Survival and Toxicity in Patients With Unresectable or Inoperable Biliary Tract Cancers With Ablative Radiation Therapy Versus Nonablative Chemoradiation.

Purpose: Conventional chemoradiation (CCRT) is inadequately effective for the treatment of unresectable or inoperable biliary tract cancers (UIBC). Ablative radiation therapy (AR), typically defined as a biologically effective dose (BED) ≥80.5 Gy, has shown some promise in terms of local control and survival in these patients. We compare the efficacy and toxicity of AR to non-AR in UIBC patients. Methods and Materials: Patients with UIBC treated with stereotactic body radiation therapy (SBRT; n = 18) or CCRT (n = 28) between 2006 and 2021 were retrospectively analyzed. The associations of treatment, BED groups, selected characteristics with overall survival (OS), progression-free survival (PFS), and local control were estimated separately using Cox proportional hazards regression. Toxicity was scored using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: Median dose fractionation was 60 Gy in 5 fractions (median BED, 127 Gy) for SBRT and 50 Gy in 25 fractions (median BED, 64 Gy) for CCRT. The median follow-up of the entire cohort was 11.5 months. The 1-year OS rate was 62% for BED <80.5 versus 66% for BED ≥80.5 (P = .069). The 1-year PFS rate was 24% for BED <80.5 and 29% for BED ≥80.5 (P = .050). The 1-year local control rate was 20% for BED <80.5 and 41% for BED ≥80.5 (P = .097). BED as a continuous variable (P = .013), BED ≥100 Gy (P = .044), and race (white versus nonwhite) (P = .037) were associated with improved overall mortality. BED ≥80.5 Gy (P = .046), smaller tumor size (<5 cm; P = .038) and N0 disease (P <.0001) were associated with improved disease progression rates. Local control was improved in patients with N0 disease compared with N1 disease (P <.0001). Both treatments were well tolerated; there was no difference in acute and late toxicity between AR and non-AR. Conclusions: In this review, there was improved PFS with BED ≥80.5 Gy with a trend toward OS benefit. BED ≥80.5 Gy was achieved mostly through SBRT and was well tolerated. AR could be considered a more effective treatment modality than CCRT in patients with UIBC.

Smoking history is associated with reduced efficacy of neoadjuvant therapy in pancreatic adenocarcinoma.

BACKGROUND: Differential responses to neoadjuvant therapy (NAT) exist in pancreatic ductal adenocarcinoma (PDAC); however, contributing factors are poorly understood. Tobacco smoke is a common risk factor for PDAC, with nicotine-induced chemoresistance observed in other cancers. This study aimed to explore the potential association between tobacco use and NAT efficacy in PDAC. METHODS: A single-center, retrospective analysis was conducted that included all consecutive patients with PDAC who underwent surgical resection after NAT with a documented smoking history (N = 208). NAT response was measured as percentage fibrosis in the surgical specimen. Multivariable models controlled for covariates and survival were modeled using the Kaplan-Meier method. RESULTS: Postoperatively, major responses to NAT (>95% fibrosis) were less frequently observed in smokers than in nonsmokers (13.7% vs 30.4%, respectively; P = .021). Pathologic complete responses were similarly less frequent in smokers than in nonsmokers (2.1% vs 9.9%, respectively; P = .023). On multivariate analysis controlling for covariates, smoking history remained independently associated with lower odds of major fibrosis (odds ratio [OR], 0.25; 95% CI, 0.10-0.59; P = .002) and pathologic complete response (OR, 0.21; 95% CI, 0.03-0.84; P = .05). The median overall survival was significantly longer in nonsmokers than in smokers (39.1 vs 26.6 months, respectively; P = .05). CONCLUSION: Tobacco use was associated with diminished pathologic responses to NAT. Future research to understand the biology underlying this observation is warranted and may inform differential NAT approaches or counseling among these populations.

Type of neoadjuvant treatment strategy is associated with differential pathologic responses in pancreatic ductal adenocarcinoma.

