Trajectory of Healthcare Contact Days for Veterans With Advanced Gastrointestinal Malignancy.

How and where patients with advanced cancer facing limited survival spend their time is critical. Healthcare contact days (days with healthcare contact outside the home) offer a patient-centered and practical measure of how much of a person's life is consumed by healthcare. We retrospectively analyzed contact days among decedent veterans with stage IV gastrointestinal cancer at the Minneapolis Veterans Affairs Healthcare System from 2010 to 2021. Among 468 decedents, the median overall survival was 4 months. Patients spent 1 in 3 days with healthcare contact. Over the course of illness, the percentage of contact days followed a "U-shaped" pattern, with an initial post-diagnosis peak, a lower middle trough, and an eventual rise as patients neared the end-of-life. Contact days varied by clinical factors and by sociodemographics. These data have important implications for improving care delivery, such as through care coordination and communicating expected burdens to and supporting patients and care partners.

Microbial dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer.

The lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated with the abysmal survival rates in patients. In addition to several potential detection tools under active investigation, we tested the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high risk for PDAC. We used a combination of 16s rRNA pyrosequencing and whole-genome sequencing of gut fecal microbiota in a genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC). Metabolic reconstruction of microbiome was done using the HUMAnN2 pipeline. Serum polyamine levels were measured from murine and patient samples using chromogenic assay. Our results showed a Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentrations. Therefore, at the early stages of tumorigenesis, there is a strong correlation between microbial changes and release of metabolites that foster host tumorigenesis, thereby fulfilling the 'vicious cycle hypothesis' of the role of microbiome in health and disease states. Our results provide a potential, precise, noninvasive tool for early detection of PDAC, which may result in improved outcomes.

Minnelide Inhibits Androgen Dependent, Castration Resistant Prostate Cancer Growth by Decreasing Expression of Androgen Receptor Full Length and Splice Variants.

BACKGROUND: With almost 30,000 deaths per year, prostate cancer is the second-leading cause of cancer-related death in men. Androgen Deprivation Therapy (ADT) has been the corner stone of prostate cancer treatment for decades. However, despite an initial response of prostate cancer to ADT, this eventually fails and the tumors recur, resulting in Castration Resistant Prostate Cancer (CRPC). Triptolide, a diterpene triepoxide, has been tested for its anti-tumor properties in a number of cancers for over a decade. Owing to its poor solubility in aqueous medium, its clinical application had been limited. To circumvent this problem, we have synthesized a water-soluble pro-drug of triptolide, Minnelide, that is currently being evaluated in a Phase 1 clinical trial against gastrointestinal tumors. In the current study, we assessed the therapeutic potential of Minnelide and its active compound triptolide against androgen dependent prostate cancer both in vitro as well as in vivo. METHODS: Cell viability was measured by a MTT based assay after treating prostate cancer cells with multiple doses of triptolide. Apoptotic cell death was measured using a caspase 3/7 activity. Androgen Receptor (AR) promoter-binding activity was evaluated by using luciferase reporter assay. For evaluating the effect in vivo, 22Rv1 cells were implanted subcutaneously in animals, following which, treatment was started with 0.21 mg/kg Minnelide. RESULTS: Our study showed that treatment with triptolide induced apoptotic cell death in CRPC cells. Triptolide treatment inhibited AR transcriptional activity and decreased the expression of AR and its splice variants both at the mRNA and the protein level. Our studies show that triptolide inhibits nuclear translocation of Sp1, resulting in its decreased transcriptional activity leading to downregulation of AR and its splice variants in prostate cancer cells. In vivo, Minnelide (0.21 mg/kg) regressed subcutaneous tumors derived from CRPC 22RV1 at our study endpoint. Our animal studies further confirmed that Minnelide was more efficacious than the standard of care therapies, Docetaxel and Enzalutamide. CONCLUSION: Our study indicates that Minnelide is very effective as a therapeutic option against CRPC at a dose that is currently tolerated by patients in the ongoing clinical trials. Prostate 77: 584-596, 2017. © 2017 Wiley Periodicals, Inc.

Race- and Sex-Based Disparities in the Therapy and Outcomes of Squamous Cell Carcinoma of the Anus.

