TGFß in pancreas and colorectal cancer: opportunities to overcome therapeutic resistance.

TGFß is a pleiotropic signaling pathway, which plays a pivotal role in regulating a multitude of cellular functions. TGFß has a dual role in cell regulation where it induces growth inhibition and cell death; however, it can switch to a growth-promoting state under cancerous conditions. TGFß is upregulated in CRC and pancreatic cancer, altering the tumor microenvironment, immune system, and promoting a mesenchymal state. The upregulation of TGFß in certain cancers leads to resistance to immunotherapy, and attempts to inhibit TGFß expression have led to reduced therapeutic resistance when combined with chemo- and immunotherapy. Here, we review the current TGFß inhibitor drugs in clinical trials for pancreatic and colorectal cancer, with the goal of uncovering advances in improving clinical efficacy for TGFß combinational treatments in patients. Furthermore, we discuss the relevance of alterations in TGFß signaling and germline variants in the context of personalizing treatment for patients who show lack of response to current therapeutics.

Metastatic Alveolar Rhabdomyosarcoma with Extensive Bone Marrow Replacement in an Older Adult.

Rhabdomyosarcoma is extremely rare in adults. Metastatic rhabdomyosarcoma can resemble other malignancies, which can delay diagnosis and prompt treatment. This case illustrates an example of metastatic alveolar rhabdomyosarcoma with concurrent bone marrow infiltration. A 67-year-old woman presented with epistaxis and diffuse bone pain. She developed progressive thrombocytopenia requiring platelet transfusions. The patient was initially thought to have leukemia. She was found to have a large sinonasal mass with extensive metastatic disease and bone marrow infiltration. The patient was ultimately diagnosed with metastatic alveolar rhabdomyosarcoma. She was started on chemotherapy with vincristine, actinomycin, and cyclophosphamide. Unfortunately, she died prior to discharge home. Alveolar rhabdomyosarcoma can resemble a primary bone marrow malignancy when it infiltrates the bone marrow. Further investigation is needed to clarify its clinical behavior and expedite diagnosis and treatment.

Predictors of Survival among Early Onset Pancreatic Adenocarcinoma Patients A Tertiary Care Center Experience.

OBJECTIVES: To characterize clinical features of early onset pancreatic adenocarcinoma (EOPC) patients and explore prognostic factors affecting their survival. Methods: Retrospective review of 95 patients, 45 years old, who presented to the University of Alabama Hospitals with pancreatic adenocarcinoma from September 1998 to June 2018. Results: Median survival time was 12.9 months for all patients. Obesity, male gender, race, and tumor location were not associated with survival. Smoking at time of diagnosis increased risk of death by three folds (HR 3.05, 95% CI, 1.45 - 6.40). Risk of death decreased by 64% (HR 0.36, 95% CI, 0.16 - 0.78) if patients underwent surgery. Median survival was 119.5 months for stage I, 29.9 months for stage II, 23.23 months for stage III, and 6.3 months for stage IV patients. The survival benefit of chemotherapy was only significant with the use of FOLFIRINOX. Conclusions: Some established prognostic features in typical pancreatic adenocarcinoma patients are not predictive of survival in young patients. Cigarette smoking, a known risk factor for the development of EOPC, is also a significant predictor of survival in this patient population. Efforts to improve prognosis of EOPC include early detection, tobacco control, individualized treatment protocols, and studying the biological behavior.

Depression among older adults with gastrointestinal malignancies.

BACKGROUND: Depression among older adults with cancer is under recognized and under treated. This study characterizes the burden of depression in older adults with gastrointestinal (GI) malignancies prior to chemotherapy and its relationship with geriatric assessment (GA) domains, health-related quality of life (HRQOL), and self-reported healthcare utilization. METHODS: Patients ≥60 years in GI oncology clinics at UAB were asked to complete a GA entitled the Cancer & Aging Resilience Evaluation (CARE). We examined depression using the Patient-Reported Outcomes Measurement Information System (PROMIS®) Depression four-item short form; moderate/severe depression was defined by a t-score ≥ 60. Multivariate analysis was used to examine associations between those with and without moderate/severe depression. RESULTS: Of 355 included patients, 46 had mild depression (13%) and an additional 46 patients had moderate/severe depression (13%). After adjustment for age, sex, education, cancer type, and cancer stage, those who reported moderate/severe depression had a significantly increased odds of reporting falls (adjusted odds ratio [aOR] 4.01, 95% confidence interval [CI] 1.94-8.26), dependence in IADLs (aOR 7.06,CI 2.91-17.1), dependence in ADLs (aOR 6.23, CI 2.89-13.4), malnutrition (aOR 5.86, CI 2.40-14.3), frailty (aOR 13.7, CI 5.80-32.1), and fatigue (aOR 11.2, CI 3.31-37.6). Moderate/severe depression was also significantly associated with worse physical (aOR 7.58, CI 3.30-17.4) and mental (aOR 26.3, CI 10.1-68.8) HRQOL sub-scores, without significant differences in healthcare utilization. CONCLUSIONS: More than one out of eight older adults with a GI malignancy reported moderate/severe depression prior to chemotherapy, which was associated with impairments in several GA domains and HRQOL.

