Clear cell sarcoma of the pancreas, an unusual cancer with unusual metastatic site or unusual primary site?

Clear cell sarcoma (CCS) is a type of malignant tumor that can arise from tendons and aponeuroses. This malignant proliferation of cells with melanocytic lineage normally occurs in young patients, and it is normally identified in extremities. However, different sites including gastrointestinal organs are also described. Due difficulties in the molecular and histopathology evaluation, the diagnosis is often confused with malignant melanoma. Most cases are treated with surgical resection, but overall, the prognosis is poor. In this editorial, we will discuss a very interesting case of CCS identified in the pancreas. We will discuss the literature and controversies in the management of this type of cancer. Furthermore, we will address molecular strategies to be incorporated in those cases to better understand the primary location of the tumor. Finally, future perspectives of the field and new strategies of treatment will be described.

Concomitant or antecedent intraductal papillary mucinous neoplasm is not a prognostic factor in resected pancreatic cancer.

Background: Intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic cancer is becoming a common subtype of pancreatic cancer found in resected specimens. The prognostic of this subtype is still under evaluation. The study aims to evaluate the prognosis of IPMN-associated pancreatic adenocarcinoma compared to the conventional pancreatic adenocarcinoma. Methods: In this study, patients with resected pancreatic neoplasms and IPMN treated at Hospital Israelita Albert Einstein, from January 2016 to December 2020, were analyzed. Overall survival (OS) was estimated using the Kaplan-Meier method, and correlations between the variables of interest and the disease specific OS was assessed by multivariate analysis. Results: Of 187 patients undergoing resection for pancreatic adenocarcinoma or IPMN, 125 (67%) had pancreatic adenocarcinoma, 33 (18%) had IPMN-associated pancreatic adenocarcinoma, and 29 (16%) had IPMN. Resected IPMN was associated with long-term OS for most of the patients. Similar OS was identified in this study in upfront resected pancreatic cancer associated or not with IPMN. No statistical differences in median OS were identified between resected pancreatic adenocarcinoma and IPMN-associated pancreatic adenocarcinoma (48 vs. 44 months, P=0.44). Size of the tumor [hazard ratio (HR), 1.33], resected stage III (HR, 1.31), perineural invasion (HR, 1.58), lymphovascular invasion (HR, 1.44), positive lymph nodes (HR, 1.34), and neoadjuvant treatment (HR, 1.70) were associated with worse outcomes. Conclusions: Our findings confirm that resected pancreatic cancer has a poor prognosis and IPMN-associated pancreatic adenocarcinoma has the same prognosis as a conventional pancreatic adenocarcinoma. More than half of the cases of IPMN-associated adenocarcinoma already had positive lymph nodes. The impact of neoadjuvant treatment in this group of patients should be investigated in larger cohorts.

Frequency of Deleterious Germline Variants in HER2-Low Breast Cancer Patients Using a Hereditary Multipanel Gene Testing.

HER2-Low is defined as low levels of HER2 expression, based on a score of 1+ on immunohistochemical (IHC) assay or as an IHC score of 2+ and negative results on in situ hybridization (ISH or FISH). They are a heterogeneous population of breast cancers that vary in prognosis and sensitivity to systemic treatments. The frequency and clinical characteristics of pathogenic germline variants (PGVs) in HER2-Low breast cancer (BC) patients is not defined. We analyzed results from patients with BC who underwent multi-gene panel testing (MGPT) (maximum 145 genes) between 2018-2019. We reclassified HER-2 status accordingly. Relationships between the variables of interest were assessed by adopting the proportional regression Cox models. Of a total of 167 BC patients who underwent MGPT, half were hormone-receptor-positive. The median age was 45 years. About two thirds of the patients were in the earlier stage of BC. A total of 57% of the cases were reclassified as HER-2-negative or -Low. PGVs were found in 19% of the patients overall, as follows: seven BRCA1, four BRCA2, two ATM, one ATR, two CFTR, three CHEK2, one FANCA, one MERTK, one MLH1, three MUTYH, one RAD50, three RAD51C, one RECQL4, and two TP53 mutations. In HER2-Low, 26.5% of the patients had PGVs, and in the overall cohort, this was 19.8%. In conclusion, differences in the prevalence of deleterious germline mutations in HER2-Low BC patients compared to non-HER2-Low BC patients were identified. Similar alterations in BRCA were observed in this group of patients compared to the overall cohort. Germline genetic tests should be evaluated in larger cohorts of patients with HER2-Low status to better address the findings.

