Malignant hyperthermia during pediatric kidney transplantation-A medical and ethical quandary.

Malignant hyperthermia (MH) is a rare life-threatening anesthetic complication with high mortality rates. MH during adult kidney transplant has been reported previously. However, the occurrence of MH after multiple previous uneventful anesthetic exposures in a pediatric kidney transplant recipient is rare. To our knowledge, this is the first reported case of MH in a child undergoing a live donor kidney transplant. The approaches for addressing perioperative challenges and ethical dilemmas to ensure successful outcomes are described. The recipient, a 5-year-old male child, weighing 20 kg, with a history of multiple previous uneventful anesthetic exposures, underwent live donor kidney transplant for end-stage renal disease (ESRD). Post-reperfusion he developed fulminant MH with rapidly progressing hyperthermia, hypercarbia, tachycardia, and muscle rigidity, which in addition to complicating the medical management raised several ethical issues as well. MH was successfully managed with dantrolene and other supportive measures. Judicious use of inotropes and fluids helped maintain stable hemodynamics and graft perfusion. Management of MH is complicated in a pediatric patient with ESRD undergoing live donor kidney transplant. Preference for non-depolarizing muscle relaxants instead of succinylcholine during endotracheal intubation can result in delayed onset of clinical manifestations. However, the metabolic complications may be more severe due to preexisting electrolyte and acid-base disturbances. Maintaining optimal graft perfusion while simultaneously combating MH can be very challenging in a child. Since the allograft is a precious commodity, critical decisions regarding the harvesting of the donor kidney need to be well thought out. Early diagnosis and prompt treatment with dantrolene are critical to preserving graft function and the recipient's life.

Genetic Variant Associated With Survival of Patients With Stage II-III Colon Cancer.

BACKGROUND & AIMS: Many genetic variants have been associated with colorectal cancer risk, although few have been associated with survival times of patients. Identification of genetic variants associated with survival times might improve our understanding of disease progression and aid in outcome prediction. We performed a genome-wide association study to identify variants associated with colon cancer survival time. METHODS: We performed a post hoc analysis of data from NCCTG N0147 (Alliance), a randomized phase 3 trial of patients with resected stage III colon cancer, and from NSABP C-08 (NRG), a phase 3 trial that compared therapy regimens for patients with resected stage II or III colon cancer. Genotype analyses were performed on DNA from blood samples from 4974 patients. We used Cox proportional hazards regression to evaluate the association of each single nucleotide polymorphism with times of overall survival and disease-free survival, adjusting for age at diagnosis, sex, treatment group, and principal components of genetic ancestry. We performed the analysis for studies N0147 and C-08 separately, and results were combined in a fixed-effects meta-analysis. RESULTS: A locus on chromosome 7p15.2 was significantly associated with overall survival time (P ≤ 5x10-08). The most significant variant at this locus, rs76766811 (P = 1.6x10-08), is common among African Americans (minor allele frequency, approximately 18%) but rare in European Americans (minor allele frequency <0.1%). Within strata of self-reported ancestry, this variant was associated with times of overall survival and disease-free survival in only African Americans (hazard ratio for overall survival, 2.82; 95% CI, 1.88-4.23; P = 5.0x10-07 and hazard ratio for disease-free survival, 2.27; 95% CI, 1.62-3.18; P = 1.8x10-06). CONCLUSIONS: In an analysis of data from 2 trials of patients with stage II or III colon cancer, we identified rs76766811 as a potential prognostic variant in African American patients. This finding should be confirmed in additional study populations. ClinicalTrials.gov Identifiers: NCT00096278 (NSABP C-08) and NCT00079274 (NCCTG N0147).

Dramatic Response to Concurrent Anti-PD-1 Therapy and Radiation in Resistant Tumors with Sarcomatoid Differentiation.

A substantial fraction of patients demonstrate resistance to immune checkpoint inhibitors, which limits their use. Use of radiation concurrently with checkpoint inhibitors has been shown to boost immune responsiveness, resulting in significant tumor regression in patients with metastatic melanoma. However, it is unknown whether radiation could play a role in reversing the inherent resistance to checkpoint inhibition in certain tumor types. Most trials testing this concurrent approach exclude such modestly responsive tumors and pursue checkpoint inhibition using anti-cytotoxic T-lymphocyte-associated protein 4 antibody (anti-CTLA-4, ipilimumab). The efficacy of anti-programmed-death-1 (anti-PD-1) therapy when used concurrently with radiation is less known but remains an attractive option due to less autoimmune toxicity compared with CTLA-4 inhibition. In this first reported experience, we have safely and effectively combined anti-PD-1 therapy (nivolumab) concurrently with radiation to treat two patients with relapsed sarcomatoid renal carcinoma and heavily pretreated pleomorphic sarcoma. Both patients experienced a dramatic response that was durable.

Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance).

Severe (grade≥3) adverse events (AEs) to 5-fluorouracil (5-FU)-based chemotherapy regimens can result in treatment delays or cessation, and, in extreme cases, life-threatening complications. Current genetic biomarkers for 5-FU toxicity prediction, however, account for only a small proportion of toxic cases. In the current study, we assessed DPYD variants suggested to correlate with 5-FU toxicity, a deep intronic variant (c.1129-5923 C>G), and four variants within a haplotype (hapB3) in 1953 stage III colon cancer patients who received adjuvant FOLFOX±cetuximab. Logistic regression was used to assess multivariable associations between DPYD variant status and AEs common to 5-FU (5FU-AEs). In our study cohort, 1228 patients (62.9%) reported any grade≥3 AE (overall AE), with 638 patients (32.7%) reporting any grade≥3 5FU-AE. Only 32 of 78 (41.0%) patients carrying DPYD c.1129-5923 C>G and the completely linked hapB3 variants c.1236 C>G and c.959-51 T>C showed at least one grade≥3 5FU-AE, resulting in no statistically significant association (adjusted odds ratio=1.47, 95% confidence interval=0.90-2.43, P=0.1267). No significant associations were identified between c.1129-5923 C>G/hapB3 and overall grade≥3 AE rate. Our results suggest that c.1129-5923 C>G/hapB3 have limited predictive value for severe toxicity to 5-FU-based combination chemotherapy.

Relationship Between Metformin Use and Recurrence and Survival in Patients With Resected Stage III Colon Cancer Receiving Adjuvant Chemotherapy: Results From North Central Cancer Treatment Group N0147 (Alliance).

BACKGROUND: Preclinical and epidemiological data suggest that metformin might have antineoplastic properties against colon cancer (CC). However, the effect of metformin use on patient survival in stage III CC after curative resection is unknown. The survival outcomes were comparable regardless of the duration of metformin use. PATIENTS AND METHODS: Before randomization to FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) with or without cetuximab, 1,958 patients with stage III CC enrolled in the N0147 study completed a questionnaire with information on diabetes mellitus (DM) and metformin use. Cox models were used to assess the association between metformin use and disease-free survival (DFS), overall survival (OS), and the time to recurrence (TTR), adjusting for clinical and/or pathological factors. RESULTS: Of the 1,958 patients, 1,691 (86%) reported no history of DM, 115 reported DM with metformin use (6%), and 152 reported DM without metformin use (8%). The adjuvant treatment arms were pooled, because metformin use showed homogeneous effects on outcomes across the two arms. Among the patients with DM (n = 267), DFS (adjusted hazard ratio [aHR], 0.90; 95% confidence interval [CI], 0.59-1.35; p = .60), OS (aHR, 0.99; 95% CI, 0.65-1.49; p = .95), and TTR (aHR, 0.87; 95% CI, 0.56-1.35; p = .53) were not different for the metformin users compared with the nonusers after adjusting for tumor and patient factors. The survival outcomes were comparable regardless of the duration of metformin use (<1, 1-5, 6-10, ≥11 years) before randomization (ptrend = .64 for DFS, ptrend = .84 for OS, and ptrend = .87 for TTR). No interaction effects were observed between metformin use and KRAS, BRAF mutation status, tumor site, T/N stage, gender, or age. CONCLUSIONS: Patients with stage III CC undergoing adjuvant chemotherapy who used metformin before the diagnosis of CC experienced DFS, OS, and TTR similar to those for non-DM patients and DM patients without metformin use. IMPLICATIONS FOR PRACTICE: The present study did not find any relationship between metformin use or its duration and disease-free survival, time to recurrence, and overall survival in a large cohort of patients with resected stage III colon cancer receiving adjuvant FOLFOX (folinic acid, fluorouracil, oxaliplatin)-based chemotherapy. This relationship was not modified by KRAS or BRAF mutation or DNA mismatch repair status. Metformin use did not increase or decrease the likelihood of chemotherapy-related grade 3 or higher adverse events.

