Mixed neuroendocrine and adenocarcinoma of gastrointestinal tract: A complex diagnosis and therapeutic challenge.

In this editorial we comment on the manuscript describing a case of adenocarcinoma mixed with a neuroendocrine carcinoma of the gastroesophageal junction. Mixed neuroendocrine and non-neuroendocrine neoplasms of the gastrointestinal system are rare heterogeneous group of tumors characterized by a high malignant potential, rapid growth, and poor prognosis. Due to the rarity of these cancers, the standard therapy is poorly defined. The diagnosis of these tumors is based on combination of morphological features, immunohistochemical and neuroendocrine and epithelial cell markers. Both endocrine and epithelial cell components can act independently of each other and thus, careful grading of each component separately is required. These cancers are aggressive in nature and the potential of each component has paramount importance in the choice of treatment and response. Regardless of the organ of origin, these tumors portend poor prognosis with increased proportion of neuroendocrine component. Multidisciplinary services and strategies are required for the management of these mixed malignancies to provide the best oncological outcomes. The etiopathogenesis of these mixed tumors remains obscure but poses interesting question. We briefly discuss a few salient points in this editorial.

Synchronous gastric and colon cancers: Important to consider hereditary syndromes and chronic inflammatory disease associations.

In this editorial we comment on the manuscript, describing management and surveillance strategies in synchronous and metachronous, gastric and colon cancers. Synchronous or metachronous primary malignancies at different sites of the gastrointestinal tract pose a unique diagnostic and therapeutic challenge. Multidisciplinary services and strategies are required for the management of multiple site primary malignancies, to provide the best oncological outcomes. Although this study highlights the dual cancers in 76 sporadic cases, the authors excluded 55 patients due to combination of factors which includes; incomplete clinical data, genetic syndrome, gastric stump cancers. In addition, the authors did not elaborate if any patients presented with signet ring cell morphology, E-cadherin mutations or presence of inflammatory bowel disease. Genetic and mutational errors and epithelial field defects from chronic inflammatory diseases of the gastrointestinal tract are important when considering synchronous gastric and colonic cancers. We will briefly discuss these in this editorial.

Converting to an international unit system improves harmonization of results for SARS-CoV-2 quantification: Results from multiple external quality assessments.

BACKGROUND: The detection of SARS-CoV-2 vRNA in clinical samples has relied almost exclusively on RT-qPCR as the gold standard test. Published results from various external quality assessments ("ring trials") worldwide have shown that there is still a large variability in results reported for the same samples. As reference standards of SARS-CoV-2 RNA are available, we tested whether using standard curves to convert Ct values into copies/mL (cp/mL) improved harmonization. METHODS: Nine laboratories using 23 test systems (15 of which were unique) prepared standard dilution curves to convert Ct values of 13 SARS-CoV-2 positive samples to cp/mL (hereafter IU/mL). The samples were provided in three rounds of a virus genome detection external quality assessment (EQA) scheme. We tested the precision and accuracy of results reported in IU/mL, and attempted to identify the sources of variability. RESULTS: Reporting results as IU/mL improved the precision of the estimated concentrations of all samples compared to reporting Ct values, although some inaccuracy remained. Variance analysis showed that nearly all variability in data was explained by individual test systems within individual laboratories. When controlling for this effect, there was no significant difference between all other factors tested (test systems, EQA rounds, sample material). CONCLUSIONS: Converting results to copies/mL improved precision across laboratory test systems. However, it seems the results are still very specific to test systems within laboratories. Further efforts could be made to improve accuracy and achieve full harmonization across diagnostic laboratories.

Anal human papilloma viral infection and squamous cell carcinoma: Need objective biomarkers for risk assessment and surveillance guidelines.

