Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial.

BACKGROUND: First-line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab-containing regimens in many countries. We report longer-term follow-up data. METHODS: This open-label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression-free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD-L1) expression of ≥1% and then in the overall population. RESULTS: A total of 970 patients were randomly assigned. After 29 months of minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46-0.76]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65-0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48-0.80]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65-0.92]). In patients with tumor cell PD-L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51-0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79-1.36]). Among all treated patients (n = 936), Grade 3-4 treatment-related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients. CONCLUSIONS: Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow-up, further supporting use as first-line standard treatment options for patients with advanced ESCC.

Factors influencing the quality of life in inflammatory bowel disease: A comprehensive review.

Inflammatory bowel disease (IBD) is a group of chronic relapsing disorders, including Crohn's disease (CD) and ulcerative colitis (UC), which affects an increasing number of people worldwide. In the last few decades, the scientific world has witnessed many developments in IBD management by controlling debilitating symptoms and remaining in remission for more protracted periods. Even so, we still have a large population suffering from active IBD. An individual's quality of life (QoL) can be severely affected by IBD, like any other chronic illness. In this article, we have reviewed factors influencing the QoL in IBD patients, including chronic pain, diet, physical activity, and psychological factors like depression, anxiety, and stress symptoms. We also discussed the mechanisms of diet-microbial-immune system interaction, currently available dietary therapies for active CD and UC, and early psycho-social interventions that can reduce the disease burden and improve QoL in IBD patients.

Treating low- and intermediate-risk acute promyelocytic leukemia with and without chemotherapy: A comparison in a tertiary care center.

Background: Acute promyelocytic leukemia (APL) comprises approximately 10% of acute myeloid leukemia (AML) cases. Material and Methods: Both options of treatment (ATRA-ATO and ATRA-chemotherapy) were discussed with patients with low- and intermediate-risk APL, pros and cons explained in details, and treatment regimen selected after getting informed written consent. Results: Total 71 patients were included in the study; among these patients, 3 were negative for both FISH for t (15,17) and RT-PCR for promyelocytic leukemia retinoic acid receptor alpha, and 36 patients with APL had white blood cell count at diagnosis >10 × 109/l. Total 30 patients with newly diagnosed as low- and intermediate-risk-APL fulfilled all inclusion criteria, treated and followed for a minimum period of 2 years up to June, 2016. Fifteen patients liked to be treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), while rest of the 15 patients preferred treatment with ATRA and chemotherapy. Conclusion: Combination of ATRA and ATO is equally effective, less toxic, and more feasible in comparison to ATRA and chemotherapy for patients with low- and intermediate-risk APL and is a viable option for this subset of patients, especially in countries with limited resources.

Heart failure in patients with metabolic syndrome X.

Metabolic syndrome X has been known to be a risk factor for the development of cardiovascular dysfunction. Insulin resistance, diabetes mellitus and serum lipid abnormalities, which are all seen in metabolic syndrome X, have been found to negatively impact heart function, leading to heart failure in particular. Heart failure is a condition resulting when the heart is unable to perform its function of providing sufficient blood flow to meet the body's requirements. The treatment of heart failure in metabolic syndrome X varies based on the various components of metabolic syndrome X, which include obesity, hyperglycemia, hypertension and dyslipidemia. Obesity is regarded as one of the derangements seen in patients with metabolic syndrome X. It is a significant risk factor in the development of cardiovascular disease, which may eventually lead to heart failure. However, the obesity paradox suggests that obesity provides a higher chance of survival in patients with metabolic syndrome and heart failure. This review article focuses on the pathophysiology of heart failure in patients who already have metabolic syndrome X, as well as the therapeutic management complexity of the two conditions taking into consideration the protective role provided by obesity.

Severe persistent marrow aplasia in chronic myeloid leukemia (CML): An unusual complication of imatinib.

