanced-disease setting, the mFOLFIRINOX regimen has been rapidly introduced in earlier disease stages with or without pre-operative radiotherapy. To this end, mFOLFIRINOX followed by (chemo)radiotherapy as a total neo-adjuvant approach has been shown to be feasible in borderline resectable PDAC, resulting in promising oncological outcomes. In a single-arm phase II trial, after 8 cycles of neo-adjuvant mFOLFIRINOX, patients received either short- or long-course radiotherapy depending on vascular involvement upon restaging, with high R0 resection rates , and median progression-free survival (mPFS) was 48.6 months , while median OS has not yet been reached . HoweverThe role of pre-operative (chemo) radiation in both resectable PDAC and borderline resectable PDAC is still strongly debated, and the highest level of evidence still favors surgical resection followed by adjuvant chemotherapy in this setting. The PREOPANC-1 study forms an important contribution to the evidence base in support of neo-adjuvant chemoradiotherapy, as it represents the first large phase III randomized trial in this space. Nonetheless, more data are needed, and future and ongoing trials incorporating radiotherapy in neo-adjuvant treatment strategies will hopefully aid in better clarifying its role in resectable PDAC and borderline resectable PDAC. Ongoing studies will hopefully address questions regarding the role of radiotherapy (non-SBRT) and the optimal systemic treatment to be given. These issues are under active investigation in the ongoing PREOPANC-2 (EudraCT: 2017-002036-17) and PRODIGE 44 trials . The former is comparing neo-adjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine vs. total neo-adjuvant mFOLFIRINOX in borderline resectable PDAC and resectable PDAC, while the latter is evaluating neo-adjuvant mFOLFIRINOX followed by the addition or omission of chemoradiotherapy and adjuvant chemotherapy after surgery in patients with borderline resectable PDAC.The drive for neo-adjuvant and peri-operative treatment in PDAC is based on the fact that this tumor has a propensity to metastasize early, thereby suggesting the presence of micrometastatic disease that requires early intervention. PDACs are often diagnosed as locally advanced or borderline resectable tumors; in those cases, an induction treatment is recommended according to international guidelines in order to increase the rate of optimal resections .FOLFIRINOX and gemcitabine/nab-paclitaxel represent the most active chemotherapy regimens investigated in PDAC in the metastatic setting over the last decade ,77. In tp = 0.01; 6 months: 20.8% vs. 35.6%). The response rates were 27% and 5.3%, respectively. Median OS was 12.7 and 10.6 months in the experimental and control arm, respectively; median PFS was 7 months in the nab-paclitaxel-containing group compared with 4 months for the gemcitabine group. These encouraging data were subsequently confirmed in the phase II LAPACT trial , which evaluated the safety and efficacy of six cycles of gemcitabine/nab-paclitaxel combination treatment in 107 locally advanced PDAC patients [Key neo-adjuvant studies in locally advanced PDAC are summarized in patients . The tripatients .p = 1) and R0 resection rates (88.9%) were similar between the two groups. Additionally, there was no significant difference between either mPFS  or mOS . These results are in line with those previously reported in the LAPACT trial [p = 0.03), tumors located in the pancreatic tail , CA-19.9 > 200 UI/L , and tumor resection  were independent prognostic factors for both PFS and OS, whereas CA-19.9 ≤ 200 UI/L  was predictive of tumor response. However, the results should be interpreted with caution due to the intrinsic limitations associated with the retrospective nature of the analysis . Additionally, the similar rates of high-grade toxicity reported between the two regimens is not in keeping with previous reports. This could be related to differences in the management of toxicity or different measures used to prevent toxicity .To date, there are no prospective, validated phase III trial data comparing FOLFIRINOX and the combination of nab-paclitaxel and gemcitabine. However, recently a European multicenter study compared these two regimens in a retrospective analysis . The stuCT trial . AbdominThe preliminary results of the phase II randomized JCOG1407 trial were recently presented at the ASCO 2021 meeting . The triPeri-operative chemotherapy for PDAC has mainly been assessed in patients with resectable disease at diagnosis. In this context, the phase II PACT-15 trial randomized patients with resectable PDAC to receive surgery followed by 6 cycles of adjuvant chemotherapy with gemcitabine—arm A; PEXG —arm B; or peri-operative chemotherapy (3 pre- and 3 post-operative cycles of PEXG schedule)—arm C . The triThe phase II randomized SWOG S1505 trial compared modified FOLFIRINOX and gemcitabine/nab-paclitaxel (12 weeks pre- and 12 weeks post-operative treatment) in 103 patients with resectable PDAC at diagnosis. The preliminary results showed no difference in 2-year OS and resection rate between the two arms  ,85. HoweOne of the most innovative strategies in the field of peri-operative approaches is the integration of biomarker research to select patients who can benefit more from this therapeutic paradigm. Based on the results of the COMPASS trial in advanced PDAC , the phaBRCA genes, with a higher incidence in high-risk populations and those with familial syndromes [BRCA or other DNA repair genes such as PALB2 are thought to have tumors with increased sensitivity to platinum agents. Increased platinum sensitivity arises because these genes are involved in the homologous recombination repair pathway. In view of this, there is a rationale to ensure that in this patient population, platinum compounds are introduced early in the treatment paradigm. Indeed, in a study evaluating the complete pathological response rate in borderline resectable PDAC, in patients treated with neo-adjuvant FOLFIRINOX, the rate was higher for germline BRCA mutation carriers (44.0%) compared with 10% in those who did not have a BRCA mutation (p = 0.009) [BRCA carriers , although this did not translate into a statistically significant difference in terms of OS benefit.In PDAC, 6–7% of patients have a germline mutation in the yndromes . Patient= 0.009) . AdditioAmong ongoing trials, the phase II NEO-Nal-IRI trial, which is currently testing the activity of NALIRIFOX  (NCT03483038), is worthy of being mentioned . The popIn conclusion, evidence suggests that both FOLFIRINOX and gemcitabine/nab-paclitaxel chemotherapy are active and may have a role in the pre-operative treatment of borderline resectable and locally advanced tumors. However, the exact role of neo-adjuvant and peri-operative treatment is still not clearly defined for PDAC. This is in part due to trials including heterogeneous populations as well as the lack of consensus