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.

BACKGROUND: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. METHODS: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. FINDINGS: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. INTERPRETATION: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. FUNDING: Bristol-Myers Squibb.

Adjuvant Nivolumab for Localized Renal Cell Carcinoma at High Risk of Recurrence After Nephrectomy: Part B of the Randomized, Placebo-Controlled, Phase III CheckMate 914 Trial.

PURPOSE: CheckMate 914 is a two-part, randomized phase III trial evaluating adjuvant nivolumab plus ipilimumab (part A) or adjuvant nivolumab monotherapy (part B) versus placebo in mutually exclusive populations of patients with localized renal cell carcinoma (RCC) at high risk of postnephrectomy recurrence. Part A showed no disease-free survival (DFS) benefit for adjuvant nivolumab plus ipilimumab versus placebo. We report results from part B. METHODS: Patients were randomly assigned (2:1:1) to nivolumab (240 mg once every 2 weeks for up to 12 doses), placebo, or nivolumab (240 mg once every 2 weeks for up to 12 doses) plus ipilimumab (1 mg/kg once every 6 weeks for up to four doses). The planned treatment duration was 24 weeks (approximately 5.5 months). The primary end point was DFS per blinded independent central review (BICR) for nivolumab versus placebo; safety was a secondary end point. RESULTS: Overall, 825 patients were randomly assigned to nivolumab (n = 411), placebo (n = 208), or nivolumab plus ipilimumab (n = 206). With a median follow-up of 27.0 months (range, 18.0-42.4), the primary end point of improved DFS per BICR with nivolumab versus placebo was not met (hazard ratio [HR], 0.87 [95% CI, 0.62 to 1.21]; P = .40); the median DFS was not reached in either arm, and 18-month DFS rates were 78.4% versus 75.4%. The HR for DFS per investigator was 0.80 (95% CI, 0.58 to 1.12; P = .19). Grade 3-4 all-cause adverse events (AEs) occurred in 17.2%, 15.0%, and 28.9% of patients with nivolumab, placebo, and nivolumab plus ipilimumab, respectively. Any-grade treatment-related AEs led to discontinuation in 9.6%, 1.0%, and 28.4%, respectively. CONCLUSION: Part B of CheckMate 914 did not meet the primary end point of improved DFS for nivolumab versus placebo in patients with localized RCC at high risk of postnephrectomy recurrence.

Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma.

PURPOSE: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

Multilayer perceptron neural network model development for mechanical ventilator parameters prediction by real time system learning.

BACKGROUND AND OBJECTIVE: In pandemic situations like COVID 19, real time monitoring of patient condition and continuous delivery of inspired oxygen can be made possible only through artificial intelligence-based system modeling. Even now manual control of mechanical ventilator parameters is continuing despite the ever-increasing number of patients in critical epidemic conditions. Here a suggestive multi-layer perceptron neural network model is developed to predict the level of inspired oxygen delivered by the mechanical ventilator along with mode and positive end expiratory pressure (PEEP) changes for reducing the effort of health care professionals. METHODS: The artificial neural network model is developed by Python programming using real time data. Parameter identification for model inputs and outputs is done by in corporating consistent real time patient data including periodical arterial blood gas analysis, continuous pulse oximetry readings and mechanical ventilator settings using statistical pairwise analysis using R programming. RESULTS: Mean square error values and R values of the model are calculated and found to be an average of 0.093 and 0.81 respectively for various data sets. Accuracy loss will be in good fit with validation loss for a comparable number of epochs. CONCLUSIONS: Comparison of the model output is undertaken with physician's prediction using statistical analysis and shows an accuracy error of 4.11 percentages which is permissible for a good predictive system.

Extracorporeal cardiopulmonary resuscitation for an out-of-hospital cardiac arrest.

Extra corporeal membrane oxygenation (ECMO) for refractory out-of-hospital cardiac arrest (OHCA) has been shown to improve outcome in many Western countries. There are no reports of ECMO being used to support OHCA in India till date. We report a case of a young man who developed cardiac arrest (CA) while driving and was given bystander cardiac massage. He was brought to tertiary care center where an ECMO was utilized for refractory CA. The patient subsequently underwent emergency coronary artery stenting and was weaned off ECMO and ventilation. We discuss the case and highlight the role of bystander cardiopulmonary resuscitation.

