Advancements in medical treatment for pancreatic neuroendocrine tumors:A beacon of hope

This editorial highlights the remarkable advancements in medical treatment strategies for pancreatic neuroendocrine tumors(pan-NETs),emphasizing tailored approaches for specific subtypes.Cytoreductive surgery and somatostatin analogs(SSAs)play pivotal roles in managing tumors,while palliative options such as molecular targeted therapy,peptide receptor radionuclide therapy,and chemotherapy are reserved for SSA-refractory patients.Gastrinomas,insul-inomas,glucagonomas,carcinoid tumors and VIPomas necessitate distinct thera-peutic strategies.Understanding the genetic basis of pan-NETs and exploring immunotherapies could lead to promising avenues for future research.This review underscores the evolving landscape of pan-NET treatment,offering renewed hope and improved outcomes for patients facing this complex disease.

Growth hormone and gastrointestinal malignancy:An intriguing link

Growth hormone(GH)excess is associated with several systemic complications,one of which is the increased risk of neoplastic processes particularly of the gastrointestinal(GI)tract.Among the GI neoplasms,the most reported association is with benign and malignant neoplasms of the colon.In the majority of published literature,an increased incidence of GI neoplasms,both colonic adenomas as well as colorectal carcinoma is reported.However,the studies on colon cancer-specific mortality rate are conflicting with recent studies reporting similar cancer-specific mortality rates in comparison to controls.Many studies have reported an association of colorectal neoplasms with GH levels.Pathogenic mechanisms put forward to explain this association of GH excess and GI neoplasms primarily involve the increased GH-insulin-like growth factor 1(IGF-1)signaling.Both GH and IGF-1 have proliferative,anti-apoptotic,and angiogenic effects on the systemic tissues leading to cellular proliferation.Other contributing factors to the increased risk of GI neoplasms include slow intestinal transit with a redundant large bowel,altered bile acids,deranged local immune response,shared genetic susceptibility factors and hyperinsulinemia.In view of the increased risk association,most guidelines for the care of acromegaly patients recommend an initial screening colonoscopy.Recommendations for further follow-up colonoscopy differ but broadly,the guidelines agree that it depends on the findings at first colonoscopy and state of remission of GH excess.Regarding the concern about the risk of colorectal cancers in patients receiving recombinant GH therapy,most cohort studies do not show an increased risk.

Treatment on Nature’s lap:Use of herbal products in the management of hyperglycemia

Diabetes mellitus(DM)is characterized by persistently elevated blood glucose concentration that lead to multisystem complications.There are about 400 medicinal plants cited to have a beneficial effect on DM.We must choose products wisely based on data derived from scientific studies.However,a major obstacle in the amalgamation of herbal medicine in modern medical practices is the lack of clinical data on its safety,efficacy and drug interaction.Trials of these herbal products often underreport the side effects and other crucial intervention steps deviating from the standards set by Consolidated Standards of Reporting Trials.Due to a lack of knowledge of the active compounds present in most herbal medicines,product standardization is difficult.Cost-effectiveness is another issue that needs to be kept in mind.In this mini-review,we focus on the antihyperglycemic effect of herbal products that are commonly used,along with the concerns stated above.

Role of bisphosphonates in the management of acute Charcot foot

Diabetes mellitus is the most common cause of Charcot neuropathy affecting foot and ankle. Acute Charcot foot(CF) presents with a red and swollen foot in co-ntrast to the painless deformed one of chronic CF. En-hanced osteoclastogenesis plays a central role in the pathogenesis of acute CF. Many studies have shown elevated levels of bone turnover markers in patients with acute CF confirming it. These findings have led cl-inicians to use anti-resorptive agents [bisphosphonates(BP), calcitonin, and denosumab] along with immobi-lization and offloading in acute CF patients. The ma-ximum evidence among all anti-resorptive agents is available for BPs, although its quality is low. Pamidronate has been shown to reduce the markers of activity of CF like raised skin temperature, pain, edema, and bone turnover markers in the majority of studies. Intravenous BPs are known to cause acute phase reactions leading to flu-like illness following their first infusion, which can be ameliorated by oral acetaminophen. Alendronate is the only oral BP used in these patients. It needs to be taken on an empty stomach with a full glass of water to avoid esophagitis. The side-effects and contraindications to BPs should be kept in mind while treating acute CF patients with them.

Diabetes and pancreatic cancer:Exploring the two-way traffic

Pancreatic cancer(PC)is often associated with a poor prognosis.Long-standing diabetes mellitus is considered as an important risk factor for its development.This risk can be modified by the use of certain antidiabetic medications.On the other hand,new-onset diabetes can signal towards an underlying PC in the elderly population.Recently,several attempts have been made to develop an effective clinical tool for PC screening using a combination of history of new-onset diabetes and several other clinical and biochemical markers.On the contrary,diabetes affects the survival after treatment for PC.We describe this intimate and complex two-way relationship of diabetes and PC in this review by exploring the underlying pathogenesis.