Background: Imatinib has changed the treatment of chronic myeloid leukemia (CML) drastically since 15 years. It is usually well tolerated, but severe persistent marrow aplasia is an unusual complication of imatinib while using it in CML. The aim of this study is to describe our experience confronting this rare side effect and review the available data worldwide. Patients and Methods: It was a retrospective analysis conducted at a center from February 2002 to February 2015. This study was endorsed by our Institutional Review Board (IRB) and written consent was taken from all patients. Patients diagnosed as Philadelphia (Ph) chromosome-positive CML either in chronic phase (CP), accelerated phase (AP), or blastic crisis (BC) were included. There were a total of 1,576 patients with CML treated with imatinib during this period. Karyotyping and quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) were done at the time of pancytopenia for all patients. Results: In total, 11 (males = 5, females = 6) patients met our inclusion criteria from 1,576 patients of CML. The median age was 58 years (range 32-76). Out of 11 patients 8, 2, and 1 patients were in CP, AP, and BC phases, respectively. The median time of administration of imatinib was 3.3 months (range 1.5-6). The average time of marrow recovery was 10.4 months (range 5-15). Two patients expired (one from septicemia and the other from intracranial hemorrhage). BCR-ABL transcripts level by RT-PCR revealed the existence of the disease in all patients. Conclusion: Imatinib is a very well-tolerated tyrosine kinase inhibitor (TKI), but is associated with persistent myelosuppression when used in older age, advanced phase of the disease, and treated previously. After confirming persistent marrow aplasia, the treatment is mainly supportive. It is striking that the disease is still persistent, which is confirmed by RT-PCR. There is no consensus regarding recalling imatinib at lower doses or the use of second-generation TKI (nilotinib, dasatinib) in these patients.

Tibio-pedal arterial pressure assessment during endovascular intervention to improve quality-of-life in patients with intermittent claudication.

Objective: The aim of this study is to compare the quality-of-life (QOL) outcomes and the tibio-pedal arterial pressure post-endovascular intervention. Background: Physiological assessment of peripheral arterial lesions is infrequently performed during endovascular interventions. Materials and methods: We retrospectively reviewed all 343 patients with intermittent claudication who underwent an endovascular intervention via tibio-pedal artery access from October 2018 to May 2021. The baseline and post-intervention tibio-pedal arterial pressures from the pedal sheaths were measured. QOL was assessed using a pre-validated Walking Impairment Questionnaire (WIQ) score before and at 30-day after intervention. We compared the baseline tibio-pedal arterial pressure, post-intervention tibio-pedal arterial pressure, delta pressure (post-intervention minus baseline), baseline WIQ scores, 30-day WIQ scores, and delta score (30-day minus baseline). Results: All 343 patients had successful tibio-pedal accesses. The average tibio-pedal arterial pressure at baseline was 87.0 ± 1.8 mmHg vs. 135.5 ± 1.7 mmHg post-intervention (p < 0.001). Average baseline and 30-day WIQ scores were summation (99.8 ± 3.3 vs. 115.0 ± 3.1, p < 0.001), walking distance (35.7 ± 1.3 vs. 42.5 ± 1.3, p < 0.001), walking speed (21.1 ± 0.9 vs. 23.6 ± 0.8, p = 0.036), stair climbing (4.7 ± 1.4 vs. 24.2 ± 1.4, p = 0.019), and symptoms (18.8 ± 0.2 vs. 20.1 ± 0.2, p < 0.001), respectively. When comparing the increased post-intervention tibio-pedal arterial pressure <60 mmHg vs. ≥60 mmHg, the average delta WIQ scores were all significantly improved with summation (10.0 ± 3.9 to 25.8 ± 5.5, p = 0.01), walking distance (4.1 ± 1.7 to 9.8 ± 2.5, p = 0.02), walking speed (1.5 ± 1.1 to 4.3 ± 1.5, p = 0.02), stair climbing (2.3 ± 1.8 to 9.4 ± 2.5, p = 0.02), and symptoms (1.0 ± 0.3 to 1.8 ± 0.4, p = 0.04), respectively. Conclusion: Increasing the post-intervention tibio-pedal arterial pressure by 60 mmHg can enhance QOL as suggested by improvement of WIQ scores.