CAR T Cell Therapy in Pancreaticobiliary Cancers: a Focused Review of Clinical Data.

OBJECTIVE: CAR T cell therapy is an innovative approach to treat cancers in the modern era. It utilizes the application of chimeric antigen receptors targeted against specific antigens expressed by the tumor cells. Although its efficacy is established in hematological malignancies, the safety and efficacy of this therapy in solid tumors, especially pancreaticobiliary cancers, is a highly investigated aspect. A focused review of clinical data was conducted to examine the outcomes of this therapy in pancreaticobiliary cancers. METHODS: A comprehensive literature search was done on Medline and Embase databases through April 24, 2020 for studies that evaluated the outcomes of CAR T cell therapy in pancreaticobiliary cancers. RESULTS: There were six phase 1 trials, while one was phase 1/2. Some of these trials were specifically done for pancreaticobiliary cancers, while others included patients of various solid organ cancers, including pancreatic and biliary tract cancers. The target antigens for therapy in these trials included mesothelin, CD133, prostate stem cell antigen, claudin 18.2, epidermal growth factor receptor, and human epidermal growth factor receptor 2. CAR T cell therapy has shown very few grade 3 and 4 side effects. Most of the adverse events are associated with cytokine release syndrome. CONCLUSION: CAR T cell therapy has a manageable safety profile based on phase 1 studies, and efficacy assessments are currently ongoing in dose expansion and phase 2 studies.

Second-line treatment for metastatic pancreatic cancer.

Pancreatic cancer is the fourth-leading cause of cancer-related death. It is commonly diagnosed at an advanced stage, when no curative options exist. Over the last decade, combination chemotherapy has shown a survival benefit compared with single-agent gemcitabine and has become established as first-line therapy in metastatic pancreatic cancer. The choice of frontline regimen, which is based on clinical factors, plays an important role in subsequent management. Limited second-line standard therapeutic options are available. Studies have not definitively established that chemotherapy with a fluoropyramidine (5-fluorouracil or capecitabine), gemcitabine, oxaliplatin, irinotecan, or a combination of oxaliplatin and irinotecan improves patient survival after the failure of first-line chemotherapy. Nanoliposomal irinotecan has been approved for use in patients who have progressive disease while on gemcitabine-based treatment. Although combination chemotherapy is associated with a modest survival benefit, this comes at the expense of increased toxicity and costs. Furthermore, the optimal sequencing of these agents in subsequent lines of treatment is unknown. Randomized controlled trials provide little evidence of greater benefit from second-line therapy compared with best supportive care alone. Therefore, treatment decisions should be patient-centered and based on functional status, medical comorbidities, and anticipated adverse effects. The clinical context and prior treatment-related toxicities have a significant influence on the choice of optimal salvage treatment. We review the published data focused on second-line treatment for advanced pancreatic cancer.

First-In-Human Phase 1 Clinical Trials - A Single-Center Experience In The Era Of Modern Oncotherapeutics.

In the era of precision medicine the treatment options for cancer patients and subsequent outcomes are expected to improve. We present a review of patients enrolled in first-in-human Phase1 trials at University of Alabama at Birmingham. Between 1/2015-6/2017, 162 cancer patients (whole cohort, WC) were enrolled on phase1 studies receiving either targeted therapy (TT) or immuno-therapy (IOT). We assessed 90 day mortality (90DM) and time to treatment failure (TTF) to determine the predictors. Of the WC (122 (TT), 40 (IOT)), 90 (56%) received ≥ 2 prior therapies and 38 (24%) ⩾ 5 prior therapies. Overall, Grade 3 or 4 events were observed in 33% (WC) vs 31% (TT) vs 38% (IOT). The 90DM was 9.3% (WC) vs 7.4% (TT) vs 15% (IOT). The median TTF was 4.2 months vs 4.5 m vs 3.6 m. The number of lines of prior therapy and performance status were identified as outcome predictors. Our data reflects the new trend in precision oncology where majority received non-cytotoxic therapeutic interventions. The observation that number of lines of prior therapy and performance status predictive of PFS and 90DM emphasizes the need to consider phase1 trials earlier, preferably upon progression following definitive therapy.