regarding the resectability criteria used. Additionally, other limitations include the lack of selection according to molecular classification of PDAC , the smaPDAC is considered to be less immunogenic compared with other neoplasms. Moreover, it is characterized by the presence of the stroma, which represents an active part in the modulation of the complex interactions between tumor and the host immune system, leading to an immunosuppressive tumor microenvironment. Additionally, the proportion of patients with high microsatellite instability (MSI) tumors is very low (1%); these cases are mainly related to the Lynch syndrome. Nevertheless, several preclinical and clinical trials have been developed in order to find some application of immunotherapeutic agents in PDAC.p = 0.98) [In the neo-adjuvant setting, there is a limited evidence base for immunotherapy. A recently published phase III trial evaluated the efficacy and safety of algenpantucel-L—a cancer vaccine based on irradiated allogenic transfected PDAC cells—with or without chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel), followed by chemoradiotherapy in 303 patients with borderline resectable or locally advanced PDAC. The mechanism of action was based on the epitope spreading, which amplified the host immune response, leading to the death of PDAC cells by activation of antibody-dependent cell-mediated cytotoxicity. Unfortunately, the trial did not show any benefit in survival by adding algenpantucel-L to the chemotherapy if compared with the control arm  .Among vaccines tested in PDAC, GVAX is the most studied. However, all published trials with this agent were conducted in the adjuvant or in the metastatic setting, and no evidence exists in the neo-adjuvant treatment for PDAC patients to date.In an attempt to improve the immunotherapeutic response in PDAC, immunotherapy alongside chemotherapy has been investigated. The preliminary data regarding the safety and efficacy of the combination of KN046 (a novel recombinant humanized bispecific antibody that blocks PD-1/PDL1 and CTLA-4) and nab-paclitaxel/gemcitabine as first-line treatment for unresectable locally advanced or metastatic PDAC were recently presented at the ASCO 2021 meeting. The ongoing phase II trial included 17 patients, who were treated with 4–6 cycles of chemotherapy plus immunotherapy, followed by immunotherapy as maintenance. The preliminary results showed that the combination is feasible and effective, with 55.6% ORR and 88.9% disease control rate. The overall incidence of KN046-related treatment-emergent adverse events was 64.7%, with 29.4% grade 3 TRAE. The most common KN046-related treatment-emergent adverse events were alanine and aspartate aminotransferase increase , nausea (17.6%), rash (17.6%), and diarrhea, pyrexia, vomiting or hyperphosphatasemia (11.8% each).No immune checkpoint inhibitors or immunological agents are currently used or approved in the neo-adjuvant setting for PDAC in clinical practice. However, the results of the ongoing trials in this field are expected and are summarized in The microbiome refers to a collection of micro-organisms and their genome in an environment . DisruptThe study conducted by Riquelme et al. provides supporting evidence for the composition of the microbiome as a prognostic biomarker in PDAC as well as the role of modulating the tumor microbiome in improving clinical outcome . They usModulation of the microbiome is an exciting area of study, and other than fecal microbiota transplantation, antibiotics, prebiotics, and probiotics have been investigated, but results have been controversial, with survival benefit reported for macrolide antibiotic use in metastatic PDAC  but a deDespite the recent improvements in surgical techniques and developments in the therapeutic armamentarium, PDAC still represents one of the most challenging tumors to treat in oncology. Surgical resection is generally feasible in very few patients at the time of diagnosis and remains the only chance of cure. However, resection alone is not sufficient, resulting in low cure rates with long-term survival generally not exceeding 20%. Therefore, other complementary treatments such as chemotherapy and radiotherapy need to be considered. It has been shown that either option can individually add benefit in the pre- or post-operative setting. The optimal integration of such different strategies urgently needs to be defined.Based on different series, up to 50% of resected patients never receive adjuvant treatments. Hence, focusing on delivering all the best available treatments before surgery is becoming increasingly important. Even more crucial is defining the optimal multimodal approach, with a combination of all the different treatment strategies likely to offer the most benefit for patients. In this regard, the so-called “total neo-adjuvant” approach looks very promising. It allows upfront delivery of what is regarded as the best polychemotherapy regimen , followed by radio-chemotherapy and ultimately surgery. This strategy has been associated with impressively high R0 resection rates that translated into significant PFS and OS improvements. As of today, this unarguably represents the most effective treatment strategy, but several questions still remain unanswered.Specifically, it will be interesting to evaluate the performance of newer potentially less toxic cytotoxic agents or their best combination and the possible association with immunotherapy  with both chemo- and radiotherapy. Additionally, the integration of biomarkers to select which patients may benefit from different treatment strategies may play an increasingly important role. For example, molecular signatures for platinum sensitivity may better define which chemotherapy regimen should be used in this setting. Modulation of the tumor microbiome for therapeutic gain is another area that warrants further research in this setting.Another key research avenue should also explore the role of the different available radiotherapy techniques and modalities and the role of immune priming in enhancing response. In particular, it will be important to define the value of SBRT incorporation as an alternative approach to conventionally fractionated external beam radiotherapy with concurrent chemotherapy due to its capability to deliver higher doses while reducing toxicity to normal tissues. Similarly, the use of smaller treatment fields, along with more conformal techniques and hypofractionated protocols, will hopefully improve final outcomes.Ultimately, well designed randomized clinical trials will define the best sequence and duration of different treatment modalities, the optimal patient selection for surgical resection, and the need for post-operative adjuvant chemotherapy. The incorporation of standardized resectability criteria across all studies, along with the integration of translational research, is likely to result in improved outcomes.