Transcatheter heart valve selection in patients with low ejection fraction and aortic stenosis.

OBJECTIVE: The aim of this study was to compare outcomes of transcatheter heart valve (THV) choice in patients with left ventricular (LV) systolic dysfunction. BACKGROUND: The management congestive heart failure with combined LV systolic dysfunction and severe aortic stenosis (AS) is challenging, yet transcatheter aortic valve replacement (TAVR) has emerged as a suitable treatment option in such patients. Head-to-head comparisons among the balloon-expandable (BEV) and self-expandable (SEV) THV remain limited in this subgroup of patients. METHODS: In this retrospective study, we included patients with severe AS with LV systolic dysfunction (LVEF ≤40%) who underwent TAVR at four high volume centers. Two thousand and twenty-eight consecutive patients were analyzed, of which 335 patients met inclusion criteria. One hundred fourty-six patients (43%) received a SEV, and 189 patients (57%) received a BEV. RESULTS: Baseline characteristics were similar except for a higher proportion of females in the SEV group. The primary composite endpoint of in-hospital mortality, moderate or greater paravalvular (PVL), stroke, conversion to open surgery, aortic valve reintervention, and/or need for permanent pacemaker (PPM) was no different among THV choice. There was more PVL in the SEV group, but higher transaortic gradients in the BEV group. Clinical outcomes and quality of life measures were similar up to 1 year follow-up. CONCLUSION: The choice of THV in patients with severe AS and systolic dysfunction must be weighed on a case-by-case basis.

Mucormycosis, Diabetes and COVID-19 Pneumonia: Unleashing the Facts.

Background Mucormycosis (MM) is an angioinvasive locally destructive fungal infection. Before the coronavirus disease 2019 (COVID-19) pandemic, it was associated with diabetes (particularly diabetic ketoacidosis), immunosuppressive drugs and trauma. Among its various forms, cerebral invasion is considered to be highly fatal even if with long-term treatment. Treatment with injection amphotericin B (Amph-B) with early surgical interventions is highly efficacious. Liposomal preparation is considered to be superior in the context of fewer side effects. Methods We present a single-centre prospective study of 124 patients with MM in a tertiary care hospital. After the approval from the ethics committee, basic information was taken from all patients including all available past history about the COVID-19 infection and treatment. The studied outcomes were discharge, death and number of days of hospitalisation. Secondary objectives were to estimate the association of MM with known risk factors, to find the association of an outcome with various inflammatory markers, to determine adverse events with the use of injection Amph-B and posaconazole and to find the case fatality rate of MM. Results In our study, we observed that the number of patients with MM was double in the less than 60 years age group. However, mortality was 33.3% in the elderly as compared to 15.29% in patients less than 60 years of age. The majority of the patients (69.35%) were males, but no significant difference in mortality was seen between males and females. The case fatality rate was 20.97%. Ocular symptoms such as orbital swelling and pain were the common presenting symptoms. Almost all patients (93.54%) were diabetics. The non-diabetic group consisted of only 8 (6.4%) patients, and therefore, the comparison was not possible. A total of 20 (16%) out of 124 patients who had received high-dose steroids showed higher mortality (55%). Maximum patients (65.32%) had presented with MM following a past COVID-19 infection. However, a significant number of MM patients (20.96%) had a recent COVID infection and had higher mortality (57.69%) compared to their counterparts. The most common site of involvement in our study was the paranasal sinus (50%) and the outcome was the best in those patients whose disease was localised only to the sinuses, although among 14 (11.29%) patients with cerebral involvement, mortality was maximum (42.85%). Renal impairment and dyselectrolytemia were the most common adverse effects of Amph-B, and 46.42% of patients required surgical removal of the local part. Conclusion We saw that diabetes was a major contributory factor in the etiopathogenesis of MM. COVID-19 could also be a major causative factor by impairing the immune system; however, further studies at the molecular level are required to establish an association. The use of steroid cannot be the only independent risk factor, and other associated factors must be present. Treatment with antifungal and early surgical intervention had good outcomes. Treatment with conventional lyophilized Amph-B was equally efficacious as lipid-based solutions, but with more side effects. Hypokalemia and hypocalcemia were the most common electrolyte abnormalities associated with the use of injection Amph-B. Uncontrolled diabetes, the severity of the COVID-19 infection at presentation, acidosis, a high C-reactive protein level (above 100) and local brain involvement were associated with a poor outcome.