Disparities in esophageal cancer care: a population-based study.

BACKGROUND: Vulnerable populations potentially have a worse prognosis for cancer. The present study aimed to identify individual and municipal characteristics of access to health, including education, use of health insurance, gross domestic product per capita (GDPpc), and urban aspects, which could impact the prognosis of patients with esophageal cancer. METHODS: Data on urban concentration, administrative hierarchy, GDPpc, individual patient characteristics, and access to healthcare were collected from national and state public databases spanning between 2013 and 2022. The study included cities in the state of Sao Paulo, Brazil. Independent variables such as GDPpc, urban concentration, municipal administrative hierarchy, health insurance status, education level, and individual cancer and patient characteristics were evaluated against the outcomes of overall survival (OS), likelihood of undergoing surgical treatment, and time-to-treatment initiation. RESULTS: A total of 9280 patients with esophageal cancer (85% squamous cell carcinoma and 15% adenocarcinoma) treated in 42 cities were included in the study. In univariate analysis, higher education (hazard ratio [HR] = 0.6; P < .001), female gender (HR = 0.85; P < .001), and having private health insurance (HR = 0.65; P < .001) were identified as protective factors for OS in esophageal cancer. After adjusting for other variables in multivariate analysis, higher education (HR = 0.77; P = .009), female gender (HR = 0.82; P < .001), and private insurance (HR = 0.65; P < .001) remained protective factors. GDPpc was not associated with OS. Urban concentration and hierarchy influenced the likelihood of receiving surgical treatment. Patients from high urban concentrations had shorter time-to-treatment initiation intervals. CONCLUSION: Populations at risk, particularly those with limited access to education and healthcare, face a worse prognosis for esophageal cancer.

Prognostic value of programmed cell death ligand 1 (PD-L1) expression in patients with stage III non-small cell lung cancer under different treatment types: a retrospective study.

OBJECTIVE: Currently programmed cell death protein 1 (PD-1) inhibitors in combination with other therapies are being evaluated to determine their efficacy in cancer treatment. However, the effect of PD-ligand (L) 1 expression on disease outcomes in stage III (EC III) non-small cell lung cancer is not completely understood. Therefore, this study aimed to assess the influence of PD-L1 expression on the outcomes of EC III non-small cell lung cancer. METHODS: This study was conducted on patients diagnosed with EC III non-small cell lung cancer who underwent treatment at a tertiary care hospital. PD-L1 expression was determined using immunohistochemical staining, all patients expressed PD-L1. Survival was estimated using the Kaplan-Meier method. Relationships between variables were assessed using Cox proportional regression models. RESULTS: A total of 49 patients (median age=69 years) with EC III non-small cell lung cancer and PD-L1 expression were evaluated. More than half of the patients were men, and most were regular smokers. The patients were treated with neoadjuvant chemotherapy, surgery, or sequential or combined chemotherapy and radiotherapy. The median progression-free survival of the entire cohort was 14.2 months, and the median overall survival was 20 months. There was no significant association between PD-L1 expression and disease progression, clinical characteristics, or overall survival. CONCLUSIONS: PD-L1 expression was not correlated with EC III non-small cell lung cancer outcomes. Whether these findings differ from the association with immune checkpoint inhibitors remains to be addressed in future studies.

Act Local, Think Global: IR and Its Role in Immuno-Oncology in Hepatocellular Carcinoma.

Interventional oncology (IO) is evolving rapidly. The treatment landscape of liver cancer is changing rapidly, and immunotherapy combinations have become the standard of care for most patients with advanced hepatocellular carcinoma (HCC). The higher response rates and improved outcomes observed with these agents are leading to initiatives for their earlier incorporation in the course of the disease, including in combination with ablative and transarterial treatment options. The intersectionality of systemic therapies and liver-directed approaches has allowed IO to be at the center stage of a rapidly evolving dynamic field across all stages of HCC. This review article will address the current state of treatment for advanced HCC and the incorporation of these options in both localized and advanced stages along with IO to further enhance the observed benefits.