A further 13.7% of households reported marginal food-security. Poor mental health status (K10 score ≥ 20) predicted household food insecurity at all levels. The presence of more than three children in the household was associated with low food-security . Those who were renting were 2.10 (95% CI: 1.09–4.05) times likely to experience very low food-security than those owning their own home. The COVID-19 pandemic may have contributed to an increased prevalence of household food insecurity. This study supports the need for a range of responses that address mental health, financial, employment and housing support to food security in Australia.This study aimed to describe the prevalence, severity and socio-demographic predictors of food insecurity in Australian households during the COVID-19 pandemic in 2020, from the perspective of women. A cross-sectional online survey of Australian (18–50 years) women was conducted. The survey collected demographic information and utilised the 18-item US Department of Agriculture Household Food Security Survey Module and the Kessler Psychological Distress Scale (K10). A multivariable regression was used to identify predictors of food security status. In this cohort ( Food security is a fundamental human right and paramount to physical, mental and social health and wellbeing . Yet fooCOVID-19 was first identified in Australia in January 2020 . AustralUnderstanding the food experience of women is particularly important due to their unique role in the household and society. Despite increasing participation by women in the workforce, either in casual, part-time or full-time work, many continue to have the primary role and investment of time in household and family food provisioning . As a reRecognition of the links between food insecurity, poor diet quality, poor mental health and chronic disease development have prompted calls for more research exploring the impact of the COVID-19 pandemic on food security worldwide . The fewThis study was part of a larger study to explore food intake, physical activity and mental wellbeing during COVID-19 pandemic in women of reproductive age (18–50 years) in Australia. This national cross-sectional online survey was undertaken between 15 October to 7 November 2020 during COVID-19 (see further detail below). This research captured a large sample of the female Australian population across age and residential location (state/territory and remoteness area).Women of reproductive age (age 18–50) who resided in Australia were recruited by an external cross-panel market research provider (Online Research Unit) with a well-established database of 400,000 members. This research provider uses multiple recruitment methods  . Men or The survey included multiple-choice questions to assess respondents’ age group, cultural or ethnic group, highest level of education completed, employment status before the pandemic, changes in employment status during the pandemic and annual household income before tax pre-pandemic and during pandemic at the time of sampling in 2020. Urban or rural/remote location was determined based on postcode.Food security status was assessed using the validated 18-item United States Department of Agriculture Household Food Security Survey Module (USDA-HFSSM), including 10 adult questions and 8 child questions . The USDThe Kessler Psychological Distress Scale (K10) was used to assess psychological distress . The K10n = 508). These non-completions are mostly due to ineligibility  as determined in the screening questions at the start of the survey. Descriptive statistics were calculated for all variables. Chi-squared was used to compare demographic, socioeconomic, mental health and food security variables between the four food security severity groups. Multivariable logistic regression was conducted. Covariates used in the multivariable model were those identified using descriptive statistics to be significant between food security severity groups. Covariates included state, marital status, children, education, pre-COVID-19 employment, pre COVID-19 income and change to employment status due to COVID-19. Descriptive statistics were used to report the responses to the USDA-HFSSM 18-items across the four food security groups. Data were analysed using the statistical software package IBM SPSS for Windows Version 26 . Significance was set at p < 0.05.Data screening and cleaning ensured data usability and an integrity script allowed discarding of surveys with less than 10% completion , 13.7% (n = 138) marginal food security, 11.8% (n = 119) low food security and 7.8% (n= 78) experiencing very low food security.A total of n = 847, 84.3%) reported living in a major city of Australia, aged 25–44 years  and in a married or de facto relationship . Forty-three percent of respondents (n = 431) reported having one or more children. With regard to education status, over half  had a university education (Bachelor’s degree or higher) and 42.7% (n = 429) reported a household income greater than AUD 100,000 per year [p < 0.001), were more likely to be renting than owning their own home (p = 0.006), be single (p < 0.005), have children (p < 0.001) and were less likely to have post-secondary education (p = 0.003) compared to households that were food secure.Survey respondent socio-demographic characteristics across the four food security categories are presented in nts n = 4 reporteddid you or other adults in your household ever cut the size of your meals or skip meals because there wasn’t enough money for food”, those that responded affirmatively were experiencing low (31.5%) or very low food security (67.6%). Of households experiencing very low food security, 79.7% reduced the size of their meals either every month or 3–4 months. Similarly, 95% of respondents experiencing very low food security reported in the last 6 months that either they or other adults in the household had not eaten for a whole day because there was not enough money for food. Households responding to the initial child experience question reported that they relied on only a few types of low-cost food items to feed children because they were running out of money to buy food . However, as the questions increased in the severity of food security experience those with low and very low food security status were more likely to respond affirmatively.The proportions of responses to the 18-item USDA-HFSSM questions according to each food security category are presented in p = 0.014) prior to the COVID-19 pandemic. There was an association between food security and changes in employment status due to COVID-19, whereby those that reported changes in their employment due to COVID-19 were more likely to experience food insecurity (p < 0.001). There was also an association between severity of food security and level of income. Women in the lowest household income brackets  were more likely to experience very low food security (p < 0.001) pre-COVID-19. While not statistically significant, there was a trend for Victoria and New South Wales, the States with the largest population size and with the highest number of COVID-19 cases, to report the highest proportion of low and very low food security (p = 0.058).Socio-demographic characteristics associated with food security status are reported in Poor mental health status (K10 score ≥ 20) of respondents was a predictor of food insecurity at all severity levels. Furthermore, women living in a household experiencing very low food security had seven times higher odds (OR 7.07:95% CI 3.40 -14.66) of having poorer mental health. Other characteristics associated with food insecurity included children and housing status. The presence of more than three children in the household was associated with low food security . Those who were renting were 2.10 (95% CI: 1.09–4.05) times likely to experience very low food security than those owning their own home.This study describes the severity of household food security experienced by Australian women during the COVID-19 pandemic in 2020. Our results indicate that, between May and early November 2020, one in five (20%) women were experiencing food insecurity. Of these, 11.8% were experiencing low food security and 7.8% were experiencing very low food security, the most severe form of food insecurity. In addition, 13.7% of respondents were living in households experiencing marginal food security, defined as the early stage of the food security continuum, including experience