The safety of telemedicine clinics as an alternative to in-person preoperative assessment for elective laparoscopic cholecystectomy in patients with benign gallbladder disease: a retrospective cohort study.

BACKGROUND: The telemedicine clinic for follow up after minor surgical procedures in general surgery is now ubiquitously considered a standard of care. However, this method of consultation is not the mainstay for preoperative assessment and counselling of patients for common surgical procedures such as laparoscopic cholecystectomy. The aim of this study was to evaluate the safety of assessing and counselling patients in the telemedicine clinic without a physical encounter for laparoscopic cholecystectomy. METHODS: We conducted a retrospective analysis of patients who were booked for laparoscopic cholecystectomy for benign gallbladder disease via general surgery telemedicine clinics from March 2020 to November 2021. The primary outcome was the cancellation rate on the day of surgery. The secondary outcomes were complication and readmission rates, with Clavein-Dindo grade III or greater deemed clinically significant. We performed a subgroup analysis on the cases cancelled on the day of surgery in an attempt to identify key reasons for cancellation following virtual clinic assessment. RESULTS: We identified 206 cases booked for laparoscopic cholecystectomy from telemedicine clinics. 7% of patients had a cancellation on the day of surgery. Only one such cancellation was deemed avoidable as it may have been prevented by a face-to-face assessment. Severe postoperative adverse events (equal to or greater than Clavien-Dindo grade III) were observed in 1% of patients, and required re-intervention. 30-day readmission rate was 11%. CONCLUSIONS: Our series showed that it is safe and feasible to assess and counsel patients for laparoscopic cholecystectomy remotely with a minimal cancellation rate on the day of operation. Further work is needed to understand the effect of remote consultations on patient satisfaction, its environmental impact, and possible benefits to healthcare economics to support its routine use in general surgery.

Autologous blood transfusion reduces the requirement for perioperative allogenic blood transfusion in patients undergoing major hepatopancreatobiliary surgery: a retrospective cohort study.

INTRODUCTION: Major hepatopancreatobiliary surgery is associated with a risk of major blood loss. The authors aimed to assess whether autologous transfusion of blood salvaged intraoperatively reduces the requirement for postoperative allogenic transfusion in this patient cohort. MATERIALS AND METHODS: In this single centre study, information from a prospective database of 501 patients undergoing major hepatopancreatobiliary resection (2015-2022) was analysed. Patients who received cell salvage ( n =264) were compared with those who did not ( n =237). Nonautologous (allogenic) transfusion was assessed from the time of surgery to 5 days postsurgery, and blood loss tolerance was calculated using the Lemmens-Bernstein-Brodosky formula. Multivariate analysis was used to identify factors associated with allogenic blood transfusion avoidance. RESULTS: 32% of the lost blood volume was replaced through autologous transfusion in patients receiving cell salvage. Although the cell salvage group experienced significantly higher intraoperative blood loss compared with the noncell salvage group (1360 ml vs. 971 ml, P =0.0005), they received significantly less allogenic red blood cell units (1.5 vs. 0.92 units/patient, P =0.03). Correction of blood loss tolerance in patients who underwent cell salvage was independently associated with avoidance of allogenic transfusion (Odds ratio 0.05 (0.006-0.38) P =0.005). In a subgroup analysis, cell salvage use was associated with a significant reduction in 30-day mortality in patients undergoing major hepatectomy (6 vs. 1%, P =0.04). CONCLUSION: Cell salvage use was associated with a reduction in allogenic blood transfusion and a reduction in 30-day mortality in patients undergoing major hepatectomy. Prospective trials are warranted to understand whether the use of cell salvage should be routinely utilised for major hepatectomy.

Preclinical characterization of ISB 1342, a CD38 × CD3 T-cell engager for relapsed/refractory multiple myeloma.

