Evolving or immutable - phase I solid tumor trials in the era of precision oncology.

In the era of precision oncology (PO), systemic therapies for patients (pts) with solid tumors have shifted from chemotherapy (CT) to targeted therapy (TT) and immunotherapy (IO). This systematic survey describes features of trials enrolling between 2010 and 2020, focusing on inclusion criteria, type of dose escalation scheme (DES) utilized, and use of expansion cohorts (ECs). A literature search identified phase I studies in adults with solid tumors published January 1, 2000- December 31, 2020 from 12 journals. We included only studies enrolling between 2010 and 2020 to better capture the PO era. Two reviewers abstracted data; a third established concordance. Of 10,744 studies, 10,195 were non-topical or enrolled prior to 2010; 437 studies were included. The most common drug classes were TT (47.6%), IO (22%), and CT (6.9%). In studies which reported race, patients were predominantly white (61.7%) or Asian (25.7%), followed by black (6.5%) or other (6.1%). Heterogeneity was observed in the reporting and specification of study inclusion criteria. Only 40.1% of studies utilized ECs, and among the studies which used ECS, 46.6% were defined by genomic selection. Rule-based DES were used in 89% of trials; a 3+3 design was used in 80.5%. Of all drugs tested, 37.5% advanced to phase II, while 10.3% garnered regulatory licensure (for an indication tested in phase I). In the era of PO, TT and IO have emerged as the most studied agents in phase I trials. Rule-based DES, which are more relevant for escalating CT, are still chiefly utilized.

Carcinoid Heart Disease Management: A Multi-Disciplinary Collaboration.

Carcinoid heart disease (CaHD) is an important complication among patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS). CS patients (25%-65%) eventually develop CaHD; these patients face a significantly increased risk of morbidity and mortality. Guidance papers (eg, clinical practice guidelines, consensus guidelines, and expert statements) have been established by major organizations across the disciplines of cardiology and oncology; however, these recommendations are not routinely implemented. The aim of this article is to encourage the integration of current recommendations from national societies into clinical practice. Early screening upon recognition of CS and prior to the development of CaHD symptoms is paramount, as no existing therapies are approved to reverse the fibrotic damage to the heart once it occurs. Valvular replacement is the only definitive treatment for CaHD once it has developed. When patients are noted to have urinary 5-hydroxyindoleacetic acid (5-HIAA) levels ≥300 µmol/24 h and/or serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels >260 pg/mL, echocardiography is recommended. Systemic approaches to control tumor growth and hormonal secretion include somatostatin analogs (SSAs), followed by options including peptide receptor radiotherapy (PRRT), everolimus and liver embolization. Telotristat is the primary choice for control of diarrhea refractory to SSA. Diuretics are the mainstay of heart failure symptom management for patients who develop CaHD. Considerations for future research are discussed, including the ongoing TELEHEART (TELotristat Ethyl in a HEART biomarker study) trial involving telotristat and not yet activated CHARRT (Carcinoid Heart disease And peptide Receptor Radiotargetted Therapy) study involving PRRT with lutetium 177 (177Lu) dotatate.

18F-FDG PET/CT improves diagnostic certainty in native and prosthetic valve Infective Endocarditis over the modified Duke Criteria.