High grade anal intraepithelial neoplasia due to human papilloma viral (HPV) infections is a precursor lesion for squamous cell carcinoma especially in high risk populations. Frequent examination and anal biopsies remain unpopular with patients; moreover they are also risk factors for chronic pain, scarring and sphincter injury. There is lack of uniform, surveillance methods and guidelines for anal HPV specifically the intervals between exam and biopsies. The aim of this editorial is to discuss the intervals for surveillance exam and biopsy, based on specific HPV related biomarkers? Currently there are no published randomized controlled trials documenting the effectiveness of anal screening and surveillance programs to reduce the incidence, morbidity and mortality of anal cancers. In contrast, the currently approved screening and surveillance methods available for HPV related cervical cancer includes cytology, HPV DNA test, P16 or combined P16/Ki-67 index and HPV E/6 and E/7 mRNA test. There are very few studies performed to determine the efficacy of these tests in HPV related anal pre-cancerous lesions. The relevance of these biomarkers is discussed in this editorial. Longitudinal prospective research is needed to confirm the effectiveness of these molecular biomarkers that include high risk HPV serotyping, P16 immuno-histiochemistry and E6/E7 mRNA profiling on biopsies to elucidate and establish surveillance guidelines.

Gut microbiome, Vitamin D, ACE2 interactions are critical factors in immune-senescence and inflammaging: key for vaccine response and severity of COVID-19 infection.

BACKGROUND: The SARS-CoV-2 pandemic continues to spread sporadically in the Unites States and worldwide. The severity and mortality excessively affected the frail elderly with co-existing medical diseases. There is growing evidence that cross-talk between the gut microbiome, Vitamin D and RAS/ACE2 system is essential for a balanced functioning of the elderly immune system and in regulating inflammation. In this review, we hypothesize that the state of gut microbiome, prior to infection determines the outcome associated with COVID-19 sepsis and may also be a critical factor in success to vaccination. METHODS: Articles from PubMed/Medline searches were reviewed using a combination of terms "SARS-CoV-2, COVID-19, Inflammaging, Immune-senescence, Gut microbiome, Vitamin D, RAS/ACE2, Vaccination". CONCLUSION: Evidence indicates a complex association between gut microbiota, ACE-2 expression and Vitamin D in COVID-19 severity. Status of gut microbiome is highly predictive of the blood molecular signatures and inflammatory markers and host responses to infection. Vitamin D has immunomodulatory function in innate and adaptive immune responses to viral infection. Anti-inflammatory functions of Vit D include regulation of gut microbiome and maintaining microbial diversity. It promotes growth of gut-friendly commensal strains of Bifida and Fermicutus species. In addition, Vitamin D is a negative regulator for expression of renin and interacts with the RAS/ ACE/ACE-2 signaling axis. Collectively, this triad may be the critical, link in determination of outcomes in SARS-CoV-2 infection. The presented data are empirical and informative. Further research using advanced systems biology techniques and artificial intelligence-assisted integration could assist with correlation of the gut microbiome with sepsis and vaccine responses. Modulating these factors may impact in guiding the success of vaccines and clinical outcomes in COVID-19 infections.