Background: Squamous cell carcinoma of the anus (SCCA) is one of the few cancers with an increasing incidence in the United States. We aimed to characterize race- and sex-based disparities in receipt of therapy and overall survival (OS) of SCCA using the SEER database. Methods: Cases of locoregional SCCA (T2-T4 any N M0) diagnosed between 2000 and 2012 in the SEER database were included. Demographics, tumor characteristics, type of therapy, and outcomes were extracted. Univariable and multivariable Cox proportional hazard models were constructed to test factors associated with OS. Data were reported as hazard ratios (HRs) and 95% CIs. Results: A total of 7,882 cases of locoregional SCCA were identified, with a median age of 58 years, 61.2% of whom were women, and 86.3% were white. Most patients (82.3%) received radiation therapy (RT), with the lowest rate in black men (76.7%) and the highest in white women (86.1%). The median OS was 135 months; OS was lower in elderly patients (age ≥65 years; 68 months), men (108 months), blacks (109 months), and those who did not receive RT (121 months). In multivariable analysis, age (HR, 1.19; 95% CI, 1.17-1.21 per 5 years increase), sex (HR, 1.59; 95% CI, 1.47-1.73, men vs women), race (HR, 1.51; 95% CI, 1.34-1.71, black vs white), and RT (HR, 0.90; 95% CI, 0.82-0.99) were independently associated with OS (P<.05). Conclusions: Significant race- and sex-based disparities exist in survival of patients with locoregional SCCA. Further investigation into the causes of these disparities and methods for elimination are warranted.

Primary effusion lymphoma: current concepts and management.

PURPOSE OF REVIEW: To summarize the current epidemiology, management, and outcomes of primary effusion lymphoma (PEL) and highlight possible future research efforts. RECENT FINDINGS: Cyclophosphamide, doxorubicin, vincristine, prednisone-based chemotherapy regimens alone or in combination with immunomodulatory agents (e.g., lenalidomide), or proteasome inhibitors (e.g., bortezomib), or targeted therapies, are commonly used to treat PEL. Highly active antiretroviral therapy should be continued or initiated in patients with HIV infection. Randomized controlled trials are lacking. Prognosis remains grim and there exists a need for further investigation into optimal treatment strategies. SUMMARY: PEL is an aggressive mature B-cell neoplasm primarily seen in young to middle aged men with HIV, though immunosuppression related to age and comorbidities such as cirrhosis or organ transplantation also predisposes to PEL. Classic cavitary PEL presents as an effusion in the pleural, pericardial, or peritoneal space. Human herpes virus-8/Kaposi's sarcoma herpes virus) is classically detected. Given its rarity, randomized controlled trials evaluating optimal treatment regimens are lacking, and cyclophosphamide, doxorubicin, vincristine, prednisone-based chemotherapy has been the mainstay of treatment. Advancement in knowledge of the oncogenic signaling pathways involved in Kaposi's sarcoma herpes virus-induced tumorigenesis may pave the way to develop targeted therapies. VIDEO ABSTRACT.

Postoperative sepsis prediction in patients undergoing major cancer surgery.

BACKGROUND: Cancer patients are at increased risk for postoperative sepsis. However, studies addressing the issue are lacking. We sought to identify preoperative and intraoperative predictors of 30-d sepsis after major cancer surgery (MCS) and derive a postoperative sepsis risk stratification tool. METHODS: Patients undergoing one of nine MCSs (gastrointestinal, urological, gynecologic, or pulmonary) were identified within the American College of Surgeons National Surgical Quality Improvement Program (2005-2011, n = 69,169). Multivariable adjusted analyses (MVA) were performed to identify the predictors of postoperative sepsis. A composite sepsis risk score (CSRS) was constructed using the regression coefficients of predictors significant on MVA. The score was stratified into low, intermediate, and high risk, and its predictive accuracy for sepsis, septic shock, and mortality was assessed using the area under the curve analysis. RESULTS: Overall, 4.3% (n = 2954) of patients developed postoperative sepsis. In MVA, Black race (odds ratio [OR] = 1.30, P = 0.002), preoperative hematocrit <30 (OR = 1.40, P = 0.022), cardiopulmonary and cerebrovascular comorbidities (P < 0.010), American Society of Anesthesiologists score >3 (P < 0.05), operative time (OR = 1.002, P < 0.001), surgical approach (OR = 1.81, P < 0.001), and procedure type (P < 0.001) were significant predictors of postoperative sepsis. CSRS demonstrated favorable accuracy in predicting postoperative sepsis, septic shock, and mortality (area under the curve 0.72, 0.75, and 0.74, respectively). Furthermore, CSRS risk stratification demonstrated high concordance with sepsis rates, 1.3% in low-risk patients versus 9.7% in high-risk patients. Similarly, 30-d mortality rate varied from 0.5% to 5.5% (10-fold difference) in low-risk patients versus high-risk patients. CONCLUSIONS: Our study identifies the major risk factors for 30-d sepsis after MCS. These risk factors have been converted into a simple, accurate bedside sepsis risk score. This tool might facilitate improved patient-physician interaction regarding the risk of postoperative sepsis and septic shock.