Renal toxicity with mammalian target of rapamycin inhibitors: A meta-analysis of randomized clinical trials.

A meta-analysis of randomized clinical trials (RCT) was done to determine the relative risk (RR) of acute kidney injury (AKI) with the use of mammalian target of rapamycin (mTOR) inhibitors. Citations from PubMed/Medline, clinical trials.gov, package inserts and abstracts from major conferences were reviewed to include RCTs comparing arms with or without mTOR inhibitors. The RR of all grade AKI in patients taking mTOR inhibitors compared to patients not on mTOR inhibitors was 1.55 (95% CI: 1.11 to 2.16, P=0.010). There was no significant difference in the risk of high-grade AKI for the two groups (RR=1.29, P=0.118, 95% CI: 0.94 to 1.77). There was no significant difference in the incidence rates for either all grade or high-grade AKI between the two groups. There was no publication bias and the trials were of high quality per Jadad scoring.

Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

Prognostic value of loss of heterozygosity and sub-cellular localization of SMAD4 varies with tumor stage in colorectal cancer.

BACKGROUND: Although loss of heterozygosity (LOH) at chromosome location 18q21 and decreased expression of SMAD4 in invasive colorectal cancers (CRCs) correlate with poor patient survival, the prognostic value of LOH at 18q21 and sub-cellular localization of SMAD4 have not been evaluated in relation to tumor stage. METHODS: Genomic DNA samples from 209 formalin-fixed, paraffin-embedded sporadic CRC tissues and their matching controls were analyzed for 18q21 LOH, and corresponding tissue sections were evaluated by immunohistochemistry for expression of SMAD4 and assessed for its sub-cellular localization (nuclear vs. cytoplasmic). In addition, 53 frozen CRCs and their matching control tissues were analyzed for their mutational status and mRNA expression of SMAD4. The phenotypic expression pattern and LOH status were evaluated for correlation with patient survival by the use of Kaplan-Meier and Cox regression models. RESULTS: LOH of 18q21 was detected in 61% of the informative cases. In 8% of the cases, missense point mutations were detected in Smad4. In CRCs, relative to controls, there was increased SMAD4 staining in the cytoplasm (74%) and decreased staining in the nuclei (37%). LOH of 18q21 and high cytoplasmic localization of SMAD4 were associated with shortened overall survival of Stage II patients, whereas low nuclear expression of SMAD4 was associated with worse survival, but only for patients with Stage III CRCs. CONCLUSIONS: LOH of 18q21 and high cytoplasmic localization of SMAD4 in Stage II CRCs and low nuclear SMAD4 in Stage III CRCs are predictors of shortened patient survival.

Effect of African-American Race on Tumor Recurrence After Radical Cystectomy for Urothelial Carcinoma of the Bladder.

BACKGROUND: African-American race appears to be associated with higher stages of urothelial carcinoma of the bladder (UCB) at presentation and poorer survival. However, the independent effect of African-American race on objective tumor recurrence after radical cystectomy (RC) after controlling for clinical and pathologic variables is unknown. PATIENTS AND METHODS: The data from consecutive patients with UCB who underwent RC with curative intent at a single institution (University of Alabama, Birmingham) from 2001 to 2012 with or without perioperative chemotherapy or chemoradiation were reviewed. The patient demographics, risk factors, clinical course, pathologic characteristics, and long-term outcomes were collected. Descriptive statistics were performed. Cox regression analysis was performed for key clinical, demographic, and pathologic variables, including race, stratified as African American versus white. RESULTS: A total of 215 patients, 163 men (76%) and 52 women (24%), with a mean age at RC of 65.6 years, were identified and reviewed. A total of 186 patients (87%) were white and 28 (13%) were African American. The median follow-up period after RC was 17.6 months. On conventional multivariate analysis, African-American race nearly attained statistical significance (hazard ratio [HR], 2.48; 95% confidence interval [CI], 0.98-6.29; P = .055). In a stepwise regression model, race was significantly associated with tumor recurrence (HR, 3.11; 95% CI, 1.2-7.4; P < .011). CONCLUSION: African-American race appears to be independently associated with a greater risk of tumor recurrence after RC for UCB. The effect of host genetics on tumor biology needs to be characterized at the genomic level to develop precision medicine.