SARS-CoV-2 (COVID-19), viral load and clinical outcomes; lessons learned one year into the pandemic: A systematic review.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is diagnosed via real time reverse transcriptase polymerase chain reaction (RT-PCR) and reported as a binary assessment of the test being positive or negative. High SARS-CoV-2 viral load is an independent predictor of disease severity and mortality. Quantitative RT-PCR may be useful in predicting the clinical course and prognosis of patients diagnosed with coronavirus disease 2019 (COVID-19). AIM: To identify whether quantitative SARS-CoV-2 viral load assay correlates with clinical outcome in COVID-19 infections. METHODS: A systematic literature search was undertaken for a period between December 30, 2019 to December 31, 2020 in PubMed/MEDLINE using combination of terms "COVID-19, SARS-CoV-2, Ct values, Log10 copies, quantitative viral load, viral dynamics, kinetics, association with severity, sepsis, mortality and infectiousness''. After screening 990 manuscripts, a total of 60 manuscripts which met the inclusion criteria were identified. Data on age, number of patients, sample sites, RT-PCR targets, disease severity, intensive care unit admission, mortality and conclusions of the studies was extracted, organized and is analyzed. RESULTS: At present there is no Food and Drug Administration Emergency Use Authorization for quantitative viral load assay in the current pandemic. The intent of this research is to identify whether quantitative SARS-CoV-2 viral load assay correlates with severity of infection and mortality? High SARS-CoV-2 viral load was found to be an independent predictor of disease severity and mortality in majority of studies, and may be useful in COVID-19 infection in susceptible individuals such as elderly, patients with co-existing medical illness such as diabetes, heart diseases and immunosuppressed. High viral load is also associated with elevated levels of TNF-α, IFN-γ, IL-2, IL-4, IL-6, IL-10 and C reactive protein contributing to a hyper-inflammatory state and severe infection. However there is a wide heterogeneity in fluid samples and different phases of the disease and these data should be interpreted with caution and considered only as trends. CONCLUSION: Our observations support the hypothesis of reporting quantitative RT-PCR in SARS-CoV-2 infection. It may serve as a guiding principle for therapy and infection control policies for current and future pandemics.

Cell plasticity in cancer: A complex interplay of genetic, epigenetic mechanisms and tumor micro-environment.

Cell plasticity, also known as lineage plasticity is defined as the ability of a cell to reprogram and change its phenotype identity. Cell plasticity is context dependent and occurs during the development of an embryo, tissue regeneration, wound healing. However when deregulated and aberrant it also contributes to cancer initiation, progression, metastases and resistance to therapies. Tumors cells exhibit varying forms of cell plasticity in each stage of the disease to evade normal regulation as would have occurred in normal cell division and homeostasis. Current evidence demonstrates complex interplay between the genes, epigenes, tumor microenvironment and the EMT in cell reprogramming and cancer cell plasticity. Herein we present experimental evidence and evolving new developments in cell plasticity in cancer cells. Additionally "Deregulated/aberrant/hijacked cell plasticity" could be considered as an additional hallmark of a cancer. In the future, combining the advances in next generation sequencing and single cell RNA techniques with evolving AI (artificial intelligence) technologies such as deep learning techniques may predict the trajectories of cancer cells and assist in navigating through the complex intricacies of the cancers. A durable, precise, personalized oncologic treatment could be a reality.

Coronavirus (Covid-19) sepsis: revisiting mitochondrial dysfunction in pathogenesis, aging, inflammation, and mortality.

BACKGROUND: Decline in mitochondrial function occurs with aging and may increase mortality. We discuss mitochondrial contribution to Covid-19 sepsis, specifically the complex interaction of innate immune function, viral replication, hyper-inflammatory state, and HIF-α/Sirtuin pathways. METHODS: Articles from PubMed/Medline searches were reviewed using the combination of terms "SARS-CoV-2, Covid-19, sepsis, mitochondria, aging, and immunometabolism". RESULTS: Evidence indicates that mitochondria in senescent cells may be dysfunctional and unable to keep up with hypermetabolic demands associated with Covid-19 sepsis. Mitochondrial proteins may serve as damage-associated molecular pattern (DAMP) activating innate immunity. Disruption in normal oxidative phosphorylation pathways contributes to elevated ROS which activates sepsis cascade through HIF-α/Sirtuin pathway. Viral-mitochondrial interaction may be necessary for replication and increased viral load. Hypoxia and hyper-inflammatory state contribute to increased mortality associated with Covid-19 sepsis. CONCLUSIONS: Aging is associated with worse outcomes in sepsis. Modulating Sirtuin activity is emerging as therapeutic agent in sepsis. HIF-α, levels of mitochondrial DNA, and other mitochondrial DAMP molecules may also serve as useful biomarker and need to be investigated. These mechanisms should be explored specifically for Covid-19-related sepsis. Understanding newly discovered regulatory mechanisms may lead to the development of novel diagnostic and therapeutic targets.