BACKGROUND: Tumor fibrosis after neoadjuvant treatment (NAT) for pancreatic ductal adenocarcinoma (PDAC) correlates with treatment response. Herein we assessed how different NAT strategies influence pathologic responses and survival. METHODS: Patients with surgically resected PDAC who received NAT (1991-2020) were included. Descriptive statistics compared outcomes amongst fibrosis groups (none, minor <50 â€‹%, partial 51%-94 â€‹%, major ≥95 â€‹%) and NAT (chemotherapy alone, chemoradiation, or chemotherapy â€‹+ â€‹chemoradiation (total neoadjuvant therapy, TNT)). RESULTS: Patients with major fibrosis most often received TNT (65.8 â€‹%, p â€‹< â€‹0.001). Major fibrosis was associated with the greatest rate of downstaging (77.8 â€‹%, p â€‹< â€‹0.001), highest R0 margin rate (100 â€‹%, p â€‹< â€‹0.01), and lowest mean positive lymph node ratio (0.80, p â€‹< â€‹0.01). Amongst complete responders, 11/14 (78.6 â€‹%) received TNT. Median overall (66.3 months, p â€‹= â€‹0.003) and disease-free (54.7months, p â€‹= â€‹0.05) survival were highest with major fibrosis. CONCLUSIONS: Major fibrosis and complete pathologic responses after NAT are most frequent with a TNT strategy and are associated with improved outcomes.

Phenotypic Characterization of Recombinant Marek's Disease Virus in Live Birds Validates Polymorphisms Associated with Virulence.

Marek's disease (MD) is a highly infectious lymphoproliferative disease in chickens with a significant economic impact. Mardivirus gallidalpha 2, also known as Marek's disease virus (MDV), is the causative pathogen and has been categorized based on its virulence rank into four pathotypes: mild (m), virulent (v), very virulent (vv), and very virulent plus (vv+). A prior comparative genomics study suggested that several single-nucleotide polymorphisms (SNPs) and genes in the MDV genome are associated with virulence, including nonsynonymous (ns) SNPs in eight open reading frames (ORF): UL22, UL36, UL37, UL41, UL43, R-LORF8, R-LORF7, and ICP4. To validate the contribution of these nsSNPs to virulence, the vv+MDV strain 686 genome was modified by replacing nucleotides with those observed in the vMDV strains. Pathogenicity studies indicated that these substitutions reduced the MD incidence and increased the survival of challenged birds. Furthermore, using the best-fit pathotyping method to rank the virulence, the modified vv+MDV 686 viruses resulted in a pathotype similar to the vvMDV Md5 strain. Thus, these results support our hypothesis that SNPs in one or more of these ORFs are associated with virulence but, as a group, are not sufficient to result in a vMDV pathotype, suggesting that there are additional variants in the MDV genome associated with virulence, which is not surprising given this complex phenotype and our previous finding of additional variants and SNPs associated with virulence.

NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023.

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

Patent Challenges And Litigation On Inhalers For Asthma And COPD.

Between 1986 and 2020 the Food and Drug Administration (FDA) approved fifty-three brand-name inhalers for asthma and chronic obstructive pulmonary disease (COPD), but by the end of 2022 only three of those inhalers faced independent generic competition. Manufacturers of brand-name inhalers have created long periods of market exclusivity by obtaining multiple patents, many on the delivery devices rather than the active ingredients, and by introducing new devices that contain old active ingredients. Limited generic competition for inhalers has raised questions about whether the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Act, for challenging patents is adequately facilitating the entry of complex generic drug-device combinations. For the fifty-three brand-name inhalers approved during the period 1986-2020, generic manufacturers filed challenges authorized by the Hatch-Waxman Act, which are known as paragraph IV certifications, on only seven products (13 percent). The median time from FDA approval to first paragraph IV certification was fourteen years. Paragraph IV certifications resulted in approved generics for only two products, each of which experienced fifteen years of market exclusivity before generic approval. Reform of the generic drug approval system is critical to ensuring the timely availability of competitive markets for generic drug-device combinations such as inhalers.