of stress and anxiety about running out of food. The prevalence of food insecurity was considerably higher  than the reported national prevalence of households (4% ) aged ovn = 1170 adults) between May-June 2020 found that 26% of the sample were experiencing marginal, low or very low food security, greater than that previously reported pre-COVID-19, particularly among economically vulnerable households and people who had lost income during the pandemic [n = 10,368), with post-stratification weighted by gender, age, race, income, and geography (state), were surveyed using the 10-item USDA adult food security module in March 2020 to explore COVID-19 related impacts on food security status. More than one-third of respondents reported to be food insecure. The increase in food insecurity was reported across the general population and higher risk groups comprised of low income and minority populations [Food insecurity prevalence and related socio-demographic factors associated with COVID-19 has been explored across high income countries. The majority of these studies have explored food insecurity specifically in the adult population. Another Australian cross-sectional study conducted in the state of Tasmania (pandemic . This stpandemic . A crossulations . Resultsulations . A surveulations . Those wulations . Consistulations . These sn = 108) of women with children in the current study were living in households experiencing food insecurity, of these 68% were low food security and 32% very low food security. An additional 17% (n = 72) of households with children were classified as experiencing marginal food insecurity. Concerningly the responses to the child experience questions of the USDA-HFSSM (n = 100) of socioeconomically disadvantaged families were experiencing low or very low food security [This is the first Australian study to explore the experience of food insecurity during the COVID-19 pandemic in households with children using the validated 18-item USDA-HFSSM that includes eight child focused questions. As described in previous studies, the food security status of adults in the households with children may be compromised in preference to that of the children, where possible adults employ child focused protective strategies. This may be in the form of a managed process attempting to shield children from the experience but also to conceal the parent’s own experience ,6,35,36.DA-HFSSM  indicatesecurity . This susecurity . In 2021security . Childresecurity . Childresecurity  and the security . While bsecurity . TherefoThe results of this study show that mental health, housing tenure, income level and change of employment status due to COVID-19 impacted food security. It has been well documented that financial stability, housing tenure and mental health and food security are interrelated factors. A recent US study showed that during the COVID-19 pandemic, having assets and a lack of financial stressors were important factors in maintaining good mental health . For exaInterestingly, despite the varied case numbers, lockdown and changes in employment as a result of pandemic restrictions, there were no differences in the prevalence of food insecurity between Australian states and territories. This could be because financial support provided by the Federal Government was available nationally. The Federal Government implemented a range of economic responses in an attempt to support and protect individuals’ and households’ income . These iA strength of this study is that it is one of the few studies to explore the impact of the COVID-19 pandemic on food insecurity in Australian households, with a specific focus on the experience of women and children. Furthermore, this national sample using the 18-item USDA-HFSSM has provided a more comprehensive insight beyond the current population one or two-item food security measure to the severity of the food insecurity experience, including perturbations to food intake and coping strategies. This tool also asks about the experience of other adults in the household. Importantly, the use of a more comprehensive tool containing the 8-item child focused experience questions has provided insight to the impacts of food insecurity for children. The USDA-HFSSM tool identifies the primary determinant of food insecurity, being limited financial resources. There are also some limitations to this study. This study was cross-sectional in design and the analyses are descriptive in nature and self reported. In addition to questions pertaining to food security this study was part of a wider study exploring the impacts of COVID-19 on women’s diet, mental health, and physical activity. Further, pre-COVID was not defined in the survey, this may have impacted on the reporting of pre-COVID variables. Due to the number of survey questions and the time to complete the survey, there was limited scope to explore reasons beyond the financial causes of food insecurity, such as food cost, food availability and physical access to food. These factors are particularly pertinent in regional and remote areas of Australia ;,and alsUsing a comprehensive and validated measure of food security, we demonstrated an increased prevalence of food insecurity during the COVID-19 pandemic in Australian women. This study identified that 20% of women were living in households experiencing food insecurity, which is considerably higher than pre-COVID-19 prevalence. Further, there were 13.7% households who were marginally food secure, who experienced high levels of worry and concern about running out of food. Food insecurity was experienced at all levels of pre-COVID-19 income levels. Mental health, housing status, income level and change of employment status due to COVID-19 were shown to be associated with food security status. This study has also highlighted the child experience of food insecurity within households during the pandemic. With ongoing restrictions and lockdowns, consideration needs to be given to the financial support provided to people and regions at risk of food insecurity. Food insecurity, poor mental health, inadequate income and lack of adequate housing existed before COVID-19. However, this study highlights the additional impact of COVID-19 restrictions on each of these factors, which has increased the prevalence of food insecurity and highlighted this as an issue previously hidden/underreported. The risk of COVID-19 lockdowns and the subsequent economic implications are not easing any time soon; if left ignored, food security status may continue to deteriorate. This study supports the need for a range of policy and programmatic responses that address mental health, financial, employment and housing support to mitigate the impacts of ongoing COVID-19 restrictions in Australia, particularly for women and children. As the pandemic continues, this study also provides a view of what to expect in the future regarding household food security status in regard to COVID-19.


Neuropathic pain (NP), often treatment-refractory, is one of the most debilitating conditions contributing to suffering and disability worldwide. Recently, non-invasive neuromodulation techniques, particularly repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have emerged as potential therapeutic alternatives due to their ability to alter cortical excitability of neural circuits. However, the magnetic field induced in rTMS may be unsafe for patients with an implanted electrode in the head or neck area while tDCS poses no theoretical risk of injury to these patients. High definition (HD)-tDCS is a novel, more focal technique of tDCS and may be safer to the patient compared to the more diffuse stimulation of conventional tDCS. To our knowledge, no study has ever demonstrated the safety and/or feasibility of HD-tDCS in patients with spinal cord stimulation (SCS) devices using computational modeling of induced electrical fields. Furthermore, this study highlights the potential use of (HD-)tDCS as predictive tool for a positive response in chronic epidural motor cortex stimulation (MCS), especially in patients with an implanted device not suitable for rTMS. In a 54-year-old woman with an implanted spinal cord stimulation (SCS) system for another pain syndrome, HD-tDCS was initiated for refractory post-surgical inferior alveolar nerve neuropathy. She was submitted to 7 days of anodal HD-tDCS over the left motor cortex at 1.5 mA for 30 min. A notable decrease in pain perception was