BACKGROUND: International guidance recognizes the shortcomings of the modified Duke Criteria (mDC) in diagnosing infective endocarditis (IE) when transoesophageal echocardiography (TOE) is equivocal. 18F-FDG PET/CT (PET) has proven benefit in prosthetic valve endocarditis (PVE), but is restricted to extracardiac manifestations in native disease (NVE). We investigated the incremental benefit of PET over the mDC in NVE. METHODS: Dual-center retrospective study (2010-2018) of patients undergoing myocardial suppression PET for NVE and PVE. Cases were classified by mDC pre- and post-PET, and evaluated against discharge diagnosis. Receiver Operating Characteristic (ROC) analysis and net reclassification index (NRI) assessed diagnostic performance. Valve standardized uptake value (SUV) was recorded. RESULTS: 69/88 PET studies were evaluated across 668 patients. At discharge, 20/32 had confirmed NVE, 22/37 PVE, and 19/69 patients required surgery. PET accurately re-classified patients from possible, to definite or rejected (NRI: NVE 0.89; PVE 0.90), with significant incremental benefit in both NVE (AUC 0.883 vs 0.750) and PVE (0.877 vs 0.633). Sensitivity and specificity were 75% and 92% in NVE; 87% and 86% in PVE. Duration of antibiotics and C-reactive Protein level did not impact performance. No diagnostic SUV cut-off was identified. CONCLUSION: PET improves diagnostic certainty when combined with mDC in NVE and PVE.

All in the Levels-Programmed Death-Ligand 1 Expression as a Biomarker for Immune Checkpoint Inhibitor Response in Patients with Gastrointestinal Cancer.

Immune checkpoint inhibitors (ICIs) benefit patients with rare subsets of gastrointestinal (GI) cancer. Significant interest exists to identify predictive biomarkers that may increase the applicability of ICI therapy for these patients. Programmed death ligand 1 (PD-L1) is one such candidate; however, this biomarker has well-chronicled limitations. Combined positive score (CPS) ≥1 is the minimum PD-L1 expression threshold necessary for patients with gastric or gastroesophageal junction (GEJ) cancer to qualify for treatment with pembrolizumab; however, studies suggest that patients with higher CPS scores may derive greater benefit. We present the cases of two patients, both with low tumor mutational burden, microsatellite stable, and CPS ≥70 GI tumors (cholangiocarcinoma and GEJ cancer), who have achieved excellent tumor control with pembrolizumab. We postulate that, by testing for CPS in all patients with GI cancer and identifying a CPS threshold predictive of ICI response, PD-L1 expression could identify the patiets with GI cancer, in tissue agnostic fashion, who could benefit from ICI therapy.

Mismatch Repair (MMR) Gene Alteration and BRAF V600E Mutation Are Potential Predictive Biomarkers of Immune Checkpoint Inhibitors in MMR-Deficient Colorectal Cancer.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. MATERIALS AND METHODS: Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. RESULTS: A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001). CONCLUSION: BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. IMPLICATIONS FOR PRACTICE: The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

Can an amino acid mixture alleviate gastrointestinal symptoms in neuroendocrine tumor patients?

BACKGROUND: Neuroendocrine tumors, although relatively rare in incidence, are now the second most prevalent gastrointestinal neoplasm owing to indolent disease biology. A small but significant sub-group of neuroendocrine tumor patients suffer from diarrhea. This is usually secondary to carcinoid syndrome but can also be a result of short gut syndrome, bile acid excess or iatrogenic etiologies. Recently, an amino acid based oral rehydration solution (enterade® Advanced Oncology Formula) was found to have anti-diarrheal properties in preclinical models. METHODS: A retrospective chart review of all NET patients treated with enterade® AO was performed after IRB approval. RESULTS: Ninety-eight NET patients who had received enterade® AO at our clinic from May 2017 through June 2019 were included. Patients (N = 49 of 98) with follow up data on bowel movements (BMs) were included for final analysis. Eighty-four percent of patients (41/49) had fewer BMs after taking enterade® AO and 66% (27/41) reported more than 50% reduction in BM frequency. The mean number of daily BMs was 6.6 (range, 3-20) at baseline before initiation of therapy, while the mean number of BMs at 1 week time point post enterade® AO was 2.9 (range, 0-11). CONCLUSIONS: Our retrospective observations are encouraging and support prospective validation with appropriate controls in NET patients. This is first published report of the potential anti-diarrheal activity of enterade® AO in NET patients.

Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

Epidemiology, Incidence, and Prevalence of Neuroendocrine Neoplasms: Are There Global Differences?