Premorbid Obesity and Mortality in Patients With Pancreatic Cancer: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Obesity is associated with an increased risk for pancreatic cancer, but it is unclear whether it affects mortality. We performed a systematic review and meta-analysis to assess the association between premorbid obesity and mortality from pancreatic cancer. METHODS: We performed a systematic search through January 2015 and identified studies of the association between premorbid obesity (at least 1 year prior to pancreatic cancer diagnosis) and pancreatic cancer-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence interval (CI), comparing data from obese (body mass index [BMI] ≥30 kg/m(2)) and overweight subjects (BMI, 25.0-29.9 kg/m(2)) with those from individuals with a normal BMI (controls) by using random-effects model. RESULTS: We identified 13 studies (including 3 studies that pooled multiple cohorts); 5 studies included only patients with pancreatic cancer, whereas 8 studies evaluated pancreatic cancer-related mortality in cancer-free individuals at inception. In the meta-analysis, we observed increase in pancreatic cancer-related mortality among overweight (aHR, 1.06; 95% CI, 1.02-1.11; I(2) = 0) and obese individuals (aHR, 1.31; 95% CI, 1.20-1.42; I(2) = 43%), compared with controls; the association remained when we analyzed data from only subjects with pancreatic cancer. Each 1 kg/m(2) increase in BMI was associated with 10% increase in mortality (aHR, 1.10; 95% CI, 1.05-1.15) with minimal heterogeneity (I(2) = 0). In the subgroup analysis, obesity was associated with increased mortality in Western populations (11 studies; aHR, 1.32; 95% CI, 1.22-1.42) but not in Asia-Pacific populations (2 studies; aHR, 0.98; 95% CI, 0.76-1.27). CONCLUSIONS: In a systematic review and meta-analysis, we associated increasing level of obesity with increased mortality in patients with pancreatic cancer in Western but not Asia-Pacific populations. Strategies to reduce obesity-induced metabolic abnormalities might be developed to treat patients with pancreatic cancer.

Novel Cell and Immune Engagers in Optimizing Tumor- Specific Immunity Post-Autologous Transplantation in Multiple Myeloma.

Autologous stem cell transplantation (ASCT) is an important component of treatment of multiple myeloma (MM). The post-ASCT setting offers a unique opportunity to increase myeloma specific immunity through enhancement of T and NK cell responses. The vast array of therapeutics being developed for MM, including cell-based therapies, dendritic vaccines, bispecific antibodies, and IL-15 agonists, provide the opportunity to increase tumor-specific immunity. Maintenance therapies, including immunomodulatory drugs, proteasome inhibitors, and daratumumab, exhibit a significant anti-myeloma response by modulating the immune system. Lenalidomide promotes an antitumoral immune microenvironment, whereas daratumumab can potentially cause NK cell fratricide. Thus, understanding the effects of commonly used maintenance drugs on the restoration of tumor specific immunity is important. In this review, we look at current and emerging therapeutics and their integration post-ASCT in the context of immune reconstitution to improve clinical responses in patients with MM. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Castleman disease: A single-center case series.