observed, lasting for approximately 5–6 h (Numeric Rating Score decreased from 8 to 4.34). No adverse events were reported. The stimulation parameters and clinical efficacy of the SCS system remained unchanged. Additionally, computational analysis indicated no meaningful alteration of current flow when considering a model with a SCS implant with respect to a model without implant. Regarding the positive therapeutic effect of HD-tDCS, the patient was selected for an epidural MCS trial and subsequent implantation, which showed short-term pain relief of 50–75%. Although one case does not demonstrate efficacy, tolerability, or safety to the novel intervention, it paves the way for better diagnosis and treatment for patients who are otherwise excluded from other non-invasive neuromodulation techniques, such as rTMS. A positive tDCS effect could be a potential biomarker for positive epidural MCS response in patients with an implanted stimulation device non-compatible with rTMS. Neuropathic pain (NP) is one of the most debilitating conditions contributing to suffering and disability worldwide. Unfortunately, NP can be very treatment-refractory, with many patients continuing to report significant pain and repercussions on quality of life (QoL) despite the recommended multimodal pharmacological and non-pharmacological management, including physical therapy and cognitive behavioral therapy. In recent years, non-invasive brain stimulation techniques have emerged as potential therapeutic alternatives, next to invasive neuromodulation strategies such as epidural motor cortex stimulation (MCS) and deep brain stimulation (DBS). Indeed, two non-invasive methods have received increased interest, i.e., transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS). The magnetic field induced in rTMS may be unsafe for patients with an implanted electrode in the head or neck area while tDCS poses no theoretical risk of injury to these patients. Cortical modulation by tDCS may increase glutamine and glutamate under the stimulating electrode, have effects on the μ-opioid receptor, and restore impaired intracortical inhibition . The anaHigh definition (HD)-tDCS may be a safer therapeutic option compared to the more diffuse stimulation of conventional tDCS. HD-tDCS is a novel approach that uses arrays of smaller electrodes , 3 that Few studies have been published to date assessing its effects in a patient population with respect to pain –12. PatiMotor cortex stimulation (MCS) has been proposed as an invasive neuromodulation technique for chronic refractory NP since the early 1990s and with variable treatment results, for patients for whom no other treatment modality is available. In MCS, an epidurally placed electrode delivers a targeted current to the very closely located precentral primary motor cortex (M1). MCS literature suffers from low level of evidence due to small retrospective series, substantial inter-study heterogeneity and confounders, making correct interpretations difficult. A systematic review concluded it to be relatively safe and effective with a “good outcome” (≥40–50% pain improvement) in 56.7% of patients . A recenTo the best of our knowledge, HD-tDCS with superior focality, more comparable to epidural MCS, has never been applied in patients with cortical or cervical SCS implants. In order to evaluate the analgesic effects of HD-tDCS in a patient with neuropathic pain with a cervical epidural electrode, we submitted our patient to 7 days of active anodal HD-tDCS to determine if HD-tDCS (1) is a safe and effective therapeutic alternative for patients with a cervical electrode implant, capable of decreasing pain perception, and (2) may serve as a valid and reliable method to select eligible patients for epidural MCS who are otherwise excluded from other non-invasive brain stimulation techniques as a pre-operative tool.A 54-year-old woman presented with uncontrollable neuropathic pain in the lower right side of her face. Three years prior, she received an SCS system to treat CRPS, after sustaining a post-operative axillary nerve lesion. The tip of the electrode was positioned a C2 which resulted in a good pain reduction. Two months prior to HD-tDCS, she underwent apex resections of teeth 25 and 47, complicated by pain and wound infections. A computed tomography (CT) scan showed the remainder of the root of tooth 47 was in contact with the mandibular canal. After revision surgery, the pain remained unabated with a Visual Analog Score (VAS) score of 9.5. In addition, she experienced sleeping difficulties and weight loss. Her pain was triggered by chewing or changes in temperature. Clinical examination showed hypoesthesia and allodynia over the mandibular nerve region (V3), resulting from a post-surgical right inferior alveolar nerve injury. The DN4 (Douleur Neuropathique 4 Questions) questionnaire was 8, suggesting neuropathic pain diagnosis. Multiple trigger points over the right masseter muscle could elicit her typical pain pattern.She was treated at another hospital with pulsed radiofrequency to the right mandibular nerve without effect. Her medication included Paracetamol, Methadone, Clonazepam & Ketorolac. She was referred to our tertiary care center, University Hospitals Leuven, for further treatment.Our patient, RT, received 7 daily sessions on consecutive business days . We employed a 4x1 Multichannel Stimulation Adaptor  connected to a conventional 1 × 1 tDCS device  to deliver direct current to the scalp via HD electrodes. Electrodes were held in place by specially designed plastic casings embedded in a modular electroencephalography (EEG) recording cap. We positioned the center anodal electrode over C3 based on the International 10/20 EEG System  which coOutcome measures were: (1) Numeric Rating Scale (NRS) assessed daily, (2) the Short Form-36 Dutch version (SF-36), and (3) the MPQ-DLV Pain Questionnaire, the Dutch version of the McGill Pain Questionnaire (MPQ) , both asNRS is a single 11-point numeric score in which a patient rates their pain by selecting a whole number (0–10 integers) that best represents the intensity of their pain  was epidurally advanced over the precentral primary motor cortex (M1) and electrode leads were externalized. Electrode position was verified using intra-operative neuromonitoring techniques of somatosensory evoked potentials (SSEPs) with phase reversal and motor evoked potentials (MEPs) with cortical stimulation, the latter which halted contractions in the painful facial area. During the trial, pain scores (NRS) and quality of life measures were rated daily. After definite MCS implantation, follow up was organized four-weekly in the first 3 months, whereafter follow-up was extended to every 2–3 months in the first year. During clinical visits, NRS was recorded, potential side effects were monitored, and stimulation parameters were reprogrammed when needed.To investigate potential deviation (intensity or location of current flow) due to the implant, we considered a whole-body female model (“Ella”) from the Virtual Family dataset . We deveAfter an initial 3-day-trial-and-error period, our patient, RT, showed a gradual and progressive improvement on the NRS  and SF-3Similar to the tDCS results, the 4-week MCS trial halted an average pain relief of 50–75% (NRS). Therefore, a second procedure with internalization of the leads and IPG placement was performed 1 week after the trial. The beneficial effect of MCS, however, lasted only 3 months. Despite extensive follow up with multiple reprogramming efforts, which only resulted once in intermittent, non-lasting pain relief at 11 months postoperatively (NRS 4) , no effect of MCS persisted after 1 year (NRS 8). There were no adverse effects of MCS. The computational model simulating transcranial application is an implant indicated a difference of 1.1% in the maximum EF with respect to the without implant case . There wFor RT received 7 daily sessions on consecutive business days. Evidently, we cannot eliminate a placebo effect or the possibility that our patient experienced a significant decrease in pain perception unrelated to HD-tDCS. However, it seems highly unlikely that uncontrollable facial neuropathic pain felt on the lower right side of her face, with a NRS score of 8 pre-intervention, decreased spontaneously and gradually to a 4.34 in the period of maximal effect . Additionally, she notably improved on the SF-36 . The overall QoL subscale of the MPQ-DLV (from a 25 to 19) also