Although treatment of multiple myeloma (MM) with daratumumab significantly extends the patient's lifespan, resistance to therapy is inevitable. ISB 1342 was designed to target MM cells from patients with relapsed/refractory MM (r/r MM) displaying lower sensitivity to daratumumab. ISB 1342 is a bispecific antibody with a high-affinity Fab binding to CD38 on tumor cells on a different epitope than daratumumab and a detuned scFv domain affinity binding to CD3ε on T cells, to mitigate the risk of life-threatening cytokine release syndrome, using the Bispecific Engagement by Antibodies based on the TCR (BEAT) platform. In vitro, ISB 1342 efficiently killed cell lines with different levels of CD38, including those with a lower sensitivity to daratumumab. In a killing assay where multiple modes of action were enabled, ISB 1342 showed higher cytotoxicity toward MM cells compared with daratumumab. This activity was retained when used in sequential or concomitant combinations with daratumumab. The efficacy of ISB 1342 was maintained in daratumumab-treated bone marrow patient samples showing lower sensitivity to daratumumab. ISB 1342 induced complete tumor control in 2 therapeutic mouse models, unlike daratumumab. Finally, in cynomolgus monkeys, ISB 1342 displayed an acceptable toxicology profile. These data suggest that ISB 1342 may be an option in patients with r/r MM refractory to prior anti-CD38 bivalent monoclonal antibody therapies. It is currently being developed in a phase 1 clinical study.

First Report With Medium-term Follow-up of Intestinal Transplantation for Advanced and Recurrent Nonresectable Pseudomyxoma Peritonei.

OBJECTIVE: To report our experience with the combination of radical surgical excision and intestinal transplantation in patients with recurrent pseudomyxoma peritonei (PMP) not amenable to further cytoreductive surgery (CRS). BACKGROUND: CRS and heated intraoperative peritoneal chemotherapy are effective treatments for many patients with PMP. In patients with extensive small bowel involvement or nonresectable recurrence, disease progression results in small bowel obstruction, nutritional failure, and fistulation, with resulting abdominal wall failure. METHODS: Between 2013 and 2022, patients with PMP who had a nutritional failure and were not suitable for further CRS underwent radical debulking and intestinal transplantation at our centre. RESULTS: Fifteen patients underwent radical exenteration of affected intra-abdominal organs and transplantation adapted according to the individual case. Eight patients had isolated small bowel transplantation and 7 patients underwent modified multivisceral transplantation. In addition, in 7 patients with significant abdominal wall tumor involvement, a full-thickness vascularized abdominal wall transplant was performed. Two of the 15 patients died within 90 days due to surgically related complications. Actuarial 1-year and 5-year patient survivals were 79% and 55%, respectively. The majority of the patients had significant improvement in quality of life after transplantation. Progression/recurrence of disease was detected in 91% of patients followed up for more than 6 months. CONCLUSION: Intestinal/multivisceral transplantation enables a more radical approach to the management of PMP than can be achieved with conventional surgical methods and is suitable for patients for whom there is no conventional surgical option. This complex surgical intervention requires the combined skills of both peritoneal malignancy and transplant teams.

An inhibitor of RORγ for chronic pulmonary obstructive disease treatment.

The role of RORγ as a transcription factor for Th17 cell differentiation and thereby regulation of IL-17 levels is well known. Increased RORγ expression along with IL-17A levels was observed in animal models, immune cells and BAL fluid of COPD patients. Increased IL-17A levels in severe COPD patients are positively correlated with decreased lung functions and increased severity symptoms and emphysema, supporting an urgency to develop novel therapies modulating IL-17 or RORγ for COPD treatment. We identified a potent RORγ inhibitor, PCCR-1 using hit to lead identification followed by extensive lead optimization by structure-activity relationship. PCCR-1 resulted in RORγ inhibition with a high degree of specificity in a biochemical assay, with > 300-fold selectivity over other isoforms of ROR. Our data suggest promising potency for IL-17A inhibition in human and canine PBMCs and mouse splenocytes with no significant impact on Th1 and Th2 cytokines. In vivo, PCCR-1 exhibited significant efficacy in the acute CS model with dose-dependent inhibition of the PD biomarkers that correlated well with the drug concentration in lung and BAL fluid, demonstrating an acceptable safety profile. This inhibitor effectively inhibited IL-17A release in whole blood and BALf samples from COPD patients. Overall, we identified a selective inhibitor of RORγ to pursue further development of novel scaffolds for COPD treatment.

Methodological and technological advances in safety pharmacology - New or simply nuanced?

This editorial previews and summarizes the content of the current themed issue of J Pharm Tox Methods derived from the recent 2018 Annual Safety Pharmacology Society (SPS) meeting held in Washington, DC. The papers highlight improvements in methods and study endpoints used in non-clinical safety pharmacology (SP) to enhance clinical translatability. Articles cover areas including the SP assessment of oligonucleotides and gene therapy, core battery clinical translation case studies, next generation non-opiate pain management strategy, aspects of cardio-oncology that extend the traditional objectives of an SP assessment, real-world advanced imaging techniques used in preclinical safety, in silico approaches including mathematical modeling, machine learning, and bioinformatics and how secondary SP studies impact clinical trial interpretation and design. The meeting included scientific content from >190 abstracts (reproduced in the current volume of J Pharm Tox Methods).