Discrepancies in survival after conversion to open in minimally invasive pancreatoduodenectomy.

BACKGROUND: The extent by which conversion to open (CTO) during minimally invasive procedures for pancreatic cancer impact survival outcomes is not fully understood. METHODS: The 2010-2017 National Cancer Database identified 12,424 non-metastatic patients who underwent pancreatoduodenectomy for ductal adenocarcinoma. Patients were stratified into three cohorts: open (OPD), completed MIPD (cMIPD), and CTO. Subgroups were dichotomized by hospital MIPD volume. RESULTS: Across the study period, 80.6% of patients underwent OPD, 19.4% MIPD, and 24% were CTO. Median overall survival was worse after CTO (21.8 months) than for OPD (23.6 months) or cMIPD (25.2 months) (p < 0.001). Although this effect persisted for <10 MIPD/year, CTO did comparably to OPD at hospitals performing ≥10MIPD/year (CTO = 26.8 months, OPD = 27.9 months; p = 0.128). Ninety-day mortality after CTO was worse at ≤ 10 MIPD/year hospitals (9.3% vs. 2.6%). CONCLUSIONS: Short and long-term survival is impacted by CTO after MIPD, especially at lower surgical volumes, stressing careful adoption while ascending the learning curve.

Total Neoadjuvant Treatment for Pancreatic Ductal Adenocarcinoma Is Associated With Limited Lymph Node Yield but Improved Ratio.

INTRODUCTION: The lymph node yield (LNY) and lymph node ratio (LNR) of nodal metastases following pancreatoduodenectomy (PD) have been reported as prognostic parameters in patients with pancreatic ductal adenocarcinoma (PDAC). However, they have not been compared in the setting of various neoadjuvant therapy modalities. METHODS: A single institutional retrospective study identified 134 patients diagnosed with resectable, BLR- and LA-PDAC who underwent PD at Fox Chase Cancer Center between 2010 and 2019. Patients were categorized based on first-line treatment as follows: surgery first (SF), total neoadjuvant therapy (TNT), and single modality neoadjuvant therapy (SMNT). The histopathological reports of the surgical specimens were examined to obtain LNY and determine the counts of lymph nodes with metastases. Subsequently, LNR was calculated as the number of positive lymph nodes divided by the number of lymph nodes examined. RESULTS: Overall, 49, 38, 27, 12, and 8 patients underwent SF approach, SMNT, incomplete TNT, induction TNT, and consolidation TNT, respectively. There was no difference in R0 resection and vascular resection between the groups (P = 0.096 and 0.794, respectively). The median counts of LNY were 22, 15, 21, 11.5, and 10, respectively (P < 0.001). The average LNR was 0.16, 0.07, 0.03, 0.02, and 0.02, respectively (P < 0.001). There were statistically significant differences in overall survival in the TNT groups (log-rank test P = 0.030). CONCLUSIONS: PDAC patients who undergo the TNT modality exhibit lower LNY and improved LNR compared with the SF approach and SMNT neoadjuvant therapy groups. This is likely explained by the increased treatment response and lymph node obliteration associated with the TNT approach. Our results question the minimal requirement of 11-18 harvested lymph nodes for PD following TNT.

Total neoadjuvant therapy is associated with improved overall survival and pathologic response in pancreatic adenocarcinoma.

BACKGROUND: Few studies have evaluated outcomes of total neoadjuvant therapy (TNT) compared with single modality neoadjuvant therapy (SMNT) or surgery first (SF) for pancreatic ductal adenocarcinoma (PDAC). METHODS: A single-institution retrospective review of PDAC patients who underwent pancreatectomy was conducted (1993-2019). Overall survival (OS) estimates from diagnosis and from surgery were determined using Kaplan-Meier methods; Cox proportional hazards models adjusted for covariates. RESULTS: Surgery was performed upfront (SF) in 168 (46.9%), while 111 (31.0%) had chemotherapy or chemoradiation before resection (SMNT), and 79 (22.1%) underwent TNT (chemotherapy and chemoradiation). Resection margins were more frequently R0 in the TNT group (86.1%) compared with SMNT (64.0%) and SF (72%) (p < 0.001). Complete pathologic response was more common in the TNT group (10.1%) compared with SMNT (3.6%) or SF (0.6%) (p = 0.001), resulting in prolonged survival (median OS = 100.2 months). TNT patients demonstrated longer median OS from surgery (33.6 months) compared with SF (19.1 months) and SMNT (17.4 months) (p = 0.010), which persisted after controlling for covariates. CONCLUSIONS: TNT is associated with more frequent complete pathologic response, a higher rate of margin negative resection, and prolonged OS as compared with SF or SMNT. Additional studies to identify subgroups that derive the greatest benefit are warranted.