CDH1 (E-Cadherin) Mutation and Gastric Cancer: Genetics, Molecular Mechanisms and Guidelines for Management.

INTRODUCTION: Germline mutation in CDH1 (E-cadherin) tumor suppressor gene is associated with hereditary diffuse gastric cancer (HDGC) and lobular breast cancers (LBC). E-Cadherin protein is necessary for physiological signaling pathways, such as cell proliferation, maintenance of cell adhesion, cell polarity and epithelial-mesenchymal transition. Dysregulation leads to tumor proliferation, invasion, migration and metastases. We review current perspectives in CDH1 genetics with molecular mechanisms and also discuss management strategies for this aggressive form of gastric cancer. METHODS: Relevant articles from PubMed/Medline and Embase (1994-2019) were searched and collected using the phrases "Hereditary diffuse gastric cancer, Familial gastric cancer, CDH1 mutation, E-Cadherin, Lobular breast cancer, Prophylactic total gastrectomy". RESULTS: Current guidelines suggest maintaining a high degree of suspicion of hereditary etiology and recommend testing for CDH1 mutations in patients with familial clustering of HDGC and LBC, especially onset at an early age (before 40 years). In families lacking CDH1 mutations but with high suspicion for hereditary predisposition, testing of CTNNA1 and other closely related HDGC susceptibility genes could be considered. Prophylactic total gastrectomy is recommended for individuals with identified pathogenic germline variants. Endoscopic surveillance with biopsies is recommended for those choosing to delay prophylactic gastrectomy. CONCLUSION: Mutation or transcriptional silencing of the CDH1 gene is associated with familial diffuse gastric cancer. Further studies on the expression and the alteration in the proteins in the E-cadherin pathways may serve as biomarkers for early detection; stratify risk and selection of appropriate therapy in these families. Until then prophylactic total gastrectomy is recommended for individuals with CDH1 mutations and family history of diffuse gastric cancer. Endoscopic surveillance and biopsies by experienced gastroenterologists is recommended for those choosing not to have prophylactic gastrectomy and in individuals with CDH1 variants.

Anal carcinoma in giant anal condyloma, multidisciplinary approach necessary for optimal outcome: Two case reports and review of literature.

BACKGROUND: Anal cancers are caused by human papilloma virus (HPV). Buschke-Lowenstein tumor also known as giant anal condyloma (GCA) is a variant of giant neglected anal tumors arising from warts caused by HPV infection. HPV are a family of double-stranded DNA viruses and primarily cause sexually transmitted disease of the genitalia and oropharyngeal mucosa. These tumors are slow growing; locally destructive large verrucous masses. CASE SUMMARY: We present a series of two cases with large anal tumors harboring invasive cancers and highlight their presentation and management. Tumors with high risk HPV subtypes (HPV 16, 18, 31, 33) may progress into invasive squamous cell carcinoma (SCC). Untreated GCA can attain enormous size and extend into the pelvic organs and bony structures. Some tumors show malignant degeneration into SCC and are often difficult to diagnose given the large size of the tumors. Complete surgical excision with negative margins is the treatment of choice and necessary to prevent recurrence. This is often not feasible and leaves large surgical wounds with tissue defects with delay in healing and increases post-operative morbidity. Pelvic reconstructive techniques including muscle flaps and grafts are often necessary to close the defects. Human immunodeficiency virus and immunocompromised patients generally do poorly with standard treatments. CONCLUSION: A multidisciplinary team of colorectal and plastic surgeons, medical and radiation oncologists along with combination treatment modalities are necessary when malignant transformation occurs in GCA, for optimal outcomes.

Adult intussusception: A case series and review.