BACKGROUND: Castleman disease (CD) is a rare lymphocytic disorder. Unicentric CD (UCD) has an excellent long-term prognosis after surgical excision; however, multicentric CD (MCD) has a severe clinical course with poor outcomes. STUDY DESIGN: We analyzed the clinical presentation of 28 patients treated at a single institution from 1995 to 2017. Demographics, clinical variables, anatomical site, centricity, histopathology, immunochemistry, and surgical approach were reviewed. We evaluated the 5-year recurrence and survival for patients with UCD and MCD. RESULTS: Of the 28 patients, 57 % (n = 16) were female, with a mean age of 41.6 ± 15.6 years. CD was asymptomatic in 57 % (n = 16) of patients, 21 % (n = 6) presented with local symptoms such as pain, and 21 % (n = 6) of patients also had systemic symptoms, including weight loss and fever. CD was unicentric in 64 % (n = 18) and multicentric in 36 % (n = 10). The hyaline vascular variant was noted in 57 % (n = 16) of the tumors, plasmacytoid variant in 36 % (n = 10), and mixed variants in 7% (n = 2) of tumors. Anatomical distributions included: head and neck (20 %), thorax and axilla (24 %), retroperitoneal (13 %), abdominopelvic (30 %) regions, and other (13 %). Complete surgical resection was performed in 95 % of patients with UCD. Surgical biopsy and medical therapy were provided to all patients with MCD. The recurrence rate for UCD and MCD was 6 % (n = 1) and 14 % (n = 1), respectively. The five-year disease-free survival rate for UCD was 95 % (n = 19) and MCD was 33 % (n = 2). We found 100 % survival in patients with UCD and histology demonstrating the HV variant. CONCLUSION: CD is rare and often misdiagnosed due to the absence of specific clinical symptoms. Surgeons should include CD in their differential diagnoses when evaluating patients with lymph node hyperplasia. Surgery can be curative in nearly all patients with UCD. Patients with MCD require a combination of surgical therapy, chemotherapy, and immunotherapy; however, cytoreductive surgery benefits for patients with MCD have not been established.

Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with an immunosuppressive microenvironment that is resistant to most therapies. IL17 is involved in pancreatic tumorigenesis, but its role in invasive PDAC is undetermined. We hypothesized that IL17 triggers and sustains PDAC immunosuppression. We inhibited IL17/IL17RA signaling using pharmacological and genetic strategies alongside mass cytometry and multiplex immunofluorescence techniques. We uncovered that IL17 recruits neutrophils, triggers neutrophil extracellular traps (NETs), and excludes cytotoxic CD8 T cells from tumors. Additionally, IL17 blockade increases immune checkpoint blockade (PD-1, CTLA4) sensitivity. Inhibition of neutrophils or Padi4-dependent NETosis phenocopies IL17 neutralization. NMR spectroscopy revealed changes in tumor lactate as a potential early biomarker for IL17/PD-1 combination efficacy. Higher expression of IL17 and PADI4 in human PDAC corresponds with poorer prognosis, and the serum of patients with PDAC has higher potential for NETosis. Clinical studies with IL17 and checkpoint blockade represent a novel combinatorial therapy with potential efficacy for this lethal disease.

Use of platelet and erythroid growth factors during induction chemotherapy for acute lymphoblastic leukaemia in a Jehovah's Witness.

We present a 21-year-old woman diagnosed with Philadelphia (Ph) chromosome-like CD20 positive B-cell acute lymphoblastic leukaemia (ALL). She was a Jehovah's Witness (JW) and declined all blood product transfusion support. She was initiated on the CALGB 10403 chemotherapy protocol for her ALL. She received darbepoetin alfa and romiplostim as supportive therapies for her disease/chemotherapy-associated anaemia and thrombocytopaenia. A complete remission was achieved with negative minimal residual disease and she remains in remission 18 months after diagnosis. This case report describes the successful treatment of an adult JW with Ph-like CD20 +B cell ALL, in the absence of blood product transfusions, using growth factor support.

Obesity is Independently Associated With Increased Risk of Hepatocellular Cancer-related Mortality: A Systematic Review and Meta-Analysis.

OBJECTIVE: Excess body weight is associated with increased risk of developing hepatocellular cancer (HCC), but its effect on HCC-related mortality remains unclear. We performed a systematic review and meta-analysis to assess the association between premorbid obesity and HCC-related mortality. MATERIALS AND METHODS: Through a systematic literature search-up to March 2016, we identified 9 observational studies (1,599,453 individuals, 5705 HCC-related deaths) reporting the association between premorbid body mass index (BMI), and HCC-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence intervals (CIs), comparing obese (BMI>30 kg/m(2)) and overweight (BMI, 25 to 29.9 kg/m(2)) individuals with normal BMI individuals using random-effects model. RESULTS: On meta-analysis, compared with individuals with normal BMI, obese (aHR, 1.95; 95% CI, 1.46-2.46), but not overweight individuals (aHR, 1.08; 95% CI, 0.97-1.21), had higher HCC-related mortality, with moderate heterogeneity. On subgroup analysis, magnitude of increased mortality was higher in obese men (aHR, 2.50; 95% CI, 2.02-3.09; 3 studies) as compared with obese women (aHR, 1.45; 95% CI, 1.08-1.97; 2 studies). The impact of premorbid obesity on HCC-related mortality was observed only in western populations (aHR, 2.10; 95% CI, 1.77-2.48; 4 studies), but not Asian populations (aHR, 1.10; 95% CI, 0.63-1.92; 1 study). There was limited assessment of competing risk because of advanced liver disease. CONCLUSIONS: On the basis of this meta-analysis, premorbid obesity may be independently associated with a 2-fold risk of HCC-related mortality. This association was more pronounced in men and western populations. Strategies targeting obesity-associated metabolic abnormalities may provide novel pathways for HCC therapy.