The Use of Bumper Wire Technique and Intravascular Ultrasound for Precise Aorto-Ostial Stenting.

Background: Aorto-ostial interventions are challenging due to the limitations of contemporary equipment, imprecise ostial demarcation, and problematic ostial lesion characteristics. Suboptimal stent placement is common and portends worse clinical outcomes. Procedural and long-term outcomes of the bumper wire technique with intravascular ultrasound (IVUS) assessment have not been investigated. Methods: A single-center retrospective study was conducted. Patients who underwent ostial lesion percutaneous coronary intervention (PCI) with the bumper wire technique between January 2019 and September 2020 were identified. The primary endpoint was to determine the geographic miss rate defined by inadequate ostial coverage or excess stent protrusion of > 2 mm by IVUS or angiography. The secondary endpoint was target lesion failure (TLF) at 6 months after PCI, defined as the composite of cardiovascular death, target vessel myocardial infarction (MI), and target lesion revascularization. Results: In total, 45 patients were identified. The average age was 71.7 years old, and 85.4% were men. Indication for PCI was acute coronary syndrome in about a third of patients. Twenty-six patients had left main ostial lesions and 19 patients had right coronary artery ostial lesions. Geographic miss was detected in two patients (4.4%): one patient (2.2%) had excess proximal stent protrusion and one patient (2.2%) had an ostial miss. Six patients were lost to follow-up. TLF, stroke, or major bleeding were not observed in any of the patients. Conclusion: The bumper wire technique is safe and efficient with low rates of geographic miss or adverse clinical outcomes. This is the first study to confirm precise aorto-ostial stent implantation with the bumper wire technique using IVUS confirmation.

Stress-Induced Hyperglycemia: Consequences and Management.

Hyperglycemia during stress is a common occurrence seen in patients admitted to the hospital. It is defined as a blood glucose level above 180mg/dl in patients without pre-existing diabetes. Stress-induced hyperglycemia (SIH) occurs due to an illness that leads to insulin resistance and decreased insulin secretion. Such a mechanism causes elevated blood glucose and produces a complex state to manage with external insulin. This article compiles various studies to explain the development and consequences of SIH in the critically ill that ultimately lead to an increase in mortality while also discussing the dire impact of SIH on certain acute illnesses like myocardial infarction and ischemic stroke. It also evaluates multiple studies to understand the management of SIH with insulin and proper nutritional therapy in the hospitalized patients admitted to the Intensive care unit (ICU) alongside the non-critical care unit. While emphasizing the diverse effects of improper control of SIH in the hospital, this article elucidates and discusses the importance of formulating a discharge plan due to an increased risk of type 2 diabetes in the recovered.

Pancreatic Cancer and the Obesity Epidemic: A Narrative Review.

Pancreatic cancer (PC) is one of the most frequent causes of death. It usually affects older individuals with incidence closely approaching mortality due to its early asymptomatic feature and highly metastatic nature. Multiple risk factors such as family history, smoking, and germline mutations are associated with PC development, with obesity being one of the controllable factors. This review article focuses on the compilation of various studies to help establish a correlation between obesity or an increased body mass index and PC development. Hence, in this review, we have summarised multiple biological mechanisms of PC development induced by obesity, including insulin resistance, inflammation, beta-cell dysfunction, and oxidative stress, to prove that their correlation when combined with other factors, such as smoking, alcohol and chronic pancreatitis, may increase its risk. We have also reviewed potential diagnostic and screening techniques, such as evaluating precancerous lesions in high-risk patients and management plans discussing upcoming advances in treatment tactics such as neoadjuvant therapy, to reduce post-operative complications.