The Assessment and Treatment of Inpatient Cancer-Related Pain with Acupuncture: Development of a Manual.

Background and Objective: Pain is a highly prevalent and distressing experience of hospitalized patients with cancer, and undertreatment is a challenging issue. Adding nonpharmacologic treatments such as acupuncture to conventional pain management may help address a patient's total pain experience. A dearth of acupuncture treatment guidelines exists, leaving individual practitioners to develop treatments themselves. The aim of the work described in this report was to develop a standardized clinical reference manual for East Asian Medicine (EAM) assessment, diagnosis, and acupuncture treatment of cancer-related pain in hospitalized patients with cancer. Design: The acupuncture manual was developed based on: (1) a narrative review of existing literature on acupuncture and cancer pain; (2) a review of acupuncture charting notes of more than 200 treatments provided in an inpatient setting; and (3) meetings of an expert panel of senior acupuncturists to reach consensus on a manual protocol. Results: The resulting manual described diagnosis of patients based on EAM constitution, symptoms and signs, and channel location of the cancer-related pain symptoms. The resulting point selections for acupuncture treatment enables adaptability, reproducibility, and individualized acupuncture treatment of cancer-related pain in hospitalized patients with cancer. Conclusions: The manual fills a vital gap in the current literature, and supports community- and hospital-based acupuncturists as a standardized clinical reference. The manual provides guidance for cancer-related pain management, using EAM acupuncture in hospitalized patients.

Tumor mutational burden and somatic mutation status to predict disease recurrence in advanced melanoma.

Tumor mutational burden (TMB) has recently been identified as a biomarker of response to immune checkpoint inhibitors in many cancers, including melanoma. Co-assessment of TMB with inflammatory markers and genetic mutations may better predict disease outcomes. The goal of this study was to evaluate the potential for TMB and somatic mutations in combination to predict the recurrence of disease in advanced melanoma. A retrospective review of 85 patients with stage III or IV melanoma whose tumors were analyzed by next-generation sequencing was conducted. Fisher's exact test was used to assess differences in TMB category by somatic mutation status as well as recurrence locations. Kaplan-Meier estimates and Cox-proportional regression model were used for survival analyses. The most frequently detected mutations were TERT (32.9%), CDKN2A (28.2%), KMT2 (25.9%), BRAF V600E (24.7%), and NRAS (24.7%). Patients with TMB-L + BRAFWT status were more likely to have a recurrence [hazard ratio (HR), 3.43; confidence interval (CI), 1.29-9.15; P = 0.01] compared to TMB-H + BRAF WT. Patients with TMB-L + NRASmut were more likely to have a recurrence (HR, 5.29; 95% CI, 1.44-19.45; P = 0.01) compared to TMB-H + NRAS WT. TMB-L tumors were associated with local (P = 0.029) and in-transit (P = 0.004) recurrences. Analysis of TMB alone may be insufficient in understanding the relationship between melanoma's molecular profile and the body's immune system. Classification into BRAFmut, NRASmut, and tumor mutational load groups may aid in identifying patients who are more likely to have disease recurrence in advanced melanoma.

Total neoadjuvant therapy for pancreatic adenocarcinoma increases probability for a complete pathologic response.