Anesthetic Challenges and Perioperative Factors Affecting Delayed Graft Function in Robotic-Assisted Kidney Transplant: A Review of a Single-Center Experience of 100 Cases.

Background and objective The advent of robot-assisted kidney transplant (RAKT) has ushered in a new set of challenges. In this single-center retrospective observational study, we aimed to highlight the anesthetic challenges and analyze perioperative parameters to identify the risk factors for delayed graft function (DGF) in RAKT. Methods A descriptive analysis of perioperative factors of the first 100 cases of RAKT at our center was performed. Data were retrieved from the hospital's electronic medical records (EMR) of donors and adult patients who underwent RAKT between July 2015 and December 2020. The data analyzed included demographics, preoperative optimization, intraoperative and postoperative management, and complications. DGF was defined as a requirement of dialysis within one week of transplant. The Fisher's exact test, independent sample t-test, and the Mann-Whitney test were used to analyze data. Results Among a total of 193 renal transplants performed during the study period, 100 patients underwent RAKT, which included 27 females and 73 males. Of these, 91 were live while the remaining involved deceased-donor transplants. Pneumoperitoneum and steep Trendelenburg position required various "anesthetic maneuvers" to maintain hemodynamics and respiratory parameters. Optimal fluid management, with frusemide and mannitol, ensured good urine output (UOP) (93%). Post-reperfusion, the release of pneumoperitoneum, maintenance of adequate perfusion pressures, immunosuppression, and regional hypothermia helped in ensuring adequate graft function (93%). The incidence of DGF in our series was 7% and the mortality rate was 3%. Recipient age (p=0.045), dyslipidemia (p=0.021), and diabetes mellitus (p=0.023) were identified as significant risk factors for DGF. Conclusion Advanced recipient age, diabetes, and dyslipidemia were factors significantly associated with DGF in RAKT in our series of 100 cases. However, the duration of the steep Trendelenburg position, docking of robot/pneumoperitoneum (console time), fluid management, warm and cold ischemia times, rewarming time, and type of graft did not influence DGF. Awareness of the systemic involvement in RAKT, proper preoperative optimization, and knowledge of potential problems are essential for the efficient anesthetic management of RAKT.

Routine Application of Lung Ultrasonography in Respiratory Care: Knowledge, Perceptions, and Barriers to Instigate.

Background: Lung Ultrasound (LUS) had proved to be beneficial in detecting respiratory disorders at the bedside. Understanding the important role of Respiratory Therapists (RTs) in the critical care, we aimed to assess their knowledge, perceived relevance of LUS to clinical practice, current skill gaps, and barriers to practice. Methods: A cross-sectional, nationwide survey conducted among the RTs working in the Kingdom of Saudi Arabia. The validated questionnaire included 4 sections; the demographics, knowledge and perceptions, applicability and self-reported proficiency, and barriers to the use of LUS by RTs. Results: A total of 256 RTs across different regions of Saudi Arabia participated in this survey. 71.9% of them were males, and 46.1% of the participants were having <5 years of working experience. Only (18.1%) of the participants used LUS in their clinical practice, and (43%) of them had never received any training. 66% of the participants perceived LUS as an effective tool in the RT practice and immensely valuable in their daily practice (70%). A large proportion of RTs perceived LUS to be ineffective in calculating the lung score (50.4%), assessing the diaphragm (40.2%), and detecting pulmonary edema (38.3%). Calculating lung score has a lower mean score of 2.55 on both skills, and identifying its applicability to clinical practice with a mean score of 2.71 than other indications. Lack of training and curriculum (154/256; 60.2%) remains the top barrier that prevented RTs from using LUS in their clinical practice. Conclusion: While many RTs in Saudi Arabia perceived LUS as an effective tool in the RT practice, considerable competence gap exist, indicating the need for LUS training. There is a need for incorporating LUS into the curriculum of RT schools and promoting competency-based training for the current RT workforce to help improve patient care.

Immunoscore Is Prognostic in Low-Risk and High-Risk Stage III Colon Carcinomas Treated With Adjuvant Infusional Fluorouracil, Leucovorin, and Oxaliplatin in a Phase III Trial.

