Who Should Receive Immunotherapy for Advanced Gastroesophageal Cancer?

OPINION STATEMENT: This paper shines a light on the exciting progress being made in using immunotherapy to treat advanced gastroesophageal cancers. The positive results from trials using drugs like Pembrolizumab and Nivolumab are certainly encouraging and open new possibilities for treating this challenging disease. However, it is clear that we still have a lot to learn about how to predict which patients will benefit most from these treatments. The exploration of combining therapies and using machine learning to guide treatment shows promise. Moving forward, it is crucial that researchers and healthcare professionals continue to work together, sharing knowledge and findings to continue the advancements in this important area.

Clinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort.

CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and preexisting anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial.

Cancer-Associated Fibroblasts in Gastrointestinal Cancers: Unveiling Their Dynamic Roles in the Tumor Microenvironment.

Gastrointestinal cancers are highly aggressive malignancies with significant mortality rates. Recent research emphasizes the critical role of the tumor microenvironment (TME) in these cancers, which includes cancer-associated fibroblasts (CAFs), a key component of the TME that have diverse origins, including fibroblasts, mesenchymal stem cells, and endothelial cells. Several markers, such as α-SMA and FAP, have been identified to label CAFs, and some specific markers may serve as potential therapeutic targets. In this review article, we summarize the literature on the multifaceted role of CAFs in tumor progression, including their effects on angiogenesis, immune suppression, invasion, and metastasis. In addition, we highlight the use of single-cell transcriptomics to understand CAF heterogeneity and their interactions within the TME. Moreover, we discuss the dynamic interplay between CAFs and the immune system, which contributes to immunosuppression in the TME, and the potential for CAF-targeted therapies and combination approaches with immunotherapy to improve cancer treatment outcomes.

Characterization of Age-Associated, Neutrophil-to-Lymphocyte Ratio (NLR) and Systemic Immune-Inflammatory Index (SII) as Biomarkers of Inflammation in Geriatric Patients with Cancer Treated with Immune Checkpoint Inhibitors: Impact on Efficacy and Survival.

BACKGROUND: Geriatric patients (≥80 years) are underrepresented in immune checkpoint inhibitor (ICIs) clinical trials. However, their unique biology may affect their response to ICIs. There are currently no established biomarkers of the response to ICIs in adult patients with cancer that can help with patient selection. METHODS: We built a multicenter, international retrospective study of 885 patients (<80 years: n = 417, 47.12%; ≥80 years: n = 468, 52.88%) with different tumor types treated with ICIs between 2011 and 2021 from 11 academic centers in the U.S. and Europe. The main outcome measures were objective response rates (ORR), progression-free survival (PFS) and overall survival (OS) stratified by age and circulating inflammatory levels (neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammatory index (SII)). RESULTS: Patients ≥80 years with low NLR (NLR-L) and SII (SII-L) had significantly higher ORR (vs. high NLR [NLR-H], p < 0.01 and SII-H, p < 0.05, respectively). At median follow-ups (13.03 months), and compared to SII-H, patients with SII-L had significantly longer median PFS and OS in patients <80 (p < 0.001), and ≥80 years (p < 0.001). SII-L was independently associated with longer PFS and OS (HR: 0.61 and 0.62, respectively, p < 0.01). CONCLUSION: Lower inflammation pre-ICI initiation may predict an improved response and survival in geriatric patients with cancer.

Anti-Inflammatory and Immune Properties of Polyunsaturated Fatty Acids (PUFAs) and Their Impact on Colorectal Cancer (CRC) Prevention and Treatment.

Colorectal cancer (CRC) remains a leading cause of death from cancer worldwide, with increasing incidence in the Western world. Diet has become the focus of research as a significant risk factor for CRC occurrence, and the role of dietary polyunsaturated fatty acids (PUFAs) has become an area of interest given their potential role in modulating inflammation, particularly in the pro-carcinogenic inflammatory environment of the colon. This work reviews the main types of PUFAs, their characteristics, structure, and physiologic role. We then highlight their potential role in preventing CRC, their signaling function vis-à-vis tumorigenic signaling, and their subsequent potential role in modulating response to different treatment modalities. We review pre-clinical and clinical data and discuss their potential use as adjunct therapies to currently existing treatment modalities. Given our understanding of PUFAs' immune and inflammation modulatory effects, we explore the possible combination of PUFAs with immune checkpoint inhibitors and other targeted therapies.