AIM: To identify factors differentiating pathologic adult intussusception (AI) from benign causes and the need for an operative intervention. Current evidence available from the literature is discussed. METHODS: This is a case series of eleven patients over the age of 18 and a surgical consultation for "Intussusception" at a single veteran's hospital over a five-year period (2011-2016). AI was diagnosed on computed tomography (CT) scan and or flexible endoscopy (colonoscopy). Surgical referrals were from the emergency room, endoscopy suites and the radiologists. RESULTS: A total of 11 cases, 9 males and 2 females were diagnosed with AI. Median age was 58 years. Abdominal pain and change in bowel habits were most common symptoms. CT scan and or colonoscopy diagnosed AI, in ten/eleven (90%) patients. There were 6 small bowel-small bowel, 4 ileocecal, and 1 sigmoid-rectal AI. 8 patients (72%) needed an operation. Bowel resection was required and definitive pathology was diagnosed in 7 patients (63%). Five patients had malignant and 2 patients had benign etiology. Small bowel enteroscopy excluded pathology in 4 cases (37%) with AI. Younger patients tend to have a benign diagnosis. CONCLUSION: Majority of AI have malignant etiology however idiopathic intussusception is being seen more frequently. Operative intervention remains the mainstay however, certain small bowel intussusception especially in younger patients may be a benign, physiological, transient phenomenon and laparoscopy with reduction or watchful waiting may be an acceptable strategy. These patients should undergo endoscopic or capsule endoscopy to exclude intrinsic luminal lesions.

Goblet cell carcinoids of the appendix: Tumor biology, mutations and management strategies.

Malignant neoplasms of the appendix are rare and represent less than 1% of gastrointestinal cancers. Goblet cell carcinoids (GCC) tumors are a distinctive group of heterogeneous appendiceal neoplasm that exhibit unique clinical and pathologic features. This review focuses on the current diagnostic procedures, pathogenesis, possible signaling mechanisms and treatment options for GCC. Perspectives for future research are discussed. The tumor likely arises from pluripotent intestinal epithelial crypt base stem cells. Previous findings of Notch signaling as a tumor suppressor in Neuroendocrine tumors may have a similar role in this tumor too. Loss of Notch signaling may be the driver mutation with other successive downstream mutations likely favors them into progressing and behavior similar to poorly differentiated adenocarcinoma with minimal neuroendocrine differentiation. A multidisciplinary approach is suggested for optimal outcomes. Surgery remains the main treatment modality. Simple appendectomy may be sufficient in early stages while right hemicolectomy is recommended for advanced tumors. Cytoreductive surgery with heated intraperitoneal chemotherapy may improve survival in a select few with metastatic peritoneal disease. These tumors have an unpredictable behavior even in early stages and local recurrence and delayed metastases may be seen. Lifelong surveillance is warranted.

Genetic risks and familial associations of small bowel carcinoma.

Adenocarcinoma of small intestines (SBA) is a relatively rare malignancy with poor outcomes due to delayed diagnosis. Fifty percent of patients have metastases on presentation and therefore early detection and treatment offers the best long term outcomes. Certain genetic polyposis syndromes and familial diseases are associated with increased risks for SBA. These include familial adenomatous polyposis (FAP), Lynch syndromes (LS), Juvenile polyposis syndrome, Peutz-Jeghers syndrome, Crohn's disease (CD) and celiac disease. Mutations in APC gene, Mismatch repair genes, STK11 gene, and SMAD4 gene have been implicated for the genetic diseases respectively. While there are no specific inherited genetic mutations for CD, genome-wide association studies have established over 140 loci associated with CD. CpG island mutations with defects in mismatch repair genes have been identified in celiac disease. Significant diagnostic advances have occurred in the past decade and intuitively, it would seem beneficial to use these advanced modalities for surveillance of these patients. At present it is debatable and no clear data exists to support this approach except for established guidelines to diagnose duodenal polyps in FAP, and LS. Here we discuss the genetic alterations, cancer risks, signaling mechanisms and briefly touch the surveillance modalities available for these genetic and clinical syndromes. English language articles from PubMed/Medline and Embase was searched were collected using the phrases "small-bowel adenocarcinoma, genetics, surveillance, familial adenomatous polyposis, lynch syndromes, Peutz-Jeghers syndrome, juvenile polyposis syndrome, CD and celiac disease". Figures, tables and schematic diagram to illustrate pathways are included in the review.