Gentamicin induced acute renal damage and its evaluation using urinary biomarkers in rats.

Consistent, sensitive biomarkers of acute kidney injury in animal models and humans have historically represented a poorly met need for investigators and clinicians. Detection of early kidney damage using urinary biomarkers is essential to assess the adversity in preclinical toxicology studies, which will help in reducing attrition of lead candidates in drug development. This study was undertaken to evaluate recently identified urinary biomarkers use in identifying acute kidney injury compared to traditional serum markers in experimentally induced nephrotoxicity in male Sprague Dawley (SD) rats. Gentamicin induced nephrotoxicity in Sprague Dawley rats is commonly detected using serum markers and histological evaluation of kidneys. Gentamicin, an aminoglycoside was administered at 30 and 100 mg/kg/day dose (subcutaneous) for seven consecutive days to induce nephrotoxicity. On day 4 and day 8 post treatment, serum and urine samples from these rats were analyzed for traditional serum/urine and novel urinary biomarkers and microscopic evaluation of kidneys. On Day 4, no statistically significant change in serum BUN and creatinine level, but increase in urinary microalbumin (mALB) and urinary protein (UP) noticed in both doses of Gentamicin treated rats. On Day 8 significant increase in serum blood urea nitrogen (BUN), serum creatinine, UP and urinary mALB at 100 mg/kg/day, increase in total protein and decrease in albumin in 30 and 100 mg/kg/day and decrease in BUN and creatinine at 100 mg/kg of Gentamicin treated rats. The BUN and creatinine levels or fold change was comparable between control and 30 mg/kg of Gentamicin on Day 8, however, there was 5.6 and 3.4 fold change in BUN and Creatinine level noticed at 100 mg/kg/day of Gentamicin. On Day 4 and 8, significant increase in urinary levels of Clusterin was noted with animals administered both doses of Gentamicin. Similarly, significant increase in urinary levels of kidney injury molecule 1 (Kim-1), Cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) were noticed with animals administered Gentamicin at 100 mg/kg/day on both Day 4 and 8. All these markers have shown dose-dependent change. Histological changes seen on Day 4 and Day 8 were of minimal to mild and moderate to severe in nature at both doses, respectively. The results demonstrated the sensitiveness and accuracy of detecting acute renal damage with novel urinary biomarkers, and their use in diagnosing early kidney damage. This helps in adversity assessment in animal toxicology studies and advocating right treatment to patients who have early renal injury which otherwise can only be diagnosed by elevated levels of traditional biomarkers in blood only after >30% of kidneys is damaged.

Does neoadjuvant doxorubicin drug-eluting bead transarterial chemoembolization improve survival in patients undergoing liver transplant for hepatocellular carcinoma?

PURPOSE: We aimed to compare the overall (OS) and disease-free survival (DFS) of patients undergoing orthotopic liver transplant (OLT) for hepatocellular carcinoma who did and did not have neoadjuvant doxorubicin drug-eluting bead transarterial chemoembolization (DEB-TACE). METHODS: This is a retrospective study of 94 patients with HCC transplanted between 2000 and 2014 in a single tertiary center. Pre- and postoperative features, DFS and OS were compared between patients who received pre-OLT DEB-TACE (n=34, DEB-TACE group) and those who did not (n=60, non-TACE group). Radiologic and histologic response to neoadjuvant treatment as well as its complications were also studied. RESULTS: There were no significant differences in post-transplantation DFS and OS rates between groups (5-year DFS: 70% in DEB-TACE group vs. 63% in non-TACE group, P = 0.454; 5-year OS: 70% in DEB-TACE group vs. 65% in non-TACE group, P = 0.532). The DEB-TACE group had longer OLT waiting time compared with the non-TACE group (110 vs. 72 days; P = 0.01). On univariate and multivariate analyses, alpha-fetoprotein (AFP) levels >500 ng/mL prior to OLT were associated with decreased OS and DFS regardless of neoadjuvant approach (hazard ratio of 6, P = 0.001 and 5.5, P = 0.002, respectively). CONCLUSION: Patients who underwent neoadjuvant DEB-TACE and OLT for hepatocellular carcinoma had no statistically different OS or DFS at 3 and 5 years from patients undergoing OLT alone.