showed some improvement while the NWC-T and PRI-T showed no difference between pre and pre and post intervention. A site-specific effect in sensory and pain threshold modulation was observed following an increase in the excitability of M1/primay sensory (S1) in healthy individuals and M1/dorsolateral prefrontal cortex (DLPFC) in patients with chronic pain . StimulaStudies in the literature that employed non-invasive neuromodulation in chronic pain patients with a permanent implanted electrode with the more focal and novel method of HD-tDCS are non-existent. Only one recent case report demonstrated that applying conventional anodal tDCS at 2 mA for 25 min over right primary motor cortex (C4) in a patient with left lower limb CRPS and implanted SCS device was feasible and safe . HoweverOur patient's steady and progressive improvement over the course of treatment implicates that with each additional treatment session, the gradual neuromodulatory effects generated by tDCS may have resulted in an additive, incremental functional brain reorganization in the motor cortex . The neuIn contrast to the case report by Houde et al. , our patOur study did not evaluate the therapeutic effects of HD-tDCS on M1 modulation beyond 6 h. Further studies are required to improve our understanding of the acute effects of HD-tDCS and the effects over time by systematically studying number of sessions, time, current intensity, and electrode size. Further, systematically searching for predictors/biomarkers  and optimal state/conditions  associated with tDCS remains crucial. Furthermore, future studies should compare the effect of tDCS over different areas of stimulation  while selecting different pain outcome measures as to better understand the responses following conventional tDCS or HD-tDCS. Finally, since pain studies predominantly use subjective outcome measures, it is paramount to include a sham condition in clinical studies and settings to warrant complete blinding.This case study highlights the potential use of non-invasive HD-tDCS as preoperative predictive tool for invasive MCS therapy, especially in patients with an implanted device. Indeed, the beneficial effect of HD-tDCS was reproduced in the epidural MCS trial with 50–75% pain relief. However, the patient showed no long-term response despite multiple reprogramming efforts , for reasons that remain elusive. The short-term MCS effect in this case cannot be seen as the “insertional effect” as reported in Hamani et al., since stimulation was immediately started postoperatively. Another non-invasive strategy, rTMS, has already been associated with positive MCS effect in some series and could serve as a potential biomarker , 19. FutOur case report demonstrates the safety and short-term efficacy of HD-tDCS treatment in a patient with an implanted SCS system. TMS, usually the preferred method of non-invasive neuromodulation , 44, 47,In conclusion, our findings, together with the similar case report using conventional tDCS in a patient with an implanted SCS device, confirms the need for sham-controlled clinical trials of (HD)-tDCS as a potential pre-operative therapeutic tool in patients with permanent electrode implants in the head area who are candidates for surgically implanted chronic epidural MCS. In addition, determining the ideal dose, duration, sessions, and maintenance protocol of tDCS remains crucial in optimizing tDCS efficacy to reduce pain intensity and maximize the QoL of patients with chronic neuropathic pain. Future studies are needed to determine if HD-tDCS could serve as an add-on treatment or biomarker to select eligible patients for MCS.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.CD wrote the manuscript, treated RT using HD-tDCS, and evaluated the acute effect of HD-tDCS. SS was responsible for the MCS data and manuscript writing and revision. BM and TT interpreted the data and revised the manuscript for intellectual content. AD and CT performed the modeling and simulation analysis. All authors participated in editing.AD and CT were employed by Soterix Medical Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Radical treatment of localized prostate cancer in elderly patients may lead to unacceptable treatment-associated toxicities that adversely impact quality of life without improving survival outcomes. This study reports on a cohort of 54 elderly (>70 years) patients that received 4000–5000 cGy of palliative external beam radiotherapy (EBRT) as an alternative to androgen deprivation therapy (ADT). The primary outcome of interest was the period of ADT-free survival, and secondary outcomes included overall survival (OS) and metastases-free survival (MFS). Kaplan–Meier regression was used to estimate survival outcomes. Thirty-six (67%) patients achieved a break in ADT post-radiotherapy, with a median time to ADT reinitiation of 20 months. Common Terminology Criteria for Adverse Events (CTCAE) were limited to low-grade gastrointestinal (GI) or genitourinary (GU) toxicities, with no skin toxicities observed. Grade 1 GI toxicity was observed in 9 (17%) patients, and grades 1 and 2 GU toxicities were observed in 13 (24%) and 3 (6%) patients, respectively, with no higher-grade toxicities reported. Five-year MFS and OS were 56% and 78%, respectively. In summary, the treatment regimen was well-tolerated and achieved durable ADT-free survival in most patients. Dose-reduced EBRT appears to be a viable alternative to ADT in elderly patients with localized prostate cancer. Prostate cancer is among the most common malignant neoplasms and causes of cancer death in North America ,2,3. ProA common clinical scenario encountered by oncologists is a new diagnosis of prostate cancer within an elderly patient (>70 years old). These patients often present with locally advanced disease which leads to increased risk of adverse outcomes including urinary incontinence, renal failure or obstructive symptoms ,6,7,8. OIn contrast to dose-escalated curative-intent therapy , radiotherapy with doses of up to 5000 cGy to the pelvis is generally well-tolerated, making it a feasible alternative in elderly patients with prostate cancer . At the After institutional ethics approval, the AriaRO Unified Reporting Application interface  was used to identify 90 patients with birthdate(s) on or before 1 September 1948 who received radiotherapy treatment(s) with doses between 4000 and 5000 cGy to the prostate between 1 January 2004 and 31 December 2018. Exclusion criteria included patients who had prior radical therapy for prostate cancer, concurrent diagnoses of rectal, bladder, and/or renal cell carcinoma, de novo metastatic prostate cancer diagnosis, prior radiotherapy to the pelvis for any reason or having received EBRT to both the prostate and pelvic lymphatics . A retroWith regard to practices surrounding management recommendations, the institutional practice over the study period was to recommend ADT for elderly patients with new diagnoses of prostate cancer. However, at the radiation oncologist’s discretion, a variation in practice to offer dose-reduced localized EBRT to the prostate was accepted as an option. Neither brachytherapy nor radical prostatectomy was routinely considered a recommended management option for these patients over the study period. When dose-reduced radiotherapy was offered, treatments were typically inverse planned using static field sliding window intensity modulated radiotherapy (IMRT) or volumetric modulated radiotherapy (VMAT). Organ at risk dose constraints were not standardized institutionally for these dose-reduced treatments and were provided by the individual radiation oncologist on a patient-specific basis. In general, constraints achieved were more conservative than those of published hypofractionation trials ,17. At tIn cases where dose-reduced radiotherapy was offered, the treatment intent was to either avoid initiating, discontinue, or provide a break in ADT treatment. The rationale for this was typically to avoid or provide respite in side effects. In such cases, follow-up was routinely lifelong in 3–6-month intervals with the primary radiation oncologist and/or medical oncologist treating the patient. At each follow-up visit, PSA, American urological association (AUA) symptom assessments and toxicity were evaluated.The radiotherapy data for all patients included in this study was extracted directly using the AriaRO Unified reporting application interface. Specifically, dose-volume-histogram