PURPOSE: The recommended duration of adjuvant fluoropyrimidine and oxaliplatin chemotherapy for patients with stage III colon cancer is based on tumor classification into clinically low-risk (T1-3 N1) and high-risk (T4 or N2) groups. We determined whether Immunoscore can enhance prognostication within these risk groups. MATERIALS AND METHODS: Patients with stage III colon carcinomas (N = 600) were randomly selected from the infusional fluorouracil, leucovorin, and oxaliplatin arm of adjuvant trial NCCTG N0147 (Alliance for Clinical Trials in Oncology). Tumors were evaluated for Immunoscore that quantifies CD3+ and CD8+ T-cell densities in the tumor center and invasive margin by digital image analysis. Disease-free survival (DFS) by Immunoscore was analyzed using a multivariable Cox regression model in each risk group with adjustment for covariates including KRAS, BRAFV600E, and mismatch repair status. RESULTS: Of 559 cancers with Immunoscore data, 299 (53.5%) were classified as clinically low-risk (T1-3 N1) and 260 (46.5%) as clinically high-risk (T4 and/or N2). Among patients with low-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors had significantly worse 5-year DFS rates (77.5% v 91.8%; hazard ratio, 1.70; 95% CI, 1.03 to 2.79; P = .037). Among patients with high-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors also had significantly worse DFS (55.3% v 70.3%; hazard ratio, 1.65; 95% CI, 1.11 to 2.47; P = .013). Tumors that were low-risk/Immunoscore-Low had similar outcomes as did tumors that were high-risk/Immunoscore-High (P = .174). Prognostication was significantly improved in multivariable models where Immunoscore was added to clinical risk parameters and limited biomarkers (likelihood ratio test P = .0003). CONCLUSION: Immunoscore can refine patient prognosis beyond clinical risk group classification, suggesting its potential utility for adjuvant decision making.

Risk stratification after recurrence of human papillomavirus (HPV)-related and non-HPV-related oropharyngeal cancer: Secondary analysis of NRG Oncology RTOG 0129 and 0522.

BACKGROUND: No risk-stratification strategies exist for patients with recurrent oropharyngeal cancer (OPC). METHODS: Retrospective analysis using data from prospective NRG Oncology clinical trials RTOG 0129 and 0522. Eligibility criteria included known p16 status and smoking history, and locoregional/distant recurrence. Overall survival (OS) was measured from date of recurrence. Recursive partitioning analysis was performed to produce mutually exclusive risk groups. RESULTS: Hundred and fifty-four patients were included with median follow-up after recurrence of 3.9 years (range 0.04-9.0). The most important factors influencing survival were p16 status and type of recurrence, followed by surgical salvage and smoking history (≤20 vs. >20 pack-years). Three significantly different risk groups were identified. Patients in the low-, intermediate-, and high-risk groups had 2-year OS after recurrence of 81.1% (95%CI 68.5-93.7), 50.2% (95%CI 36.0-64.5), and 20.8% (95%CI 10.5-31.1), respectively. CONCLUSION: Patient and tumor characteristics may be used to stratify patients into risk groups at the time of OPC recurrence.

Adaptive Dosing of Nivolumab + Ipilimumab Immunotherapy Based Upon Early, Interim Radiographic Assessment in Advanced Melanoma (The ADAPT-IT Study).

PURPOSE: Nivolumab + ipilimumab (nivo + ipi) is highly efficacious but has high toxicity. Standard treatment in advanced melanoma is four doses of nivo + ipi followed by nivo alone. Whether four doses of nivo + ipi are needed is unclear. METHODS: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT) study (NCT03122522) is a multicenter, single-arm phase II clinical trial. Patients received two doses of nivo (1 mg/kg) + ipi (3 mg/kg) followed by a computed tomography scan at week 6. Patients without new lesions or index lesion tumor growth of > 4% had protocol-defined early favorable antitumor effect (FATE) and ceased nivo + ipi, transitioning to nivo monotherapy. Patients without FATE at week 6 received the standard third and fourth doses of nivo + ipi followed by nivo monotherapy. The primary end point was response rate by RECIST 1.1 at week 12. Secondary end points included additional efficacy assessments and safety. RESULTS: Sixty patients were enrolled; 41 patients (68%) had FATE at week 6 and met criteria for stopping nivo + ipi. Best overall response rates by RECIST at week 12 or any time afterward were 48% (95% CI, 35 to 62) and 58% (95% CI, 45 to 71), respectively. With a median follow-up of 25 months, the estimated 18-month progression-free survival and overall survival are 52% and 80%, respectively. Fifty seven percent of patients had grade 3-5 treatment-related toxicity. CONCLUSION: The efficacy and toxicity of standard four dose nivo + ipi induction therapy in melanoma is likely driven by the first two doses. An interim computed tomography scan after two doses guided cessation of combination dosing and identified almost all responders. Longer follow-up and further study are needed to fully understand the implications of a shortened induction course of nivo + ipi.