Crimean-Congo Hemorrhagic Fever Presented in Dengue Epidemic: A Case Report.

In Pakistan, hemorrhagic diseases, including dengue and Crimean-Congo hemorrhagic fever (CCHF), are common. Therefore, an accurate diagnosis is challenging in the early stages of sickness owing to geographic overlap and early clinical similarities between the two disorders. A 35-year-old man who had previously experienced hematemesis and high-grade fever presented to our hospital. Despite receiving supportive care for a preliminary diagnosis of dengue hemorrhagic fever, the patient's condition worsened. The results of the dengue IgM antibody test were negative. On the fourth day of admission, a qualitative polymerase chain reaction test for CCHF virus RNA was performed, and the result returned positive. All medical personnel and attendants who had contact with the patient had to receive ribavirin prophylaxis, which required significant investment in resources. Because CCHF can have long-term financial and health repercussions for contacts, including healthcare personnel in developing nations, it is essential to identify and treat it as soon as possible. It is necessary to keep track of dengue and CCHF cases more closely to develop predictors of disease diagnosis that are reasonably trustworthy, affordable, and quick. These predictors can aid in directing future choices regarding the care of similar situations. Ultimately, such an approach might result in improved cost control in environments with limited resources. Consideration should also be given to patients who receive ribavirin prophylaxis.

Fluorescence Spectroscopy for the Assessment of Microbial Load in UVC Treated Water.

In this article, Fluorescence spectroscopy has been employed for the assessment of microbial load and it has been compared with the gold standard colony forming unit (CFU) and optical density (OD) methods. In order to develop a correlation between three characterization techniques, water samples of different microbial loads have been prepared by UVC disinfection method through an indigenously developed NUVWater sterilizer, which operates in close cycle flow configuration. A UV dose of 58.9 mJ/cm2 has been determined for 99.99% disinfection for a flow rate of 0.8 l/min. The water samples were excited at 270 nm which results in the tryptophan like fluorescence at 360 nm that decreases gradually with increase of UVC dose, indicating the bacterial degradation and it has been confirmed by OD and CFU methods. In addition, it has been proved that a close cycle water flow around UV lamp is imperative so that an appropriate dose must be delivered to microorganisms for an efficient disinfection. It has been found that due to the sensitive nature of Fluorescence spectroscopy, it yields immediate results, whereas, for CFU and OD methods, water samples needs to be inoculated for 24 h. Fluorescence spectroscopy, therefore, provide a fast, online, reliable and sensitive method for the monitoring of pathogenic quantification in drinking water.

Comparing Medication Non-adherence in Cardiovascular Disease Patients at Public and Private Hospitals in Peshawar: A Cross-Sectional Study of Prevalence and Contributing Factors.

Introduction The incidence of cardiovascular diseases continues to increase, becoming one of the leading causes of mortality globally. The proper use of medication can greatly reduce the death rate by slowing the progression of the disease. Yet, many patients struggle with following their medication regimen due to various reasons. Effective treatment management relies on patients' self-care and understanding of their illness and medications, which can impact their adherence to taking their prescribed drugs. The objective of the study was to determine the prevalence of medication non-compliance among patients in two public and private tertiary care hospitals in Peshawar and to identify the factors that contribute to this behavior. Material and methods A comparative cross-sectional study design was employed for the research. The study was conducted at Hayatabad Medical Complex and Rehman Medical Institute in Peshawar, as these two hospitals provide care for a significant proportion of cardiovascular disease patients in the area. To assess adherence, a quantitative scale was devised with scores of 8 considered high adherence, scores between 6 and 7 considered medium adherence, and scores below 6 considered low adherence. The factors impacting medication non-adherence were analyzed using a self-administered questionnaire, which was developed following a preliminary study conducted at both hospitals. Results In total, 168 eligible patients from the two hospitals were given the questionnaire. Out of these patients, 107 (63.7%) were male, and 61 (36.3%) were female, with ages ranging from 19 to 84 and a mean age of 55.33. The level of medication adherence was calculated among the participants, with 20.2% reporting high adherence, 22.6% reporting medium adherence, and 57.1% reporting low adherence. The results showed that monthly income (p = 0.006), the presence of co-morbidities (p = 0.002), and the fear of addiction to medication (p = 0.048) were the main factors influencing medication adherence. In regression analysis with high adherence as the reference category and a 95% confidence interval, hospital affiliation was found to be significantly associated with adherence levels. Conclusions The study found that medication adherence among cardiovascular disease patients in private tertiary care hospitals is generally high. However, the level of adherence was seen to be impacted by the patient's monthly income. In light of this, the government should implement programs to reduce the cost of healthcare provision and increase affordability for patients.

Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results.

This is the phase Ib part of the phase I/II CAMILLA trial evaluating cabozantinib plus durvalumab in advanced chemo-refractory proficient mismatch repair or microsatellite stable (pMMR/MSS) gastrointestinal malignancies including gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma, colorectal cancer (CRC), and hepatocellular carcinoma (HCC). Thirty-five patients are enrolled. There are no observed dose-limiting toxicities during dose escalation. The overall grade 3/4 treatment-related adverse event rate is 34%. Among evaluable patients (n = 30), the objective response rate (ORR) is 30%, disease control rate (DCR) 83.3%, 6-month progression-free survival (PFS) 36.7%, median PFS 4.5 months, and median overall survival (OS) 8.7 months. Responses are seen in 4 of 17, 3 of 10, and 2 of 3 patients with CRC, G/GEJ/E adenocarcinoma, and HCC, respectively. Participants with a PD-L1 combined positive score (CPS) ≥5 have numerically higher ORR, PFS, and OS. Cabozantinib plus durvalumab demonstrates a tolerable safety profile and potential efficacy in previously treated advanced pMMR/MSS gastrointestinal malignancies.

Tumor Molecular and Microenvironment Characteristics in EBV-Associated Malignancies as Potential Therapeutic Targets: Focus on Gastric Cancer.

Although most people are infected with Epstein-Barr Virus (EBV) during their lifetime, only a minority of them develop an EBV-associated malignancy. EBV acts in both direct and indirect ways to transform infected cells into tumor cells. There are multiple ways in which the EBV, host, and tumor environment interact to promote malignant transformation. This paper focuses on some of the mechanisms that EBV uses to transform the tumor microenvironment (TME) of EBV-associated gastric cancer (EBVaGC) for its benefit, including overexpression of Indoleamine 2,3-Dioxygenase 1 (IDO1), synergism between H. pylori and EBV co-infection, and M1 to M2 switch. In this review, we expand on different modalities and combinatorial approaches to therapeutically target this mechanism.

The rhombic honeycomb - a new mode of self-assembly in liquid crystalline soft matter.

Rod-like liquid crystalline (LC) polyphilic compounds with a linear oligo(phenyleneethynylene) core, sticky glycerol groups at each end and two long alkyl side chains (C20-C32) at opposite sides form rhombic honeycombs with inner angles around 60/120°, occurring between triangular and square tiling patterns.

Ciprofloxacin-Induced Acute Delirium in a Young Female.

Ciprofloxacin is a commonly used drug in our setup. Neurological disturbances are rare side effects of its use and are reported in older adults, patients with comorbidities, or patients with a background of psychiatric illness and antipsychotic drug use. We report the case of a 21-year-old female who developed delirium after taking ciprofloxacin for a urinary tract infection. She underwent extensive workup and her final diagnosis was based on the exclusion of other causes. Her symptoms completely settled within three weeks of ciprofloxacin discontinuation.

Third reported patient with RAP1B-related syndromic thrombocytopenia and novel clinical findings.

RAP1B is a RAS-superfamily small GTP-binding protein involved in numerous cell processes. Pathogenic gain-of-function variants in this gene have been associated with RAP1B-related syndromic thrombocytopenia, an ultrarare disorder characterized by hematologic abnormalities, neurodevelopmental delays, growth delay, and congenital birth defects including cardiovascular, genitourinary, neurologic, and skeletal systems. We report a 23-year-old male with a novel, de novo RAP1B gain-of-function variant identified on genome sequencing. This is the third reported case which expands the molecular and phenotypic spectrum of RAP1B-related syndromic thrombocytopenia.

