Immunotherapy resistance in solid tumors: mechanisms and potential solutions.

While the emergence of immunotherapies has fundamentally altered the management of solid tumors, cancers exploit many complex biological mechanisms that result in resistance to these agents. These encompass a broad range of cellular activities - from modification of traditional paradigms of immunity via antigen presentation and immunoregulation to metabolic modifications and manipulation of the tumor microenvironment. Intervening on these intricate processes may provide clinical benefit in patients with solid tumors by overcoming resistance to immunotherapies, which is why it has become an area of tremendous research interest with practice-changing implications. This review details the major ways cancers avoid both natural immunity and immunotherapies through primary (innate) and secondary (acquired) mechanisms of resistance, and it considers available and emerging therapeutic approaches to overcoming immunotherapy resistance.

Liver Transplantation in a Woman with Mahvash Disease.

Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.

Colon adenocarcinoma and Birt-Hogg-Dubé syndrome in a young patient: case report and exploration of pathologic implications.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN) that result in the functional loss of the tumor suppressor folliculin. It is classically associated with cutaneous hamartomas, pulmonary cysts with spontaneous pneumothorax, and various renal cancers. In this case, we present a patient initially diagnosed with chromophobe renal cell carcinoma and subsequently found to have colorectal cancer (CRC). The presence of two separate malignancies in a young patient with a strong family history of CRC (father and paternal grandfather) led to genetic testing, which revealed an FLCN c.1177-5_1177-3del mutation, and a diagnosis of BHD was made. Out of the more than 300 known unique mutations of the FLCN coding region, the c.1285dupC mutation on exon 11 has been the only one convincingly associated with CRC thus far. While larger cohort studies are needed to further clarify this association, we present the first patient with CRC to our knowledge with an FLCN c.1177-5_1177-3del mutation and loss of heterozygosity implicating it as an initiating factor in tumorigenesis. We further explore the studies supporting and refuting the connection between BHD and CRC and highlight the molecular signaling pathways that may play a role in pathogenesis.

Understanding the role of sex on outcomes for the cancer patient undergoing treatment with immune checkpoint inhibitors: a scoping review protocol.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for multiple cancer types. Sex plays an important role in both the development of cancer as well as the functioning of the immune system. Though a difference in response to immune therapy is emerging between men and women it is unclear how this difference affects cancer outcomes and what the potential underlying mechanisms are for those effects. The objective of this study is to describe the influence that sex has on the outcomes experienced by cancer patients on ICI therapy and to identify and analyse any knowledge gaps in the field. METHOD AND ANALYSIS: The framework for this methodology was guided by the Joanna Briggs Institute Manual for Evidence Synthesis. The search and review will be conducted from January 2022 to June 2022. Two independent researchers will screen titles and abstracts followed by full-text screening for manuscript inclusion. Full length studies published between 2010 and December 2021 found in PubMed, Cochrane, CINAHL, and Scopus describing the influence of sex differences on cancer outcomes in patients treated with ICIs will be included. After data are extracted it will be summarised for presentation. ETHICS AND DISSEMINATION: The findings of this scoping review will be published in a peer-reviewed journal. The results will be used to inform future studies on the potential differential impacts of ICIs. All data are from published openly accessible sources and therefore no ethical clearance is necessary.

Immune checkpoint inhibitors in luminal gastrointestinal malignancies: going beyond MSI-H/dMMR, TMB and PD-L1.

In luminal gastrointestinal tumors, immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1 and CTLA-4 have been investigated in multiple settings. The indications for these drugs are primarily dependent on specific biomarkers that imply immunogenicity: overexpression of PD-L1, tumor mutational burden, loss of mismatch repair proteins (dMMR) and/or high microsatellite instability status. Although these markers can be both predictive and prognostic, there is variability in how they are measured and used to guide therapies. Moreover, the use of ICIs can be further refined with a better understanding of the tumor microenvironment and interactions with other available therapies. The purpose of this review is to characterize luminal gastrointestinal tumors' responses to ICIs considering known predictive biomarkers and discuss emerging therapeutic approaches using ICIs.

Immune checkpoint inhibitors (ICIs) are medications that help the natural immune system fight cancer cells, preventing their growth. In tumors of the gastrointestinal tract, mounting research has shown that ICIs are useful in treatment regimens. However, this depends on certain characteristics of individual cancers, such as how many mutations they have, if they are missing certain enzymes and other considerations. ICIs can also be paired with standard ­ and nonstandard ­ treatments like chemotherapy, radiation and other targeted therapy to increase their effectiveness against cancer. This article discusses how ICIs are used in gastrointestinal tract cancers according to the available evidence in the medical literature, and it explores the directions of the research on the forefront of immunotherapy.