An overview of up-and-coming immune checkpoint inhibitors for pancreatic cancer.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1/PD-L1) pathway as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have demonstrated substantial potential in several malignancies. Pancreatic adenocarcinoma (PC) still carries a high mortality despite tremendous advances in the anti-cancer arsenal. AREAS COVERED: In this review, we discuss completed and ongoing studies on various ICIs in PC. ICIs have not yielded significant benefits as monotherapy. However, the combination with currently utilized therapies as well as with several other newer forms of therapy has delineated encouraging results. Larger trials are currently underway to definitively characterize the utility of ICIs in the treatment algorithm of PC. ICIs are approved for cancers with mismatch repair deficiency (dMMR) or microsatellite instability-high tumors (MSI-H) as a tumor-agnostic treatment strategy usually referred to as hot tumors. EXPERT OPINION: Studies evaluating different drugs to transform the tumor microenvironment (TME) from 'cold' to 'hot' have not shown promise in PC. There still needs to be more prospective trials evaluating the efficacy of the combination of ICIs with different therapeutic modalities in PC that can augment the immunogenic potential of those 'cold' tumors. Exploratory biomarker analysis may help us identify those subsets of PC patients who may particularly benefit from ICIs.

Prognostic value of programmed cell death ligand 1 (PD-L1) expression in patients with stage III non-small cell lung cancer under different treatment types: a retrospective study

ABSTRACT Objective Currently programmed cell death protein 1 (PD-1) inhibitors in combination with other therapies are being evaluated to determine their efficacy in cancer treatment. However, the effect of PD-ligand (L) 1 expression on disease outcomes in stage III (EC III) non-small cell lung cancer is not completely understood. Therefore, this study aimed to assess the influence of PD-L1 expression on the outcomes of EC III non-small cell lung cancer. Methods This study was conducted on patients diagnosed with EC III non-small cell lung cancer who underwent treatment at a tertiary care hospital. PD-L1 expression was determined using immunohistochemical staining, all patients expressed PD-L1. Survival was estimated using the Kaplan-Meier method. Relationships between variables were assessed using Cox proportional regression models. Results A total of 49 patients (median age=69 years) with EC III non-small cell lung cancer and PD-L1 expression were evaluated. More than half of the patients were men, and most were regular smokers. The patients were treated with neoadjuvant chemotherapy, surgery, or sequential or combined chemotherapy and radiotherapy. The median progression-free survival of the entire cohort was 14.2 months, and the median overall survival was 20 months. There was no significant association between PD-L1 expression and disease progression, clinical characteristics, or overall survival. Conclusions PD-L1 expression was not correlated with EC III non-small cell lung cancer outcomes. Whether these findings differ from the association with immune checkpoint inhibitors remains to be addressed in future studies.

Clinical Utility of Ivosidenib in the Treatment of IDH1-Mutant Cholangiocarcinoma: Evidence To Date.

Ivosidenib is an isocitrate dehydrogenase 1 (IDH1) inhibitor that is FDA approved for patients with IDH1 mutation and acute myeloid leukemia and previously treated locally advanced or metastatic cholangiocarcinoma. In the Phase III trial ClarIDHy ivosidenib improved progression-free survival, 2.7 months versus 1.4 months (p < 0.0001) and overall survival (OS), median OS was 10.8 months for ivosidenib and 9.7 months for the placebo arm (p = 0.06) for patients with previously treated and IDH1 mutated cholangiocarcinoma. In this review article, we will address the mechanism of action of ivosidenib and data from early trials and safety from the randomized trial in cholangiocarcinoma. As a conclusion, future perspectives of IDH1 inhibition in IDH1 mutated tumors and possible strategies of sequencing and combinations will be reviewed and discussed.

Targeting Fibroblast Growth Factor Receptor Pathway: Precision Medicine for Biliary Cancer and Beyond.

Fibroblast growth factor receptor 2 (FGFR2) inhibitors are now being included in the treatment guidelines of multiple countries for patients with advanced cholangiocarcinoma (CCA). Activation of the FGF-FGFR pathway is related to proliferation and tumor progression. Targeting the FGF-FGFR pathway is effective and can yield durable responses in patients with CCA harboring FGFR2 fusions or rearrangements. In this review article, we address molecules and clinical trials evaluating FGFR inhibitors in advanced CCA. We will further discuss identified mechanisms of resistance and the strategies to overcome it. The incorporation of next-generation sequencing in advanced CCA and circulating tumor DNA on disease progression will unveil mechanisms of resistance and improve the development of future clinical trials and more selective drugs and combinations.

Response to Abemaciclib and Immunotherapy Rechallenge with Nivolumab and Ipilimumab in a Heavily Pretreated TMB-H Metastatic Squamous Cell Lung Cancer with CDKN2A Mutation, PIK3CA Amplification and TPS 80%: A Case Report.

Inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene is considerably more frequent in squamous cell lung cancer (SqCLC) than in other subtypes of lung cancer and may be a promising target for this histology. Here, we present the course of diagnosis and treatment of a patient with advanced SqCLC, harboring not only CDKN2A mutation but also PIK3CA amplification, Tumor Mutational Burden-High (>10 mutations/megabase), and a Tumor Proportion Score of 80%. After disease progression on multiple lines of chemotherapy and immunotherapy, he responded favorably to treatment with the CDK4/6i Abemaciclib and later achieved a durable partial response to immunotherapy rechallenge with a combination of anti-PD-1 and anti-CTLA-4, nivolumab, and ipilimumab.

Novel precision therapies for cholangiocarcinoma: an overview of clinical trials.

INTRODUCTION: The treatment landscape of biliary cancers is rapidly changing. Inhibitors against the actionable targets FGFR and IDH1 are now being included in the treatment guidelines of multiple countries for patients with advanced cholangiocarcinoma. However, there remains an unmet need in identifying the mechanisms of resistance and treatment strategies involving possible tumor sequencing. AREAS COVERED: In this review article, we address clinical trials evaluating FGFR, IDH, BRAF and HER2 inhibitors in advanced cholangiocarcinoma. We also review the mechanisms of resistance described thus far and approaches to overcome them. Articles selected for this review were based on reported studies indexed in PubMed (2010-2022). EXPERT OPINION: Precision medicine in biliary cancers has already been incorporated into the treatment landscape of the disease in many countries. Fusions of FGFR2 and mutations in IDH1 are the first drivers with targetable treatments approved in these cancers. HER2 and BRAF would be the next drivers with possible tumor-agnostic or cholangiocarcinoma-specific approvals. The advent of ctDNA could improve the accessibility of sequencing and recruitment in these clinical trials. However, limitations of detecting fusions should be considered and addressed in these platforms.

Recommendations for the treatment of vulvar cancer in settings with limited resources: Report from the International Gynecological Cancer Society consensus meeting.

Introduction: Due to scant literature and the absence of high-level evidence, the treatment of vulvar cancer is even more challenging in countries facing limited resources, where direct application of international guidelines is difficult. Recommendations from a panel of experts convened to address some of these challenges were developed. Methods: The panel met in Rio de Janeiro in September 2019 during the International Gynecological Cancer Society congress and was composed of specialists from countries in Africa, Asia, Eastern Europe, Latin America, and the Middle East. The panel addressed 62 questions and provided recommendations for the management of early, locally advanced, recurrent, and/or metastatic vulvar cancer. Consensus was defined as at least 75% of the voting members selecting a particular recommendation, whereas a majority vote was considered when one option garnered between 50.0% and 74.9% of votes. Resource limitation was defined as any issues limiting access to qualified surgeons, contemporary imaging or radiation-oncology techniques, antineoplastic drugs, or funding for the provision of contemporary medical care. Results: Consensus was reached for nine of 62 (14.5%) questions presented to the panel, whereas a majority vote was reached for 29 (46.7%) additional questions. For the remaining questions, there was considerable heterogeneity in the recommendations. Conclusion: The development of guidelines focusing on areas of the world facing more severe resource limitations may improve medical practice and patient care.

Clinical Course, Genetic, and Immunohistochemical Characterization of Solid Pseudopapillary Tumor of the Pancreas (Frantz Tumors) in a Brazilian Cohort.

Frantz tumors or solid pseudopapillary pancreatic neoplasm (SPN) are rare exocrine neoplasms that carry a favorable prognosis; they represent up to 3% of all tumors located in the region of the pancreas and have specific age and gender predispositions. In recent years, the rising curve of diagnosis is entitled to the evolution and access of diagnostic imaging. In this paper, we have retrospectively reviewed and described the clinical course of 40 patients with SPN from three institutions in Brazil, who had their diagnosis between 2005 and 2020, and analyzed the clinicopathological, genetic, and surgical aspects of these individuals. In accordance with the literature, most patients were women, 60% with unspecified symptoms at diagnosis, with tumors mainly located in the body and tail of the pancreas, of whom 70% underwent a distal pancreatectomy with sparing splenectomy as a standard procedure, and none of the cases have experienced recurrence to date. Surgery still remains the mainstay of treatment given the low metastatic potential, but more conservative approaches as observed in this cohort are evolving to become the standard of care. Herein, we present an in-depth analysis of cases focusing on the latest literature and report some of the smallest tumor cases in the literature. To our knowledge, this is the first report evaluating germline genetic testing and presenting a case of detected Li-Fraumeni syndrome.