PURPOSE OF REVIEW: The purpose of our review is to explore global epidemiologic trends of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). Specifically, we sought to examine whether there are differences in incidence, prevalence, distribution (by primary tumor site, tumor grade, tumor stage at presentation), and overall survival of GEP NETs between different regions of the world. RECENT FINDINGS: GEP NET incidence rates are rising steadily in North America, Asia, and Europe, though this rise appears to be most profound in North America. The distribution of GEP NETs differs regionally as in North America small intestinal and rectal NETs are most prevalent, in Asia rectal and pancreatic NETs are most prevalent, and in Europe small intestinal and pancreatic NETs are most prevalent. Overall survival for patients with GEP NETs appears to be improving with time. Some of the global increase in GEP NET incidence can be explained by increased health care utilization. This factor alone, however, does not explain the rise completely. Population-based studies utilizing uniform data collection instruments and a standard pathologic grading system are needed to identify other factors which may be contributing to this phenomenon.

Molecular biohydrogen production by dark and photo fermentation from wastes containing starch: recent advancement and future perspective.

Changing lifestyle is increasing the energy demand. Fossil fuel is unable to deliver such huge energy. Clean energy from renewable source can solve this problem. Hydrogen is a clean and energy-efficient fuel and used for electricity generation by fuel cells or can be used in combustion engine. Easy availability of starch wastes from different industrial food processing wastes makes it a potential source for hydrogen (H2) generation. Among various processes such as steam reforming, electrolysis, biophotolysis of water and anaerobic fermentation, anaerobic fermentation technique is environmentally friendly and requires less external energy, making it a preferred process for H2 generation. Dark fermentation process can use wide range of substrates including agricultural and industrial starchy waste with low level of undesirable compounds. Application of both anaerobic dark and photofermentation can improve H2 yield and production rate. H2 production from wastes containing starch serves dual benefit of waste reduction and energy generation. As starch is a polymer and all hydrogen-producing bacteria cannot produce amylase to hydrolyze it, a pretreatment step is required to convert starch into glucose and maltose. In this present review paper, we have summarized: (i) potential of various types of starch-containing wastes as feedstock, (ii) various fermentation techniques, (iii) optimization of external process parameter, (iv) application of bioreactor and simulation in fermentation technique and (v) advancement in H2 production from starchy wastes.

Association of Vegetation Size With Valve Destruction, Embolism and Mortality.

AIM: The mortality of patients with infective endocarditis (IE) is high. The management of patients with large vegetations is controversial. This study sought to investigate the association of vegetation size on outcomes including valve destruction, embolism and mortality. METHODS AND RESULTS: One hundred and forty-two (142) patients with definite IE and transoesophageal echocardiography (TEE) imaging available for analysis were identified and data retrospectively reviewed. Vegetation length, width and area were measured. Severe valve destruction was defined as the composite of one or more of severe valve regurgitation, abscess, pseudoaneurysm, perforation or fistula. Associations with 6-month mortality were identified by Cox regression analysis. Eighty (80) (56.3%) patients had evidence of valve destruction on TEE. Vegetation length ≥10 mm and vegetation area ≥50 mm2 were significantly associated with increased risk of valve destruction, (both odds ratio OR 1.21, p=0.03 and p=0.02 respectively). Thirty-nine (39) (72.2%) patients who had an embolic event, did so prior initiation of antibiotics. Six (6)-month mortality was 18.3%. In the surgically managed group, vegetation size was not associated with mortality. In the medically managed group, vegetation area (mm2) was associated with increased mortality (HR 1.01, p<0.01) along with age (HR 1.06, p=0.03). CONCLUSION: Vegetation length ≥10 mm or area ≥50 mm2 are associated with increased risk of valve destruction. Vegetation size may also predict mortality in medically managed but not surgically managed patients with IE. Further studies to evaluate whether surgery in patients with large vegetation size improves outcomes is warranted.