Small bowel sarcoma: Tumor biology and advances in therapeutics.

Spindle cell neoplasms are rare mesenchymal tumors of the gastrointestinal tract. GIST (Gastrointestinal stromal tumor) and leiomyosarcoma share similar clinical presentations, gross and microscopic characteristics making distinction difficult in the absence of immunohistochemical (IHC) studies. A multidisciplinary approach is required for treatment planning and ensuring best outcomes. Surgery remains the mainstay of curative treatment for both tumors. Significant advances in targeted molecular therapies have occurred in the past decade in the treatment of GIST with improvement in morbidity and mortality. Similar newer discoveries for treatment of leiomyosarcoma have failed to show any significant survival benefits as yet. Early diagnosis and R0 surgical resection offers the best long term outcome for leiomyosarcoma. Here in we review and discuss the concepts of genetic alterations, newer markers, possible cancer pathways and advances in treatment strategies for these sarcomas.

PIK3CA mutations in small bowel adenocarcinoma.

AIMS AND BACKGROUND: PIK3CA mutations involving exons 9 and 20 are among the most common aberrations seen in human malignancies. The identification of PIK3CA mutations in small bowel adenocarcinoma (SBA) is sparse. There is some evidence that tumors with this mutation may be a good target for inhibitors of the PI3K pathway. CASE REPORT: We report an exon 9 (G1624A: E542K) hot spot mutation in a 69-year-old man with sporadic jejunal cancer (T3, N1). A systemic search was made for other reports using Medline/Embase along with Sangers Institute Cancer Genome Project database. We analyzed and describe this mutation in these patients, including one of ours. RESULTS AND CONCLUSION: A total of 8 tumor samples with confirmed somatic mutations out of a total of 86 samples were noted: rate 9.3% (95% confidence interval 4.5% to 17.5%). Overall, PIK3CA mutations were more common in duodenum (62.5%) and located most commonly on exon 9. The significance of PIK3CA mutation in SBA is unclear. Further studies on mutation analysis in larger cohorts with SBA are in order to identify and confirm relationships between these mutations and various clinical and pathologic variables such as age, lymph node status, distant metastasis, stage, and progression-free survival and association with other gene mutations.

Primary small-bowel malignancy: update in tumor biology, markers, and management strategies.

PURPOSE: Primary small-bowel malignancies (SBM) are rare tumors but their incidence is rising. An estimated 9160 new cases and 1210 deaths due to SBM may occur in the USA in 2014. We review advances made in tumor biology, immunohistochemistry, and discuss treatment strategies for these malignancies. METHODS: Relevant articles from PubMed/Medline and Embase searches were collected using the phrases "small-bowel adenocarcinoma, gastrointestinal carcinoids, gastrointestinal stromal tumors, small-bowel leiomyosarcoma, and small-bowel lymphoma". RESULTS: Advances in imaging techniques such as wireless capsule endoscopy, CT and MRI enterography, and endoscopy (balloon enteroscopy) along with discovery of molecular markers such as c-kit and PDGFRA for GIST tumors have improved our ability to diagnose, localize, and treat these patients. Early detection and surgical resection offers the best chance for long-term survival in all tumors except bowel lymphoma where chemotherapy plays the main role. Adjuvant therapy with imatinib has improved overall survival for GIST tumors, somatostatin analogs have improved symptoms and also inhibited tumor growth and stabilized metastatic disease in carcinoid disease, but chemotherapy has not improved survival for adenocarcinoma. CONCLUSIONS: Recent advances in molecular characterization holds promise in novel targeted therapies. Currently ongoing trials are exploring efficacy of targeted therapies and role of adjuvant therapy for adenocarcinoma and results are awaited. Early detection and aggressive surgical therapy for all localized tumors and lymph node sampling particularly for adenocarcinoma remains the main treatment modality.