Obscure Gastrointestinal Bleeding and Capsule Endoscopy: A Win-Win Situation or Not?

Obscure gastrointestinal bleeding (OGIB) refers to bleeding of uncertain origin that persists or recurs after negative workup using any of the radiologic evaluation modalities. It can be divided into two types based on whether clinically evident bleeding is present, namely, obscure overt and obscure occult bleeding. As the visualization of the bowel mucosa is challenging, capsule endoscopy (CE) is the ideal go-to procedure as the process is wireless, ingestible, small, disposable, and, most importantly, non-invasive. This review article has compiled various studies to shed light on the guidelines for using CE, its structure and procedure, patient preferences, diagnostic yield, cost-effectiveness, and the future. The goal of this review is to show the influence of CE on OGIB on the aspects mentioned earlier.

Neuropathy in Human Immunodeficiency Virus: A Review of the Underlying Pathogenesis and Treatment.

This article explores the various causes of the human immunodeficiency virus (HIV), and its associated neuropathy, including the effects of HIV on the nervous system and the long-standing therapy that is often provided to patients with HIV. Several studies regarding the neurotoxic effects of combined antiretroviral therapy (cART) and HIV were reviewed and various hypotheses were discussed. Furthermore, we present the nature of HIV-sensory neuropathy (HIV-SN) among different demographic populations and their subsequent risk factors predisposing them to this condition. It was observed that the incidence of the disease increases in increased survival of the patients as well as in males. Finally, the current approach to HIV-SN and its overlapping features with other causes of peripheral neuropathy have been discussed which demonstrates that a clinical examination is the most important clue for a healthcare professional to suspect the disease. Our main aim was to study the current perspectives and guidelines for diagnosing and managing a patient with HIV-SN to reduce disease prevalence and bring about a more aware frame of mind when following up with an HIV patient.

Migraine With Comorbid Depression: Pathogenesis, Clinical Implications, and Treatment.

Migraine is a neurological disorder that strongly relates to psychiatric conditions like depression. Lately, the increased prevalence of depression in migraineurs has come to attention. This article compiled various literature to explore the association between migraine and depression. Genetic overlap of various gene segments was studied, and heritability patterns were explored. Shared mechanisms such as serotonergic dysfunction, methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and hormonal effects were investigated, and commonalities like comorbidities, stress, and environmental factors were analyzed. Migraine with comorbid depression (MID) affects various aspects of life and its clinical impact on migraine disability, quality of life (QOL), progression, and medication overuse was investigated. We further inspected several types of research in order to provide options on various treatment modalities. Pharmacotherapy such as antidepressants and anti-Calcitonin Gene-Related Peptide (CGRP) monoclonal antibodies like fremanezumab were studied. Alternative treatment options such as onabotulinumtoxinA (OBTA) injections, cognitive behavioral therapy (CBT), and vagal nerve stimulations (VNS) were also appraised and the efficacies of each were compared.

Nivolumab in Recurrent/Metastatic Squamous Cell Carcinoma of Head and Neck: A Tertiary Cancer Center Experience.