Knocking down Israa, the Zmiz1 intron-nested gene, unveils interrelated T cell activation functions in mouse.

We previously reported Israa (immune-system-released activating agent), a novel gene nested in intron 6 of the mouse Zmiz1 gene. Zmiz1 is involved in several functions such as fertility and T cell development and its knockout leads to non-viable embryos. We also reported ISRAA's expression in lymphoid organs, particularly in the thymus CD3+ T cells during all developmental stages. In addition, we showed that ISRAA is a binding partner of Fyn and Elf-1 and regulates the expression of T cell activation-related genes in vitro. In this paper, we report the generation and characterization of an Israa -/- constitutive knockout mouse. The histological study shows that Israa -/- mice exhibit thymus and spleen hyperplasia. Israa -/- derived T cells showed increased proliferation compared to the wild-type mice T cells. Moreover, gene expression analysis revealed a set of differentially expressed genes in the knockout and wild-type animals during thymus development (mostly genes of T cell activation pathways). Immunological phenotyping of the thymocytes and splenocytes of Israa -/- showed no difference with those of the wild-type. Moreover, we observed that knocking out the Zmiz1 intron embedded Israa gene does not affect mice fertility, thus does not disturb this Zmiz1 function. The characterization of the Israa -/- mouse confirms the role ISRAA plays in the expression regulation of genes involved in T cell activation established in vitro. Taken together, our findings point toward a potential functional interrelation between the intron nested Israa gene and the Zmiz1 host gene in regulating T cell activation. This constitutively Israa -/- mice can be a good model to study T cell activation and to investigate the relationship between host and intron-nested genes.

Refined pancreatobiliary UroVysion criteria and an approach for further optimization.

Pancreatobiliary strictures are a common source of false negatives for malignancy detection. UroVysion is more sensitive than any other method but remains underutilized because of conflicting sensitivities and specificities due to a lack of standardized cutoff criteria and confusion in interpreting results in the context of primary sclerosing cholangitis. We set out to determine the sensitivities and specificities of UroVysion, brushing cytology, forceps biopsies, and fine needle aspiration (FNAs) for pancreatobiliary stricture malignancy detection. A retrospective review was performed of all biopsied pancreatobiliary strictures at our institution over 5 years. UroVysion was unquestionably the most sensitive method and all methods were highly specific. Sensitivity was highest while maintaining specificity when a malignant interpretation was limited to cases with 5+ cells with the same polysomic signal pattern and/or loss of one or both 9p21 signals. Only UroVysion detected the metastases and a neuroendocrine tumor. In reviewing and analyzing the signal patterns, we noticed trends according to location and diagnosis. Herein we describe our method for analyzing signal patterns and propose cutoff criteria based upon observations gleaned from such analysis.

2,6-Dibromogallates as a new building block for controlling π-stacking, network formation and mirror symmetry breaking.

Achiral multi-chain (polycatenar) compounds based on the 2,7-diphenyl substituted [1]benzothieno[3,2-b]benzothiophene (BTBT) unit and a 2,6-dibromo-3,4,5-trialkoxybenzoate end group lead to materials forming bicontinuous cubic liquid crystalline phases with helical network structures over wide temperature ranges.

Exceptional response to Erlotinib monotherapy in EGFR Exon 19-deleted, KRAS wild-type, Chemo-refractory advanced pancreatic adenocarcinoma.

Advanced pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor with an abysmal prognosis. Beyond the first-line setting, treatment for advanced PDAC is limited and suboptimal. Also, the efficacy of epidermal growth factor receptor (EGFR) targeted therapy alone in the chemo-refractory setting in PDAC tumors harboring druggable EGFR mutations is unclear. Here we describe the case of a patient with chemo-refractory advanced PDAC with an activating exon-19 EGFR mutation who had an exceptional response to erlotinib monotherapy.

High-level MYC expression associates with poor survival in patients with acute myeloid leukemia and collaborates with overexpressed p53 in leukemic transformation in patients with myelodysplastic syndrome.