Ultra-short course of low-dose amiodarone-induced post-operative fatal pulmonary toxicity.

A 58-year-old male diabetic patient with severe left ventricular dysfunction and pulmonary arterial hypertension successfully underwent coronary artery by pass grafting (CABG) and was extubated 48 hours after surgery. Patient had atrial fibrillation on 3rd post-operative day requiring loading dose of amiodarone followed by maintenance dose to control the arrhythmia. On 4th post operative day patient became tachypnoiec and required higher concentration of oxygen to maintain SpO2 >90%. There was new infiltrates on the x-ray, which was more on right side. Initially treated as pulmonary infection and antifailure measures. The patient did not respond and the lesions progressed to opaque hemithorax by the 10th postoperative day. On 11th POD he was reintubated due to respiratory distress. After excluding pulmonary infections, pulmonary oedema, embolism and vascular obstruction, the possibility of drug induced pulmonary toxicity was considered. Hence amiodarone was withdrawn and steroid was initiated. There was good radiological and gas exchange improvement and he was extubated the following day. After one week course of steroids the infiltrates cleared and oxygenation also improved. Post CABG patients are prone for acute amiodarone toxicity and high index of suspicion is needed to diagnose this early so that fatal complication can be averted by timely intervention.

Critical care as a career for anaesthesiologists.

Anaesthesiologists by virtue of their understanding of physiology, pharmacology and resuscitation skills are best suited to manage critical care units. Armed with this varied knowledge, the anaesthesiologist is 'physician to the surgeon and a surgeon to the physician'. Specialised training helps them to provide extended postoperative and critical care. During the past few months in the battle with coronavirus disease (COVID)-19, anaesthesiologists have stood up to the challenge of caring for critically ill patients, compromising on their operating room responsibilities. The fact from a growing body of literature suggests that an anaesthesiologist as a critical care specialist provides efficient care and better outcomes. With an increasing awareness and need for critical care, government support is going to increase with an increase in avenues for training and research leading to better professional development and earning potential.

Comparison of efficacy of two different doses of tranexamic acid in prevention of post operative blood loss in patients with congenital cyanotic heart disease undergoing cardiac surgery.

Background: The optimal dose of tranexamic acid in minimizing perioperative bleeding is uncertain. We compared efficacy of two different doses of tranexamic acid in reducing post-operative blood loss and its side effects in patients with congenital cyanotic heart disease undergoing cardiac surgery. Settings and Design: Prospective observational study at a pediatric cardiac center in South India. Methods: Consecutive cyanotic patients undergoing cardiac surgery were divided into groups I and II to receive either 10 mg/kg or 25 mg/kg of tranexamic acid administered as triple dose regime after induction, during cardiopulmonary bypass, and after protamine. Post-operative blood loss at 24 hours, blood component utilization, incidence of renal dysfunction and seizures were compared. Results: Totally, 124 patients were recruited, 62 in each group. The pre-operative variables and cardiopulmonary bypass time were comparable. Patients receiving 25 mg/kg had lower post-operative blood loss compared to patients in lower dose group (8.04 ± 8.89 vs 12.41 ± 19.23 ml/kg/24 hours, P = 0.03). There was no difference in the transfused volume of packed red cells (9.21 ± 7.13 ml/kg vs 12.41 ± 9.23 ml/kg, P = 0.712), fresh frozen plasma (13.91 ± 13.38 ml/kg vs 11.02 ± 8.04 ml/kg, P = 0.19), platelets (9.03 ± 6.76 ml/kg vs 10.90 ± 6.9 ml/kg, P = 0.14) or cryoprecipitate (0.66 ± 0.59 ml/kg vs 0.53 ± 0.54 ml/kg, P = 0.5) in group II and I, respectively. Two patients developed renal dysfunction secondary to low cardiac output in lower dose group. There were no seizures. Conclusions: Tranexamic acid administered at a dose of 25 mg/kg as triple dose regime is associated with lower post-operative blood loss compared to a lower dose of 10 mg/kg in cyanotic patients undergoing cardiac surgery without causing major adverse effects.