values for the body, rectum, bladder and planning-target-volume (PTV) were exported and amalgamated into a single database. Treatment start and end dates, doses and fractionations were all available in this record. For retrospective chart reviews, the patient’s electronic medical record and the jurisdictional electronic health record were reviewed for all patients included in the study. Systematically structured pathology reports, as dictated by dedicated genitourinary pathologists were used to extract all pathological information. All CT reports, bone scan reports, and consultation notes were reviewed for clinical staging information. PSA values were reviewed to determine the pre-treatment PSA, the PSA nadir, the first post-RT PSA >0.5 ng/mL, the first post-RT PSA >10.0 ng/mL, and the corresponding measurement dates. In addition, the start and end dates of all hormone administration(s) were collected . Finally, for survival and toxicity outcomes, the electronic medical and electronic health records were reviewed. Charts were reviewed for radiographic confirmation of systematic spread of disease, follow-up notes , AUA symptom assessments, death, or any presentation to any acute care facility (researchers focused on presentation for possible radiotherapy toxicity). All potential toxicities were reviewed at the time of follow-up by the attending radiation oncologist to determine if it was related to radiotherapy. If a comment on whether the toxicity was attributable to radiotherapy was not found in the follow-up note, an independent radiation oncologist reviewed the event and determined causation. If causation could not be determined confidently, it was assumed as due to radiotherapy.The primary study outcome was the rate and duration of ADT free period following radiotherapy. Secondary outcomes included the rates of common terminology criteria for adverse events reporting (CTCAE) version 5.0 grade 3 genitourinary (GU) and gastrointestinal (GI) toxicity, PSA response to treatment, and metastasis-free and overall survival . www.r-project.org).Descriptive statistics were used to characterize the cohort. For continuous variables median (interquartile range) and for categorical variables numbers (%) were used for description purposes. PSA nadirs were calculated as the lowest PSA taken at least 6 months post-radiotherapy in patients on continuous ADT and at least 6 months after completion of ADT  in patients who did not receive continuous androgen blockade. For estimations of survival outcomes, the Kaplan–Meier method was used. Metastasis-free-survival was calculated as from the time of diagnosis to the time to radiographic evidence of metastatic disease or death and censured to last follow-up. Overall survival was calculated as time to death and censured to last follow-up. All analyses were performed using the R programming language version 4.3.1 (Fifty-four patients meeting the inclusion criteria for the study were identified. No patients were lost to follow-up. Baseline patient demographics are summarized in Radiotherapy treatment parameters are reported in No (0%) patient received systemic therapy other than leuprolide and/or bicalutamide prior to radiotherapy. Fifty-two (96%) patients had ADT for at least one time point before, during or immediately following their radiotherapy with a median duration of ADT of 24 (12–34) months. Fifty patients (93%) received ADT prior to radiotherapy for a median of 8 (5–17) months. Of these, three patients were on a break from ADT at the time of RT. Times from the end of their last ADT to radiotherapy were 10, 15, and 36 months. The patient receiving a 36-month break received 1 year of ADT adjuvantly with their radiotherapy. The patient receiving a 10-month break required no further ADT.Sixteen (30%) patients received continuous ADT surrounding their radiotherapy. In the 36  patients who did not receive continuous ADT, median duration of combined neoadjuvant and adjuvant ADT was 18 (10–25) months. Overall, 5 of 38 (13%) patients restarted or started ADT after having received radiotherapy. Median time to re-initiation of ADT was 20 (13–23) months. Ten (19%) patients received only neoadjuvant ADT. Of these 10, 3 (30%) patients restarted ADT within the study period. Time to restarting ADT was 13, 23, and 83 months from the end of adjuvant radiotherapy in these patients. One patient (2%) received 33 months of neoadjuvant/adjuvant ADT and then restarted ADT 20 months later. No other patient receiving neoadjuvant/adjuvant ADT re-initiated ADT.Prior to radiotherapy, median AUA symptom score across the patient cohort was 7 (3–16). Pre-radiotherapy trans-urethral resection of the prostate (TURP) was performed on 19 (35%) of patients. In total, 14 (26%) patients were on tamsulosin; three (6%) of which were also on dutasteride prior to radiotherapy.After completion of radiotherapy, median AUA symptom score was 9 (4–15). Seventeen (32%) patients used tamsulosin post-radiotherapy. Post-radiotherapy CTCAE toxicity scores are depicted in PSA response after radiotherapy is summarized in Twenty-nine (54%) patients either had a post-radiotherapy PSA never decrease below or had subsequent post-radiotherapy PSAs rise to above 0.5 ng/mL. Within this group, median time to PSA > 0.5 ng/mL was 15 (2–24) months from completion of radiotherapy. Fourteen (26%) patients had a post-radiotherapy PSA rise above 10.0 ng/mL. Within this group, median time to PSA > 10 was 12 (1–17) months from completion of radiotherapy.A total of 13 (24%) patients developed metastatic disease. Kaplan–Meier estimated 5-year metastasis-free survival (MFS) was 56% (41–76) as shown in This study is the first report on the use of dose-reduced radiotherapy in elderly patients with prostate cancer. Outcomes were well annotated and without loss to follow-up. Overall, dose-reduced radiotherapy of 4000–5000 cGy to the prostate was well-tolerated. In total, 67% of patients who were on ADT had a treatment break after radiotherapy with a typical duration of 1.5 years.The treatment of elderly patients with prostate cancer poses unique clinical challenges. Within this demographic, patients are more likely to have co-morbidities that decrease anticipated survival. For low-risk disease, the most common management strategy is watchful waiting ,20,21. TThis finding is important as androgen deprivation therapies have been associated with cardiac mortality ,24,25. IWithin this study the use of radiotherapy resulted in no grade 3 or higher CTCAE toxicity in skin, GI, or GU domains. This result is corroborated by emergency room presentations related to GI or GU concerns, with no further need for surgical intervention  and limited need for procedural intervention . There was a slight increase in AUA symptom score reporting, as well as use of alpha-agonists post-radiotherapy. However, these differences are unlikely to be clinically significant. Furthermore, without radiotherapy, worsening urinary dysfunction and need for medical or procedural intervention is likely inevitable with local progression. The results of this study should be interpreted with caution as there are several limitations to it beyond its retrospective nature and the likelihood of inherent bias by design. The variability in tumor characteristics and PSA at the time of diagnosis meant there was variability in duration of ADT. Otherwise, this study is at high risk of selection bias for both the decision to initiate radiotherapy treatment and for the dose selected. Although the PSA kinetics post-radiotherapy suggest good efficacy of treatment, there was no firm criteria oncologists standardly followed for re-initiating ADT post-treatment or restaging patients. Given this, it is possible that the time to re-initiation of ADT or metastatic disease may be different than the experiences of other physicians should they adopt this protocol. Finally, this study only analyzed outcomes as related to external beam radiotherapy in elderly patients. Other treatment modalities with known low toxicity rates such as brachytherapy might be a preferred approach. This could be explored in future prospective studies.Despite these limitations to the present study, the administration of dose-reduced local radiotherapy to the prostate may allow select elderly patients breaks in ADT use with delays to re-initiation or perhaps avoidance of ADT completely. It appears to be a safe, non-invasive option that can be considered by treating oncologists.