Apurva A. PatelAnanya PareekBackground Immunotherapy is a proven therapeutic option in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) after platinum therapy. At present, there are no published Indian data regarding administration of nivolumab in this setting. Aim The aim of this study is to retrospectively evaluate the efficacy and toxicity of nivolumab in R/M HNSCC among Indian patients who progressed after one or more lines of chemotherapy, including platinum agents. Methods All patients of R/M HNSCC who received nivolumab between 2/6/2018 to 31/3/2020 were assessed retrospectively for the efficacy and toxicity of nivolumab therapy. Statistical Analysis All the data analysis was performed using IBM SPSS Statistics for Windows, version 25 (IBM Corp., Armonk, N.Y., USA). Descriptive analysis was performed to obtain baseline characteristic of the study sample. Survival analysis was done using the Kaplan-Meier method. Results Nivolumab therapy was tolerated well, with no new safety concerns, except one (8.3%) patient experienced grade ¾ toxicity (gastrointestinal). The clinical benefit rate (CBR) was found to be 66.7%. The median progression-free survival (PFS) was 3 months (95% CI; 2.093-3.907), and median overall survival (OS) was 8 months (95% CI; 3.731-12.269) from the date of first dose of nivolumab. Conclusions In our study, efficacy and toxicity were comparable with international data with no new safety concerns. Nivolumab emerged as an astonishing treatment option with tolerable toxicity profile in patients with R/M HNSCC postplatinum therapy, although limited treatment options are available at present.

Experience of Nivolumab Prior to Autologous Stem Cell Transplant for Relapsed Refractory Hodgkin Lymphoma.

Purpose Nivolumab is an anti-programmed cell death protein 1 (PD1) monoclonal antibody that is indicated in relapsed/refractory Hodgkin lymphoma (R/R HL) after autologous stem cell transplant (autoSCT). Purpose of our retrospective study was to assess safety and efficacy of Nivolumab in R/R HL as a bridge to autoSCT in patients who are refractory to ≥ 2 lines of chemotherapy. Methods Demographic data, number of chemotherapy regimens given previously, number of Nivolumab doses taken, and disease status on PET/CT were noted. Nivolumab was administered as a 3 mg/kg IV infusion every 2 weeks. The immunotherapy related adverse events (irAEs) were noted if any and documented. Results A total of 16 patients were included in the study. Ten patients were male and 6 were female. Median age was 22 years (range 3-32 years). The median number of treatment lines prior to Nivolumab was 3 (range 2-7). Nine patients had Complete Response (CR), 3 had Partial response (PR), 2 had Stable Disease (SD), 1 patient had pseudo-progression; classified as IR (3) and 1 expired before end of treatment evaluation. The drug was well tolerated, with mild irAEs noted. Twelve patients (75%) successfully underwent autoSCT. At a median follow up of 17.5 months (range 0.5-35 months), the progression- free survival (PFS) was 75% and overall survival (OS) was 87.5%. Conclusion Nivolumab is effective and safe in patients with R/R HL and is a good bridging therapy to autoSCT.

Erythroderma: An unusual manifestation of imatinib - A rare case report.

Imatinib is a tyrosine kinase inhibitor that selectively inhibits several protein tyrosine kinases which is central to the pathogenesis of human cancer. It forms the first-line treatment for chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Usually, the drug is well-tolerated with relatively few side effects. Adverse effects most commonly associated with imatinib include mild-to-moderate edema, nausea and vomiting, diarrhea, muscle cramps, and cutaneous reactions. Other side effects such as the elevation of hepatic transaminase and myelosuppression occur less frequently and resolve with interruption of imatinib therapy. Skin rash is one of the most common adverse effects of imatinib incidence of which range from 7% to 88.9%. Exfoliative dermatitis, i.e., erythroderma has been very rarely reported with this drug. We here report a rare case of erythroderma in a patient with CML on imatinib 400 mg/day therapy within 3 months of starting the treatment.

Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.

BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. CONCLUSIONS: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).

Migration of biliary stent into the gallbladder: A surprising intraoperative finding.

Post-endoscopic retrograde cholangiopancreatography stenting is a well-established treatment for benign as well as malignant biliary obstruction. The most frequently encountered complication is stent clogging. Stent migration (proximal or distal), on the other hand, is not very common. Proximal migration of a choledochal endoprosthesis into the gallbladder has not yet been reported in the literature.