Islet cell dysfunction in patients with chronic pancreatitis

Chronic pancreatitis(CP)is characterized by progressive inflammation and fibrosis of the pancreas that eventually leads to pancreatic exocrine and endocrine insufficiency.Diabetes in the background of CP is very difficult to manage due to high glycemic variability and concomitant malabsorption.Progressive beta cell loss leading to insulin deficiency is the cardinal mechanism underlying diabetes development in CP.Alpha cell dysfunction leading to deranged glucagon secretion has been described in different studies using a variety of stimuli in CP.However,the emerging evidence is varied probably because of dependence on the study procedure,the study population as well as on the stage of the disease.The mechanism behind islet cell dysfunction in CP is multifactorial.The intra-islet alpha and beta cell regulation of each other is often lost.Moreover,secretion of the incretin hormones such as glucagon like peptide-1 and glucose-dependent insulinotropic polypeptide is dysregulated.This significantly contributes to islet cell disturbances.Persistent and progressive inflammation with changes in the function of other cells such as islet delta cells and pancreatic polypeptide cells are also implicated in CP.In addition,the different surgical procedures performed in patients with CP and antihyperglycemic drugs used to treat diabetes associated with CP also affect islet cell function.Hence,different factors such as chronic inflammation,dysregulated incretin axis,surgical interventions and anti-diabetic drugs all affect islet cell function in patients with CP.Newer therapies targeting alpha cell function and beta cell regeneration would be useful in the management of pancreatic diabetes in the near future.

Evidence for current diagnostic criteria of diabetes mellitus

Diabetes mellitus is a non-communicable metabolicderangement afflicting several millions of individuals globally. It is associated with several micro and macro-vascular complications and is also a leading cause of mortality. The unresolved issue is that of definition of the diagnostic threshold for diabetes. The World Health Organization and the American Diabetes Asso-ciation(ADA) have laid down several diagnostic criteria for diagnosing diabetes and prediabetes based on the accumulating body of evidence.This review has attempted to analyse the scientific evidence supporting the justification of these differing criteria. The evidence for diagnosing diabetes is strong, and there is a concordance between the two professional bodies. The controversy arises when describing the normal lower limit of fasting plasma glucose(FPG) with little evidence favouring the reduction of the FPG by the ADA. Several studies have also shown the development of complications specific for diabetes in patients with prediabetes as defined by the current criteria though there is a significant overlap of such prevalence in individuals with normoglycemia. Large multinational longitudinal prospective studies involving subjects without diabetes and retinopathy at baseline will ideally help identify the threshold of glycemic measurements for future development of diabetes and its complications.

SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: A systematic review

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a common comorbidity with type 2 diabetes.The existing therapeutic options for NAFLD are not adequate.Hypocaloric diet and exercise is the cornerstone of therapy in NAFLD.Pioglitazone is the only drug recommended in diabetes patients with biopsy proven non-alcoholic steatohepatitis.The frequent coexistence of NAFLD and type 2 diabetes with their combined adverse health consequences and inadequate therapeutic options makes it necessary to search for newer alternatives.AIM To assess the effect of sodium glucose cotransporter-2(SGLT-2)inhibitors on liver enzymes in type 2 diabetes patients with NAFLD.METHODS We searched PubMed/MEDLINE,Cochrane library,Google scholar,and Clinicaltrials.gov for the relevant articles to be included in this systematic review.Human studies done in type 2 diabetes patients with NAFLD treated with SGLT-2 inhibitors for at least 12 wk were included.Data from eight studies(four randomised controlled trials and four observational studies)were extracted and a narrative synthesis was done.A total of 214 patients were treated with SGLT-2 inhibitors in these studies(94 in randomised controlled trials and 120 in observational studies).RESULTS The primary outcome measure was change in serum alanine aminotransferase level.Out of eight studies,seven studies showed a significant decrease in serum alanine aminotransferase level.Most of the studies revealed reduction in serum level of other liver enzymes like aspartate aminotransferase and gamma glutamyl transferase.Five studies that reported a change in hepatic fat exhibited a significant reduction in hepatic fat content in those treated with SGLT-2 inhibitors.Likewise,among the three studies that evaluated a change in indices of hepatic fibrosis,two studies revealed a significant improvement in liver fibrosis.Moreover,there was an improvement in obesity,insulin resistance,glycaemia,and lipid parameters in those subjects taking SGLT-2 inhibitors.The studies disclosed that about 17%(30/176)of the subjects taking SGLT-2 inhibitors developed adverse events and more than 40%(10/23)of them had genitourinary tract infections.CONCLUSION Based on low to moderate quality of evidence,SGLT-2 inhibitors improve the serum level of liver enzymes,decrease liver fat,and fibrosis with additional beneficial effects on various metabolic parameters in type 2 diabetes patients with NAFLD.