Then, traumatic brain injury (TBI) incidence is high in these sports. Ischemia-modified albumin (IMA), brain natriuretic peptide (BNP) and copeptin have diagnostic and prognostic value for cardiac and non-cardiac ischemic events. The purpose of this study is to evaluate exercise-induced variations of serum IMA, BNP and copeptin.twenty male boxers, twenty-three male kick boxers and twenty-three age-matched male were enrolled in the study. Health assessment data were analysed. Boxers and kick boxers underwent an exercise program including training plus fighting matches. Serum samples were collected in the pre- and post-exercise periods. Serum IMA, BNP and copeptin concentrations were measured in these specimens using ELISA reagents.comparative analysis of analytes before and after exercise showed that exercise significantly increased serum IMA, BNP and copeptin levels both in boxers and kick boxers.in conclusion, IMA, BNP and copeptin levels may be candidate biomarkers for exercise-related traumatic brain injuries. The identification of new biomarkers in patients with acute and chronic neurological disorders is of considerable interest to clinicians. Then, further studies should be conducted to evaluate the possible role of IMA, BNP and copeptin in TBI pathophysiology. There has been a growing interest in boxing, kick boxing and other martial arts due to the benefits of personal protection and keeping the body fit. Since boxing and kick boxing are combat sports, they are closely associated with health risks. Hitherto, various studies have been conducted to investigate traumatic effects of high-intensity exercise on some laboratory parameters including enzymes, lipids, some injury biomarkers, hormones, and others -5.Traumatic brain injury can be defined as a concussion, impact or penetrating head injury that causes normal brain functions to deteriorate . ProfessA review of the available records indicates that there have been a substantial number of fatalities in boxers due to intracranial injuries sustained in the ring in comparison to the numbers engaged at both amateur and professional levels . The spoFew studies investigating the diagnostic role of IMA in non-cardiac ischemic states have suggested that elevated IMA levels may be considered as a sensitive biomarker of ischemic stroke . Brain nStudy design and settings: the research group was composed of 20 volunteer boxers from Atatürk University Kazim Karabekir Faculty of Education Department of Physical Education and Sports, 23 volunteer elite athletes  from Erzurum Pasinler Municipality Kickboxing sports club, and 23 volunteer participants who are healthy and have no sports background. The collected samples were studied in the Medical Biochemistry Department of Erzurum Atatürk University Medical Faculty Hospital in March 2014.Study population: twenty healthy professional boxers , 23 healthy professional kick-boxers  and 23 healthy controls  were included in the study. All participants were Caucasian. Individual information forms about sports and medical history of participants were fulfilled by an expert physician. The participants had no chronic disease and were not taking any medications. All sportsmen were regularly-training ones for at least three years at a frequency of at least three days per week. Boxers, kick-boxers and healthy control groups were consisted of participants with similar demographical characters, showing homogenous groups  according to the manufacturer´s instructions. Adrenocorticotropic hormone (ACTH) and cortisol were analyzed by chemiluminescence method in Siemens Immulite 2000 analyzer and Beckman Coulter DXI800 analyzer, respectively. Serum creatinine measurements were performed by kinetic modification of the Jaffe procedure on Beckman Coulter AU5800 . To evaluate the kidney functions of sportsmen, estimated glomerular filtration rates (EGFR) were calculated using the formula described by Levey et al. [y et al. .Statistical analysis: data were analyzed using the SPSS statistical software package . All results were expressed as mean ± standard deviation. Normality of biochemical parameters was analyzed by Kolmogorov-Smirnov test. Kolmogorov-Smirnov test was used to reveal whether the data were suitable for normal distribution. Analyze - Nonparametric Tests - 1-Sample K-S process was followed, the variables to be tested for normality were transferred to the “Test Variable List” cell in the opened window, and the “Output” file created was evaluated for the details of the analysis. Since all parameters were normally distributed the Student´s t test and paired samples t-tests were used to evaluate the significance of differences between groups . Pearson correlation analysis were used. P values less than 0.05 were considered significant, at 95% confidence interval. Post-exercise values were adjusted due to do decrement in the plasma volume using a formula suggested by Dill and Costill [ Costill .Ethical statement: the study protocol was reviewed and approved by an institutional ethical board (26.12.2013/6). Informed consent was obtained from each participant and patient anonymity was preserved. Study protocol was in accordance with the Helsinki Declaration of 1975, as revised in 1983.Demographical data of sportsmen are given in Body weights of boxers significantly decreased from 69.82 ± 9.39 kg to 69.25 ± 9.48 kg and BMI values significantly decreased from 22.52 ± 2.12 to 22.33 ± 2.16 by exercise (p<0.001 for both parameters). These changes accounted for approximately 1% decrement in plasma volumes of boxers. Similarly, body weights of kick-boxers significantly decreased from 65.20 ± 10.41 kg to 62.08 ± 16.87 kg and BMI values significantly decreased from 22.11 ± 3.04 to 22.01 ± 3.05 by exercise (p<0.001 for both parameters). These changes accounted for approximately 6% decrement in plasma volumes of kick-boxers.Statistical evaluations of the biochemical analytes are given in There were significant differences between pre- and post-exercise levels of IMA, BNP, copeptin and ACTH both in boxers and kick-boxers . The study was presented as a poster (Published as Poster Abstracts) at the 21There are a few studies investigating the variations of IMA, BNP and copeptin after exercise , 19. In Our results showed that there were significant differences between pre- and post-exercise levels of IMA, BNP, copeptin and ACTH both in boxers and kick-boxers. In order to prevent the confounding effects of the decline in the plasma volume caused by weight loss, we performed an adjustment suggested by Dill and Costill . When weBased on these results, we can conclude that although copeptin is reported to be altered in response to stress , the altIMA is a structurally different form of albumin and is produced by reactive oxygen species during ischemia. IMA has been referred to as a sensitive biomarker of myocardial ischemia , 24. FurNatriuretic peptides, on the other hands, are a group of hormones with vasodilator and antiproliferative properties, which are produced against the vasoconstrictor effects of neurohormones released from sympathetic nerve system and renin-angiotensin aldosteron system. These peptides are produced in order to make natriuresis and diuresis via the increase in intracellular cGMP levels, and it is well known that the plasma natriuretic peptides rise in the hearth failure . ConsequBased on the usage of brain-type natriuretic peptide (BNP) in estimating stretch-activated heart failure, the diagnostic value of BNP in other stretch-activated conditions, such as head injury, is investigated , 30. In Copeptin, another parameter in this study, is the C-terminal part of arginine vasopressin precursor peptide (pro-AVP) and is a specific indicator of arginine vasopressin (AVP) release. The triggered co-release of AVP and copeptin in response to a stress stimulant from posterior pituitary results in ACTH and cortisol release . Since aCortisol have a tendency to increase as stress factor within 30-60 minutes following exercise . In our In conclusion, although sports is globally accepted as having numerous benefits to the body, it should be noted that it may not always be safe, especially in branches including exhaustive exercise and trauma. To the best of our knowledge, this is the first study underlining the possible importance of BNP, IMA and copeptin in boxers and kick boxers exposed to TBI. Since boxers and kick-boxers are highly exposed to acute and chronic brain injury, further studies to be conducted on this population including using of neuroimaging techniques may be helpful in identifying and clinical usage of new biomarkers for acute and chronic traumatic brain injury. Our results were in accordance with previous studies, showing altered levels of BNP, copeptin, ischemia modified albumin and ACTH after exercise in sportsmen exposed to head trauma. We suggest that sportsmen under high risk of head trauma be subjected to regular health controls including evaluation of BNP, IMA and copeptin, candidate biomarkers of traumatic brain injury.Since boxing and kick-boxing are combat sports, serious injuries may occur to the head, neck, face and hands during fighting, and traumatic brain injury (TBI) incidence is high in these sports;Ischemia-modified albumin (IMA), brain-type natriuretic peptide (BNP) and copeptin have diagnostic and prognostic value in cardiac and non-cardiac ischemic events.The comparative analysis of analytes before and after exercise showed that the exercise causes significant increase in serum IMA, BNP and copeptin levels both in boxers and kick-boxers;IMA, BNP and copeptin levels may be candidate biomarkers of exercise-related traumatic brain injury.