BACKGROUND: Multiple neoadjuvant therapy protocols have been proposed in the treatment of pancreatic adenocarcinoma, including chemotherapy (CT), chemoradiation (CRT), and total neoadjuvant therapy (TNT), defined as a CT plus CRT. A pathologic complete response (pCR) can be achieved in a minority of cases. We hypothesize that TNT is more likely to confer pCR than other neoadjuvant therapies, which may improve overall survival (OS). METHODS: A retrospective review of the National Cancer Database (NCDB) from 2006 to 2016 was performed, identifying patients who underwent any neoadjuvant therapy followed by definitive pancreatic resection for locally advanced or borderline resectable pancreatic adenocarcinoma. A pathologic complete response was defined as down-staging from any clinical stage to pathologic stage 0. RESULTS: A total of 5402 patients who received neoadjuvant therapy followed by resection were identified. 177 patients (3.3%) achieved a pCR. Of the patients who achieved a pCR, 57 received CT, 41 CRT and 79 received TNT. On multivariate analysis, TNT was more likely to confer a pCR than CRT (OR 1.67, CI 1.13-2.46, p = 0.0103) or CT (OR 2.61, CI 1.83-3.71, p < 0.0001). Patients who achieved pCR had a significantly higher OS, with median survival of 64.9 months, compared to 21.6 months in patients who did not achieve pCR (p < 0.0001). CONCLUSION: TNT may be more likely to achieve a pCR than CT or CRT. Patients who achieve a pCR have a significant OS benefit as compared to those who have residual disease. TNT should be considered for patients requiring neoadjuvant therapy, as it may increase the likelihood of achieving a pCR, thus potentially improving OS.

Neoadjuvant Chemoradiation Impacts the Prognostic Effect of Surgical Margin Status in Pancreatic Adenocarcinoma.

BACKGROUND: Many studies show significantly improved survival after R0 resection compared with R1 resection in pancreatic adenocarcinoma (PAC); however, the effect of neoadjuvant chemoradiation (NACRT) on this association is unknown. OBJECTIVE: The aim of this study was to evaluate the prognostic significance of positive surgical margins (SMs) after NACRT compared with upfront surgery + adjuvant therapy in PAC. METHODS: All cases of surgically resected PAC at a single institution were reviewed from 1996 to 2014; patients treated with palliative intent, metastatic disease, and biliary/ampullary tumors were excluded. The primary endpoint was overall survival (OS). RESULTS: Overall, 300 patients were included; 134 patients received NACRT with concurrent 5-fluorouracil or gemcitabine followed by surgery, and 166 patients received upfront surgery (+ adjuvant chemotherapy in 72% of patients and RT in 65%); 31% of both groups had a positive SM (+SM). The median OS for patients with a +SM or negative SM (-SM) was 26.6 and 31.6 months, respectively for NACRT, and 12.0 and 24.5 months, respectively, for upfront surgery. OS was significantly improved with -SM compared with +SM in both groups (p = 0.006). When resection yielded +SM, NACRT patients had improved OS compared with upfront surgery patients (p < 0.001). On multivariable analysis, +SM in the upfront surgery group (hazard ratio [HR] 2.94, 95% confidence interval [CI] 2.04-4.24; p < 0.001) and older age (HR 1.01, 95% CI 1.00-1.03, per year; p = 0.007) predicted worse OS. +SM in the NACRT group was not associated with worse OS (HR 1.09, 95% CI 0.72-1.65; p = 0.70). CONCLUSION: Patients with a positive margin after NACRT and surgery had longer survival compared with patients with a positive margin after upfront surgery. NACRT should be strongly considered for patients at high risk of R1 resections.

Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor.