Incretin based therapy and pancreatic cancer:Realising the reality

Incretin-based therapies like glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors help maintain the glycaemic control in patients with type 2 diabetes mellitus with additional systemic benefits and little risk of hypoglycaemia.These medications are associated with low-grade chronic pancreatitis in animal models inconsistently.The incidence of acute pancreatitis was also reported in some human studies.This inflammation provides fertile ground for developing pancreatic carcinoma(PC).Although the data from clinical trials and population-based studies have established safety regarding PC,the pathophysiological possibility that low-grade chronic pancreatitis leads to PC remains.We review the existing literature and describe the relationship between incretin-based therapies and PC.

Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases:Current evidence

Dipeptidyl peptidase-4 inhibitors(DPP-4i)have an important place in the management of type 2 diabetes.The DPP-4 enzyme is ubiquitously distributed throughout the human body and has multiple substrates through which it regulates several important physiological functions.DPP-4 regulates several immune functions,including T-cell activation,macrophage function,and secretion of cytokines.Studies have reported an increase in autoimmune diseases like bullous pemphigoid,inflammatory bowel disease,and arthritis with DPP-4i use.The relationship of DPP-4i and autoimmune diseases is a complex one and warrants further research into the effect of DPP-4 inhibition on the immune system to understand the pathogenesis more clearly.Whether a particular cluster of autoimmune diseases is associated with DPP-4i use remains an important contentious issue.Nevertheless,a heightened awareness from the clinicians is required to identify and treat any such diseases.Through this review,we explore the clinical and pathophysiological characteristics of this association in light of recent evidence.

Primary hyperparathyroidism presenting as acute pancreatitis: An institutional experience with review of the literature

BACKGROUND Acute pancreatitis(AP)presenting as an initial manifestation of primary hyperparathyroidism(PHPT)is uncommon,and its timely diagnosis is crucial in preventing recurrent attacks of pancreatitis.AIM To determine the clinical,biochemical,and radiological profile of PHPT patients presenting as AP.METHODS This is a retrospective observational study,51 consecutive patients admitted with the diagnosis of PHPT during January 2010 and October 2021 at a tertiary care hospital in Puducherry,India was included.The diagnosis of AP was established in the presence of at least two of the three following features:abdominal pain,levels of serum amylase or lipase greater than three times the normal,and characteristic features at abdominal imaging.RESULTS Out of the 51 consecutive patients with PHPT,twelve(23.52%)had pancreatitis[5(9.80%)AP,seven(13.72%)chronic pancreatitis(CP)].PHPT with AP(PHPT-AP)was more common among males with the presentation at a younger age(35.20±16.11 vs 49.23±14.80 years,P=0.05)and lower plasma intact parathyroid hormone(iPTH)levels[125(80.55-178.65)vs 519.80(149-1649.55,P=0.01)]compared to PHPT without pancreatitis(PHPT-NP).The mean serum calcium levels were similar in both PHPT-AP and PHPT-NP groups[(11.66±1.15 mg/dL)vs(12.46±1.71 mg/dL),P=0.32].PHPT-AP also presented with more gastrointestinal symptoms like abdominal pain,nausea,and vomiting with lesser skeletal and renal manifestations as compared to patients with PHPT-NP.CONCLUSION AP can be the only presenting feature of PHPT.Normal or higher serum calcium levels during AP should always draw attention towards endocrine causes like PHPT.

Impact of surgery for chronic pancreatitis on the risk of pancreatic cancer:Untying the Gordian knot

Pancreatic ductal adenocarcinoma is an aggressive tumor with poor long-term outcomes.Chronic pancreatitis(CP)is considered a risk factor for the development of pancreatic cancer(PC).Persistent pancreatic inflammation and activation of pancreatic stellate cells play a crucial role in the pathogenesis of CPrelated PC by activating the oncogene pathway.While genetic mutations increase the possibility of recurrent and persistent pancreatic inflammation,they are not directly associated with the development of PC.Recent studies suggest that early surgical intervention for CP might have a protective role in the development of CP-related PC.Hence,the physician faces the clinical question of whether early surgical intervention should be recommended in patients with CP to prevent the development of PC.However,the varying relative risk of PC in different subsets of CP underlines the complex gene-environment interactions in the disease pathogenesis.Hence,it is essential to stratify the risk of PC in each individual patient.This review focuses on the complex relationship between CP and PC and the impact of surgical intervention on PC risk.The proposed risk stratification based on the genetic and environmental factors could guide future research and select patients for prophylactic surgery.