Recommendations for the prevention, screening, diagnosis, staging, and management of cervical cancer in areas with limited resources: Report from the International Gynecological Cancer Society consensus meeting.

Introduction: Nearly 85% of cervical cancer new cases are diagnosed in limited resources countries. Although several strategies have been proposed to reduce the disease burden, challenges remain to provide the best possible care. We report recommendations from an expert consensus meeting convened to address from prevention to management of cervical cancer in limited resources countries. Methods: The expert panel, composed by invited specialists from 38 developing countries in Africa, Asia, Eastern Europe, Latin America, and the Middle East, convened in Rio de Janeiro in September 2019, during the Global Meeting of the International Gynecological Cancer Society (IGCS). Panel members considered the published scientific evidence and their practical experience on the topics, as well as the perceived cost-effectiveness of, and access to, the available interventions. The focus of the recommendations was on geographic regions rather than entire countries because medical practice varies considerably in the countries represented. Resource limitation was qualified as limited access to qualified surgeons, contemporary imaging or radiation-oncology techniques, antineoplastic drugs, or overall funding for provision of state-of-the-art care. Consensus was defined as at least 75% of the voting members selecting a particular answer of the multiple-choice questionnaire, whereas the majority vote was considered as 50% to 74.9%. Results: Consensus was reached for 25 of the 121 (20.7%) questions, whereas for 54 (44.6%) questions there was one option garnering between 50% to 74.9% of votes (majority votes). For the remaining questions, considerable heterogeneity in responses was observed. Discussion: The implementation of international guidelines is challenging in countries with resource limitations or unique health-care landscapes. The development of guidelines by the health care providers in those regions is more reflective of the reality on the ground and may improve medical practice and patient care. However, challenges remain toward achieving that goal at political, economic, social, and medical levels.

Immunotherapy in biliary tract cancers: Current evidence and future perspectives.

Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder tumors. These are aggressive tumors and chemotherapy is still the main treatment for advanced-stage disease and most of these cases have a poor overall survival. Strategies are aimed at treatments with better outcomes and less toxicity which makes immunotherapy an area of ​​significant importance. Recent Food and Drug Administration approvals of immune checkpoint inhibitors (ICI) for agnostic tumors based on biomarkers such as microsatellite instability-high and tumor mutation burden-high are important steps in the treatment of patients with advanced bile duct tumors. Despite limited responses with isolated checkpoint inhibitors in later lines of systemic treatment in advanced disease, drug combination strategies have been demonstrating encouraging results to enhance ICI efficacy.

Neoadjuvant chemotherapy or upfront surgery in localized pancreatic cancer: a contemporary analysis.

Neoadjuvant chemotherapy is considered a new treatment option for potentially resectable pancreatic cancer. However, data are not well established on overall survival and delaying surgery in resectable pancreatic cancer, as well as on those patients that ultimately cannot undergo surgery. We analyzed pancreatic cancer patients treated in a tertiary hospital from January 2016 to December 2020. Patients with resectable stage I and II pancreatic cancer were evaluated regarding surgery, neoadjuvant treatment, and other clinical demographics. The survival function was estimated using the Kaplan-Meier method, and the relationship between the variables of interest and the overall survival (OS) was assessed by adopting the proportional regression Cox models. A total of 216 patients were evaluated. 81 of them with resectable/borderline resectable disease and 135 with unresectable /metastatic disease at diagnosis. Median OS for stage I and II disease were 36 and 28 months, respectively. For resectable pancreatic cancer median OS was 28 months, for borderline resectable pancreatic cancer median OS was 11 months. Median OS for stage III (locally advanced) and stage IV (metastatic) were 10 and 7 months, respectively (p < 0.0001). Median OS of 9 months were obtained for patients with stage I and II that did not undergo surgery compared to 25 months in patients that underwent surgery in any time (p < 0.001). Comparing patients with localized disease, median OS for patients treated with upfront surgery was 28 months, compared to 15 months in patients treated with neoadjuvant approach (p = 0.04). Most patients that did not undergo surgery have decline of performance status or disease progression on neoadjuvant treatment. On multivariable analysis in pancreatic cancer stages I and II, including age, sex, borderline or resectable disease, CA 19-9, positive lymph nodes and neoadjuvant treatment, the surgery was the only factor associated with improved overall survival (p = 0.04). Upfront surgery should still be considered a standard of care approach for resectable pancreatic cancer. Biomarker driven studies and randomized trials with combination therapies are necessary to address neoadjuvant chemotherapy and delaying surgery in purely resectable pancreatic cancer.