INTRODUCTION: Patients with mutated and overexpressed p53 have an aggressive course in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Studies on the impact of MYC expression in AML are limited. This is the first study to evaluate MYC expression and p53 status in AML and MDS. METHODS: We identified 214 patients, 101 AML, 79 MDS, and 34 negative control patients. We retrospectively assessed p53 and MYC expression by immunohistochemistry and correlated MYC expression with p53 expression and aberrational status of TP53. RESULTS: The level of both p53 and MYC expression was significantly higher in AML (mean: 9.7%; 12.1%) and MDS (mean: 5.2%; 5.5%) patients compared with control cases (mean: 0.18%; 2.3%; P = .001-0.02). p53 and MYC expression levels were even more elevated in AML when compared to MDS patients (P < .001). MYC expression was significantly associated with p53 expression and TP53 aberration in AML patients but not in MDS patients (P < .001). p53 expression and >20% MYC expression showed an adverse impact on overall survival (OS) (P < .05) in AML patients while p53 but not MYC expression showed an adverse impact on OS in MDS patients. MYC and p53 dual expression, as well as combined MYC expression and TP53 aberration, showed negative impact on OS in AML patients. MDS patients with leukemic transformation revealed an interval increase in expression of both p53 and MYC. CONCLUSION: High-level MYC expression associates with p53 abnormality and poor survival in AML. MYC may provide proliferative advantage for leukemic progression in p53 dependent and independent manner.

Immuno-Oncotherapeutic Approaches in Advanced Hepatocellular Carcinoma.

Advanced hepatocellular carcinoma has limited treatment options, but there has been extensive growth recently with cabozantinib, regorafenib, lenvatinib, nivolumab, atezolizumab, and bevacizumab, which are some of the treatments that have received FDA approval just over the last three years. Because HCC tumor microenvironment is potentially immunogenic and typically characterized by inflammation, immunotherapy has been proposed as a potential novel therapeutic approach, which has prompted studies in advanced HCC patients investigating various immune-therapeutic strategies such as CAR-T cell therapy, checkpoint inhibitors, and onco-vaccines. The anti-PD-1 checkpoint inhibitors nivolumab and pembrolizumab have been FDA approved as a second line treatment in patients who progressed or are intolerant to Sorafenib. To build up on the success of PD-1 monotherapy, combinatorial regimens with PD-1/PD-L1 inhibitors plus VEGF targeted agents have shown positive results in various malignancies including HCC. The combination of atezolizumab plus bevacizumab is the new addition to the HCC treatment armamentarium following a pivotal study that demonstrated an improvement in OS over frontline sorafenib. Other novel immune-based approaches and oncolytic viruses are in the early phases of clinical evaluation. These innovative approaches enhance the intensity of cancer-directed immune responses and will potentially impact the outlook of this aggressive disease.

Immune Checkpoint Inhibitors versus VEGF Targeted Therapy as Second Line Regimen in Advanced Hepatocellular Carcinoma (HCC): A Retrospective Study.

Several targeted agents including multi-tyrosine kinase inhibitors (mTKIs) and immunotherapy (IO) agents have been approved for use beyond the frontline setting in patients with advanced hepatocellular carcinoma (HCC). Due to lack of prospective head-to-head comparative trials, there is no standardized way for alternating those agents beyond frontline. Therefore, we performed a retrospective review of the Kansas University (KU) cancer registry to determine whether IO may be superior to non-IO therapy. Patients with advanced HCC were divided into two groups based on the second-line systemic regimen received (IO vs. non-IO). Progression-free survival (PFS) and overall survival (OS) were calculated under the Kaplan-Meier and Cox proportional hazards models. No statistically significant differences in PFS and OS were found, although a non-significant delayed separation in the survival curve favoring IO was identified (median PFS 3.9 months vs. 3 months; median OS 10 months vs. 10 months respectively for IO vs. non-IO). This retrospective analysis is one of the earliest and largest studies comparing second-line IO and non-IO therapies thus far reported. Future studies should aim to define specific biomarkers for response prediction and treatment optimization based on individual patient and tumor characteristics. Furthermore, combinatorial therapeutic strategies is an evolving approach showing early promising signal.