Partial treatment response to capmatinib in MET-amplified metastatic intrahepatic cholangiocarcinoma: case report & review of literature.

Cholangiocarcinoma is a highly morbid gastrointestinal malignancy for which available therapies are limited. Standard of care includes cytotoxic chemotherapies such as gemcitabine, platinum agents, nab-paclitaxel, and fluoropyrimidine analogues. However, tolerability of these regimens varies, and patients who do not tolerate chemotherapy have limited targeted therapies and immunotherapy options. In cholangiocarcinoma, mesenchymal-epithelial transition factor (MET) amplification may present an additional opportunity for a targeted therapeutic approach, especially considering emerging data in non-small cell lung cancer. In this case, we present a metastatic cholangiocarcinoma patient with high-level MET gene amplification for whom capmatinib, a tyrosine kinase inhibitor with activity against c-MET, provided a partial response after cessation of chemotherapy.

The Effects of Physical Activity on Cancer Patients Undergoing Treatment with Immune Checkpoint Inhibitors: A Scoping Review.

BACKGROUND: Cancer therapies are associated with multiple adverse effects, including (but not limited to) cancer-related fatigue (CRF). Fatigue is one of the most common side effects of immune checkpoint inhibitors (ICIs), occurring in up to 25% of patients. Physical activity has been shown to help reduce CRF through modulating the immune system, and may synergistically aid in the anti-tumor effects of ICIs. This review describes the nature and scope of evidence for the effects associated with concurrent physical activity while undergoing ICI therapy. METHOD: Scoping review methodology was utilized to identify studies, extract data, and collate and summarize results. RESULTS: In literature published from January 2010 through to August 2021, only one human study and three pre-clinical studies met inclusion criteria. CONCLUSION: Existing evidence supports that physical activity is associated with decreased treatment-related toxicities such as CRF. However, further investigation is warranted. The dearth of clinical studies illustrates the need for more research to address this question, to guide patients and their providers in the application of appropriate physical activity interventions in those patients undergoing ICI.

Soluble glycoprotein VI is a predictor of major bleeding in patients with suspected heparin-induced thrombocytopenia.

We have shown that patients with suspected heparin-induced thrombocytopenia (HIT) have a high incidence of major bleeding. Recent studies have implicated elevated soluble glycoprotein VI (sGPVI) levels as a potential risk factor for bleeding. We sought to determine if elevated sGPVI plasma levels are associated with major bleeding events in patients with suspected HIT. We used a cohort of 310 hospitalized adult patients with suspected HIT who had a blood sample collected at the time HIT was suspected. Plasma sGPVI levels were measured by using enzyme-linked immunosorbent assay. Patients were excluded who had received a platelet transfusion within 1 day of sample collection because of the high levels of sGPVI in platelet concentrates. We assessed the association of sGPVI (high vs low) with International Society on Thrombosis and Haemostasis major bleeding events by multivariable logistic regression, adjusting for other known risk factors for bleeding. Fifty-four patients were excluded due to recent platelet transfusion, leaving 256 patients for analysis. Eighty-nine (34.8%) patients had a major bleeding event. Median sGPVI levels were significantly elevated in patients with major bleeding events compared with those without major bleeding events (49.09 vs 31.93 ng/mL; P < .001). An sGPVI level >43 ng/mL was independently associated with major bleeding after adjustment for critical illness, sepsis, cardiopulmonary bypass surgery, and degree of thrombocytopenia (adjusted odds ratio, 2.81; 95% confidence interval, 1.51-5.23). Our findings suggest that sGPVI is associated with major bleeding in hospitalized patients with suspected HIT. sGPVI may be a novel biomarker to predict bleeding risk in patients with suspected HIT.

Maximum 24-hour platelet count fall: Metric for improving the diagnosis of heparin-induced thrombocytopenia among patients with intermediate probability 4Ts scores.