The majority of gastrointestinal stromal tumor (GIST) patients develop resistance to the first-line KIT inhibitor, imatinib mesylate (IM), through acquisition of secondary mutations in KIT or bypass signaling pathway activation. In addition to KIT, AKT is a relevant target for inhibition, since the PI3K/AKT pathway is crucial for IM-resistant GIST survival. We evaluated the activity of a novel pan-AKT inhibitor, MK-4440 (formerly ARQ 751), as monotherapy and in combination with IM in GIST cell lines and preclinical models with varying IM sensitivities. Dual inhibition of KIT and AKT demonstrated synergistic effects in IM-sensitive and -resistant GIST cell lines. Proteomic analyses revealed upregulation of the tumor suppressor, PDCD4, in combination treated cells. Enhanced PDCD4 expression correlated to increased cell death. In vivo studies revealed superior efficacy of MK-4440/IM combination in an IM-sensitive preclinical model of GIST compared with either single agent. The combination demonstrated limited efficacy in two IM-resistant models, including a GIST patient-derived xenograft model possessing an exon 9 KIT mutation. These studies provide strong rationale for further use of AKT inhibition in combination with IM in primary GIST; however, alternative agents will need to be tested in combination with AKT inhibition in the resistant setting.

Methods for the Manipulation of Herpesvirus Genome and the Application to Marek's Disease Virus Research.

Herpesviruses are a group of double-strand DNA viruses that infect a wide range of hosts, including humans and animals. In the past decades, numerous methods have been developed to manipulate herpesviruses genomes, from the introduction of random mutations to specific genome editing. The development of genome manipulation methods has largely advanced the study of viral genes function, contributing not only to the understanding of herpesvirus biology and pathogenesis, but also the generation of novel vaccines and therapies to control and treat diseases. In this review, we summarize the major methods of herpesvirus genome manipulation with emphasis in their application to Marek's disease virus research.

Steroid use during COVID-19 infection and hyperglycemia - What a physician should know.

BACKGROUND AND AIMS: The COVID-19 pandemic continues to challenge us. Despite several strides in management, steroids remain the mainstay for treating moderate to severe disease and with it arises challenges such as hyperglycemia. The review aims to enhance awareness amongst physicians on steroid use and hyperglycemia. METHODS: An advisory document describing various strategies for hyperglycemia management was prepared in the public interest by DiabetesIndia. RESULTS: The review provides awareness on steroids and hyperglycemia, adverse outcomes of elevated blood glucose levels and, advice at the time of discharge. CONCLUSIONS: The article emphasizes enhancing awareness on effective management of hyperglycemia during COVID-19.

A Retrospective, Observational Analysis of Tumor Infiltrating Lymphocytes and Tumor Regression in Melanoma.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) and regression are thought to be distinct markers of the immune response to melanoma. OBJECTIVE: This study sought to analyze the relationship of TIL grade and presence of regression to each other and to other prognostic histopathologic and clinical values in melanoma. MATERIALS AND METHODS: A retrospective analysis was conducted using patients diagnosed with melanoma between 2013 and 2019 whose complete histopathologic reports were available. RESULTS: Regression was seen in 48.9%, 30.1% and 37.9% of patients with brisk, non-brisk, and absent TILs respectively (P=0.019). Melanoma tumors with brisk TILs were found to have a lower Breslow thickness than those with non-brisk or absent (P= 0.001). Tumors with regression were also found to have lower Breslow thickness (P<0.001). Neither TIL grade nor regression were protective of nodal metastasis or associated with improved survival. CONCLUSION: Brisk TILs have a positive association with thinner tumors and the presence of tumor regression relative to non-brisk or absent TILs. This may suggest a more robust immune response in tumors with brisk TILs. Further exploration of the interplay between TIL grade, lymphocyte cell subtype and lymphocyte density may help explain this finding.

Latest Insights into Unique Open Reading Frames Encoded by Unique Long (UL) and Short (US) Regions of Marek's Disease Virus.

Marek's disease virus (MDV) is an oncogenic avian alphaherpesvirus whose genome consists of unique long (UL) and short (US) regions that are flanked by inverted repeat regions. More than 100 open reading frames (ORFs) have been annotated in the MDV genome, and are involved in various aspects of MDV biology and pathogenesis. Within UL and US regions of MDV, there are several unique ORFs, some of which have recently been shown to be important for MDV replication and pathogenesis. In this review, we will summarize the current knowledge on these ORFs and compare their location in different MDV strains.