Durable complete remission with combination chemotherapy and bortezomib in HIV-associated plasmablastic lymphoma.

Plasmablastic lymphoma (PBL) is an aggressive form of non-Hodgkin's lymphoma (NHL) classically seen in patients infected with the human immunodeficiency virus, but can also be seen in other immunocompromised states such as transplant recipients, autoimmune diseases and the elderly. PBL is generally associated with a poor prognosis despite chemotherapy. There is evidence supporting the use of bortezomib in combination with standard chemotherapy to achieve durable responses in patients with PBL. We describe a patient with acquired immunodeficiency syndrome who presented with rectal pain and bright red blood per rectum. He was diagnosed with stage IVA PBL with anorectal, nodal, calvarial and hepatic involvement. Along with highly active antiretroviral therapy, he was treated with six cycles of dose adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-EPOCH) plus bortezomib resulting in durable complete remission 30 months after diagnosis.

Biological agents in gastrointestinal cancers: adverse effects and their management.

Biological therapy comprises agents that by virtue of their unique mechanisms of action, are able to specifically incite a response against or target malignant cells. They differ from conventional chemotherapy with regard to mechanisms of action, indications and side effect profile. Biologic agents have revolutionized therapy for a number of malignancies. In the setting of gastrointestinal (GI) malignancies, agents targeting vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (Her2/Neu) and epidermal growth factor receptor (EGFR) have proven to be invaluable additions to chemotherapy. However, these agents bring with them a set of side effects attributable to their unique mechanisms of action. The anti VEGF agents-bevacizumab, aflibercept and ramucirumab, can result in renal and vascular complications such as hypertension, arterial thrombotic events (ATE), proteinuria and GI perforations. The anti EGFR agents classically cause dermatological toxicities, in addition to hypomagnesemia, which can be dose limiting for patients. Trastuzumab, a monoclonal antibody that targets Her2/Neu, is known to cause cardiotoxicity, especially when used with anthracyclines. Use of immunotherapy agents such as nivolumab is associated with the development immune related adverse events (irAEs). The use of these agents is expected to increase over the next few years and it is crucial that patients and practitioners are aware of their adverse effects and current management strategies. This review highlights the adverse events associated with the use of biologic and immunologic therapies in GI cancers, their incidence and current management strategies.

Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer.

Pancreatic tumors are renowned for their extremely hypoxic centers, resulting in upregulation of a number of hypoxia mediated signaling pathways including cell proliferation, metabolism and cell survival. Previous studies from our laboratory have shown that Minnelide, a water-soluble pro-drug of triptolide (anti-cancer compound), decreases viability of cancer cells in vitro as well as in vivo. However, its mechanism of action remain elusive. In the current study we evaluated the effect of Minnelide, on hypoxia mediated oncogenic signaling as well as stemness in pancreatic cancer. Minnelide has just completed Phase 1 trial against GI cancers and is currently awaiting Phase 2 trials. Our results showed that upon treatment with triptolide, HIF-1α protein accumulated in pancreatic cancer cells even though hypoxic response was decreased in them. Our studies showed even though HIF-1α is accumulated in the treated cells, there was no decrease in HIF-1 binding to hypoxia response elements. However, the HIF-1 transcriptional activity was significantly reduced owing to depletion of co-activator p300 upon treatment with triptolide. Further, treatment with triptolide resulted in a decreased activity of Sp1 and NF-kB the two major oncogenic signaling pathway in pancreatic cancer along with a decreased tumor initiating cell (TIC) population in pancreatic tumor.