BACKGROUND: Most patients with suspected heparin-induced thrombocytopenia (HIT) and an intermediate probability 4Ts score do not have HIT. We aimed to develop a metric based on the rate of platelet count fall to aid in discriminating HIT status among patients with an intermediate 4Ts score. METHODS: We derived a measure of the maximum 24-hour percentage decrease in platelet count (Fallmax ) in a cohort of patients with suspected HIT and an intermediate 4Ts score at the University of Pennsylvania. We validated this metric in a prospectively collected cohort of patients with suspected HIT and an intermediate 4Ts score from four hospitals in Hamilton, Ontario. RESULTS: One hundred fifty-eight and 139 patients were included in the analysis from the derivation and validation cohorts, respectively. Fallmax was significantly higher in HIT-positive patients in the derivation cohort (49.6% versus 38.6%, P = .009) and validation cohort (43.5% versus 29.3%, P = .027). The area under the receiver operating characteristic curve was 0.68 (95% confidence interval [CI] 0.57-0.78) and 0.71 (0.59-0.83) in the two cohorts, respectively. At Fallmax  ≥ 30%, sensitivity and specificity were 95.5% and 29.4% in the derivation cohort and 80.0% and 52.7% in the validation cohort. CONCLUSIONS: Among patients with suspected HIT and an intermediate 4Ts score, Fallmax aided in discriminating HIT-negative from HIT-positive patients. Using a measure that accounts for the rate of platelet count fall may help to avoid unnecessary suspension of heparin and treatment with an alternative anticoagulant in HIT-negative patients with an intermediate probability 4Ts score, though further evaluation is warranted.

The risk of major bleeding in patients with suspected heparin-induced thrombocytopenia.

BACKGROUND: The presence of a hypercoagulable disorder such as heparin-induced thrombocytopenia (HIT) may protect against anticoagulant-associated bleeding. OBJECTIVES: To determine the incidence of major bleeding in patients with suspected HIT. METHODS: We performed a retrospective analysis of 310 patients suspected of having HIT from the Hospital of the University of Pennsylvania and an affiliated community hospital. We compared the cumulative incidence of major bleeding following suspicion for HIT by ultimate HIT status (HIT+ or HIT-) and exposure to an alternative anticoagulant (Tx+ or Tx-). Secondary outcomes included the incidence of new/progressive thrombosis and 30-day mortality. RESULTS: The incidence of major bleeding was high in the HIT+Tx+, HIT- Tx+, and HIT-Tx- groups (35.7%, 44.0%, and 37.3%, respectively). The time to first major bleeding event did not differ between groups (P = .24). Factors associated with increased risk of major bleeding included intensive care unit admission (HR 2.24, 95% CI 1.44-3.47), platelet count < 25 × 109 /L (HR 2.13, 1.10-4.12), and renal dysfunction (HR 1.56, 1.06-2.27); 35.7% of HIT+Tx+, 13.8% HIT-Tx+, and 9.3% of HIT-Tx- patients experienced new or progressive thrombosis. Mortality was similar among the three groups (26.2% HIT+Tx+, 34.5% HIT-Tx+, and 26.7% of HIT-Tx- [P = .34]). CONCLUSIONS: Among patients with suspected HIT, major bleeding was common regardless of HIT status. Contrary to our hypothesis, HIT+ patients were not protected from major bleeding. A better understanding of bleeding risk is needed to inform management decisions in patients with suspected HIT.

Prospective comparison of the HEP score and 4Ts score for the diagnosis of heparin-induced thrombocytopenia.

The HIT Expert Probability (HEP) score compared favorably with the 4Ts score in a retrospective study. We assessed the diagnostic accuracy of the HEP score compared with the 4Ts score in a prospective cohort of 310 patients with suspected heparin-induced thrombocytopenia (HIT). A member of the clinical team calculated the HEP score and 4Ts score. An independent panel adjudicated HIT status based on a clinical summary as well as the results of HIT laboratory testing. The prevalence of HIT in the study population was 14.7%. At a cutoff of ≥3, the HEP score was 95.3% sensitive (95% confidence interval [CI], 84.2-99.4) and 35.7% specific (95% CI, 29.8-42.0) for HIT. A 4Ts score of ≥4 had a sensitivity of 97.7% (95% CI, 86.2-99.8) and specificity of 32.9% (95% CI, 27.2-39.1). The areas under the receiver operating characteristic (ROC) curves (AUCs) for the HEP score and 4Ts score were similar (0.81 [95% CI, 0.74-0.87] vs 0.76 [95% CI, 0.69-0.83]; P = .12). The HEP score exhibited a significantly higher AUC than the 4Ts score in patients in the intensive care unit (ICU) (0.86 vs 0.79; P = .03). Among trainee scorers, the HEP score performed significantly better than the 4Ts score (AUC, 0.80 vs 0.73; P = .03). Our data suggest that either the 4Ts score or the HEP score may be used in clinical practice. The HEP score may be preferable in ICU patients and among less experienced clinicians.