Laboratory variables as predictors of progression in gastroenteropancreatic neuroendocrine tumors in different lines of antineoplastic treatments.

OBJECTIVE: To determine the association of red cell blood counts, and liver panel tests to predict outcomes in patients with gastroenteropancreatic neuroendocrine tumors who underwent systemic antineoplastic treatments. METHODS: Patients with gastroenteropancreatic neuroendocrine tumors in systemic treatment were assessed according to laboratory tests within the same period. Progression free survival was determined by the period between the beginning of treatment and the date of progression. We used conditional models (PWP model) to verify the association between laboratory tests and tumor progression. The level of significance used was 5%. RESULTS: A total of 30 treatments given to 17 patients in the intention-to-treat population were evaluated. Treatment included octreotide, lanreotide, everolimus, lutetium, and chemotherapy. We had statistically significant results in chromogranin A, neutrophils and platelets-to-lymphocyte ratio. The risk of progression increases by 2% with the addition of 100ng/mL of chromogranin A (p=0.034), 4% with the increase of 100 neutrophil units (p=0.006), and 21% with the addition of 10 units in platelets-to-lymphocyte ratio (p=0.002). CONCLUSION: Chromogranin A, neutrophils and platelets-to-lymphocyte ratio were associated with disease progression during systemic treatment in gastroenteropancreatic neuroendocrine tumors. Further prospective studies with larger cohorts are necessary to validate our findings.

Cell-Free Tumor DNA Dominant Clone Allele Frequency Is Associated With Poor Outcomes in Advanced Biliary Cancers Treated With Platinum-Based Chemotherapy.

PURPOSE: This investigation sought to evaluate the prognostic value of pretreatment of circulating tumor DNA (ctDNA) in metastatic biliary tract cancers (BTCs) treated with platinum-based first-line chemotherapy treatment. MATERIALS AND METHODS: We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis, we considered the detected gene with highest variant allele frequency as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients' demographics, progression-free survival (PFS), and overall survival (OS). RESULTS: The median age of patients was 67 (27-90) years. Fifty-four (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma, and six gallbladder cancers. Forty-six (68.6%) of the patients were treated with cisplatin plus gemcitabine, and 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations, whereas 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20, or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11, and IDH1 were the genes with highest frequency as DCAF. The median DCAF was 3% (0%-97%). DCAF > 3% was associated with worse OS (median OS: 10.8 v 18.8 months, P = .032). Stratifying DCAF in quartiles, DCAF > 10% was significantly related to worse PFS (median PFS: 3 months, P = .014) and worse OS (median OS: 7.0 months, P = .001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9. CONCLUSION: DCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decreases survival probabilities.

Immune Checkpoint Inhibitors as Therapy to Down-Stage Hepatocellular Carcinoma Prior to Liver Transplantation.

Hepatocellular Carcinoma (HCC) is the most common liver malignancy and third leading cause of cancer death worldwide. For early- and intermediate-stage disease, liver-directed therapies for locoregional control, or down-staging prior to definitive surgical therapy with hepatic resection or liver transplantation, have been studied broadly, and are the mainstays of current treatment guidelines. As HCC incidence has continued to grow, and with more patients presenting with advanced disease, our current treatment modalities do not suffice, and better therapies are needed to improve disease-specific and overall survival. Until recently, sorafenib was the only systemic therapy utilized, and was associated with dismal results. The advent of immuno-oncology has been of significant interest, and has changed the paradigm of therapy for HCC. Lately, combination regimens including atezolizumab plus bevacizumab; durvalumab plus tremelimumab; and pembrolizumab plus Lenvatinib have shown impressive responses of between 25-35%; this is much higher than responses observed with single agents. Complete responses with checkpoint inhibitor therapy have been observed in advanced-stage HCC patients. These dramatic results have naturally led to several questions. Can or should checkpoint inhibitors, or other immunotherapy combinations, be used routinely before resection or transplant? Is there a synergistic effect of immunotherapy with locoregional therapy, and will pre-treatment increase disease-free survival after surgical intervention? Is it immunologically safe to use these therapies prior to transplantation? Much is still to be learned in terms of the dosing, timing, and overall utility of the use of immune checkpoint inhibitors for pre-transplant care and down-staging. More studies will be needed to understand the management of adverse events while maximizing the therapeutic window of these agents. In this review, we look at the current data on therapy with immune checkpoint inhibitors in advanced HCC, with a focus on pre-transplant treatment prior to liver transplant.