Long-term effects of metformin use in gestational diabetes mellitus on offspring health

Metformin is the first-line drug for the treatment of type 2 diabetes mellitus,but its role in gestational diabetes mellitus(GDM)management is not clear.Recent evidence suggests a certain beneficial effect of metformin in the treatment of GDM,but a high treatment failure rate leads to the initiation of additional medications,such as insulin.Moreover,since metformin crosses the placental barrier and reaches a significant level in the fetus,it is likely to influence the fetal metabolic milieu.The evidence indicates the long-term safety in children exposed to metformin in utero except for mild adverse anthropometric profiles.Diligent follow-up of metformin-exposed offspring is warranted from the clinician’s point of view.

Do preoperative pancreatic computed tomography attenuation index and enhancement ratio predict pancreatic fistula after pancreaticoduodenectomy?

BACKGROUND The commonly used predictors of clinically relevant postoperative pancreatic fistula(CR-POPF)following pancreaticoduodenectomy(PD)have subjective assessment components and can be used only in the postoperative setting.Also,the available objective predictors based on preoperative cross-sectional imaging were not prospectively studied.AIM To evaluate the accuracy of the pancreatic attenuation index(PAI)and pancreatic enhancement ratio(PER)for predicting CR-POPF following PD and its correlation with pancreatic fat fraction and fibrosis.METHODS A prospective observational study included patients who underwent PD for benign and malignant pathology of the periampullary region or pancreatic head between February 2019 and February 2021.Patients undergoing extended or total pancreatectomy and those with severe atrophy of pancreatic tissue or extensive parenchymal calcifications in the pancreatic head and neck precluding calculation of PAI and PER were excluded from the study.Preoperatively PAI was measured in the neck of the pancreas by marking regions of interest(ROI)in the non-contrast computed tomography(CT),and PER was measured during the contrast phase of the CT abdomen.Also,the fibrosis score and fat fraction of the pancreatic neck were assessed during the histopathological examination.Demographic,clinical and preoperative radiological indices(PAI,PER)were evaluated to predict CR-POPF.Preoperative pancreatic neck CT indices were correlated with the histopathological assessment of fat fraction and fibrosis.RESULTS Of the 70 patients who underwent PD,61 patients fulfilling the inclusion criteria were included in the analysis.The incidence of CR-POPF was 29.5%(18/61).PAI had no association with the development of CR-POPF.Of the preoperative parameters,PER(mean±standard deviation[SD])was significantly lower in patients developing CR-POPF(0.58±0.20 vs 0.81±0.44,P=0.006).The area under the curve for the PER was 0.661(95%CI:0.517-0.804),which was significant(P=0.049).PER cut-off of 0.673 predicts CR-POPF with 77.8%sensitivity and 55.8%specificity.PAI and PER had a weak negative correlation(Strength-0.26,P=0.037).Also,PER showed a moderately positive correlation with fibrosis(Strength 0.50,P<0.001).Patients with CR-POPF had a significantly higher incidence of the intraabdominal abscess(50%vs 2.3%,P<0.001),delayed gastric emptying(83.3%vs 30.2,P<0.001),and prolonged mean(±SD)postoperative hospital stay(26.8±13.9 vs 9.6±3.6,P=0.001).CONCLUSION PER exhibited good accuracy in predicting the development of CR-POPF.PER additionally showed a good correlation with PAI and fibrosis scores and may be used as an objective preoperative surrogate for assessing pancreatic texture.However,ROI-based PAI did not show any association with CR-POPF and pancreatic fat fraction.

Dipeptidyl peptidase 4 inhibitors in COVID-19:Beyond glycemic control

Coronavirus disease 2019(COVID-19)is associated with a high risk of mortality and complications in patients with diabetes mellitus.Achieving good glycemic control is very important in diabetic patients to reduce complications and mortality due to COVID-19.Recent studies have shown the mortality benefit and anti-inflammatory effects of Dipeptidyl-peptidase-4 inhibitors(DPP-4i)in diabetic patients with COVID-19.DPP-4i may have a beneficial role in halting the severity of infection primarily by three routes,namely viral entry inhibition,anti-inflammatory and anti-fibrotic effects and glycemic control.This has raised the promising hypothesis that DPP-4i might be an optimal strategy for treating COVID-19 in patients with diabetes.This review aims to summarise the possible therapeutic non-glycemic effects of DPP-4i in diabetic patients diagnosed with COVID-19 in the light of available evidence.