A simple and effective heat induced antigen retrieval method.

In this paper, we describe an additional step to the standard method of heat induced antigen retrieval to improve the detection of antibody staining of formalin fixed paraffin embedded tissue sections. Direct heating of tissues in buffer is an efficient epitope retrieval method but often results in the damage or loss of tissues. In this modified method, before keeping in buffer for heating, we overlapped the tissue on the slide with a plain slide by clipping one end using a normal paperclip, keeping a minimum gap between the slides. Tissues heated in this way in buffer had following advantages over normal heat treatment for epitope retrieval. •Tissues were intact even at high temperatures which improved the quality of staining by preventing fold, damage or detachment of tissues from the slides.•The method is very safe and economical compared to the methods using microwave or pressure cooker.•This simple method also appears to be very effective and less time consuming compared to the existing methods.

Nonsystemic locally invasive thymic T-cell lymphoma in a fifteen-week-old male CD-1 mouse.

A male CD-1 mouse from a segment I reproduction toxicity study died at the age of fifteen weeks. At necropsy, the thymus was abnormally enlarged and virtually obliterated the thoracic cavity. Histopathological examination of thymus revealed abundant cell population consisting of mature lymphocytes and few lymphoblasts arranged in cords and sheets. Neoplastic cells completely obliterated the thymic architecture, and loss of corticomedullary junction was evident. Microscopically, neoplastic cells were round with moderate cytoplasm. Nuclei were spherical and hyperchromatic with centrally placed nucleoli. Mitotic figures and tingible body macrophages imparting "starry sky appearance" were seen. Multifocal necrotic areas were also observed. Proliferating neoplastic cells invaded the thymic capsule, surrounding adipose tissue and neighboring organs such as lungs, heart and fat pad of aorta, esophagus, trachea, and thoracic vertebrae. No evidence of systemic metastasis was observed in other organs. Immunostained neoplastic cells were positive for CD3 antigen. Gross, histopathology, and immunohistochemistry results were suggestive of thymic T-cell lymphoma.

Differential gene expression analysis of a known hepatotoxin, N-acetyl-p-amino-phenol (APAP) as compared to its non-toxic analog, N-acetyl-m-amino-phenol (AMAP) in mouse liver.

Drug-induced hepatotoxicity is one of the most common adverse events associated with drug withdrawal from the market. Elucidating the molecular mechanism of hepatotoxicity is essential to predict the safety of a new molecule. To examine genes involved in hepatotoxicity, we have used oligonucleotide CodeLink Bioarrays and determined the transcriptional profile of mice liver treated with hepatotoxic drug N-acetyl-p-amino-phenol (APAP) as well as its non-toxic analog N-acetyl-m-amino-phenol (AMAP). Out of 20,000 genes analyzed, 896 showed differential expression of > or = 2-fold (648 upregulated and 248 downregulated) within the liver of APAP treated mice as compared to control. In comparison to AMAP treated mice, 62 genes were upregulated and 70 genes were downregulated in mice liver after APAP treatment. Functional classification of these differentially expressed genes identified genes associated with stress response, cell cycle, growth inhibition, cell death, structural components, cell signaling and inflammation. Gene expression profile was further correlated with biochemical analysis and histopathological lesions. These data show that gene expression profiling would help in better understanding the molecular basis of drug-induced hepatotoxicity that will lead to rational development of safer drugs, particularly in pre-clinical stages.

Histological changes in intestine in semichronic diarrhoea induced by lactose enriched diet in rats: effect of Diarex-Vet.

Efficacy of Diarex-Vet (The Himalaya Drug Company, Makali, Bangalore, India) was evaluated histologically in semichronic diarrhoea induced by lactose enriched diet in rats. The rats in different groups were given lactose enriched diet alone for 2 days before starting the treatment with Diarex-Vet at a dose of 250, 500 and 750 mg/kg body weight along with lactose enriched diet for 5 days. Animals were euthanised at the end of 5 days of treatment and histological changes were observed in the ileum, caecum and colon. Semiquantitative analysis of goblet cells in intestines showed dose dependent response among the treated groups. The morphological changes were comparable to normal in the group given 750 mg/kg body wt Diarex-Vet. The effects observed were attributed to the lactase like analogous activity of Diarex-Vet or the inhibition of the osmotic processes in the intestinal lumen thereby reducing the morphological changes in the intestines.