Bailout Surgery for Difficult Gallbladders: Surgical Approach and Outcomes.

INTRODUCTION: Inflammation in acute cholecystitis may cause a cholecystectomy to be more challenging. Due to the difficult dissection, conversion to subtotal cholecystectomy via laparoscopic or open procedure may be required. This is done to reduce the risk of bile duct injury and hemorrhage. We sought to describe the incidence and risk factors, safety, morbidity, and outcomes associated with bailout procedures. METHODS: A single academic center, retrospective review of laparoscopic cholecystectomies that resulted in bailout procedures performed between January 2015 and December 2020. Data collected from the chart review included demographics, comorbidities, length of presenting symptoms, vital signs, laboratory and imaging, intraoperative findings, length of surgery, and outcome. RESULTS: A total of 1892 cholecystectomies were performed with 147 bailout procedures. For bailout 92 (63.4%) were converted to open, with 66% resulting in complete cholecystectomy. Hypertension and diabetes were the most common comorbidities. The median duration of symptoms was 4 days. Difficult anatomy in the hepatocystic triangle (66%) and dense adhesions (31%) were the most common reasons for bailout. The mean duration of surgery was 145.76 (SD 102.94) minutes. There were 2 bile duct injuries, both in open total cholecystectomy subgroup. Bile leak occurred in 23.8% with majority in subtotal cholecystectomy group. There was no difference in hospital length of stay, surgical site infection, or mortality among different bailout procedures. CONCLUSIONS: Subtotal cholecystectomy represents a safe alternative to total cholecystectomy during challenging cases to avoid damaging surrounding structures. The choice of laparoscopic or open subtotal approach is dependent on the surgeons' expertise.

Correlation between changes in intraocular pressure and refractive error indices post Cataract Surgery.

OBJECTIVE: To evaluate the correlation between refractive errors and change in intraocular pressure in patients undergoing cataract surgery. METHODS: This interventional retrospective case study was carried out from September 2018 to April 2019 at Bodla Eye Care and Multan Medical and Dental College, Multan. A total of 127 eyes were recruited in the study among which six were excluded. Out of remaining 121, 53 eyes were emmetropes, 41 were mild myopes and 27 were high myopes. Single surgeon performed the procedure. Pre-operative investigations of IOP and refractive error were done by goldmann tonometry and auto refractometry. IOP was reviewed at day 1, 7, 14 and 28 post cataract surgeries. RESULTS: Out of 121 eyes, 53 eyes were emmetropes, 41 were mild myopes and 27 were high myopes, who underwent phacoemulsification. There was an elevation of 2-3mm Hg at Day-1, in emmetropes and mild myopes, and further on, a constant drop was noticed on follow ups. In high myopes a significant fluctuation of IOP was noted in first fourteen days followed by an unremarkable gradual decline afterwards. CONCLUSION: Cataract surgery helps lowering the IOP in patients with refractive errors. Mild myopic and emmetropic patients showed a linear swift pattern while high myopes presented instable and gradual reduction in IOP. A total decrease of 1-2mm Hg was seen at the end of the study depicting that relation between IOP and cataract surgery is insignificant.

Amino-terminal Pro-B-Type Natriuretic Peptide Among Patients Living With Both Human Immunodeficiency Virus and Heart Failure.

BACKGROUND: Among persons living with human immunodeficiency virus (PHIV), incident heart failure (HF) rates are increased and outcomes are worse; however, the role of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations among PHIV with HF has not been characterized. METHODS: Patients were derived from a registry of those hospitalized with HF at an academic center in a calender year. We compared the NT-proBNP concentrations and the changes in NT-proBNP levels between PHIV with HF and uninfected controls with HF. RESULTS: Among 2578 patients with HF, there were 434 PHIV; 90% were prescribed antiretroviral therapy and 62% were virally suppressed. As compared to controls, PHIV had higher admission (3822 [IQR, 2413-7784] pg/ml vs 5546 [IQR, 3257-8792] pg/ml, respectively; P < .001), higher discharge (1922 [IQR, 1045-4652] pg/ml vs 3372 [IQR, 1553-5452] pg/ml, respectively; P < .001), and lower admission-to-discharge changes in NT-proBNP levels (32 vs 48%, respectively; P = .007). Similar findings were noted after stratifying based on left ventricular ejection fraction (LVEF). In a multivariate analysis, cocaine use, a lower LVEF, a higher NYHA class, a higher viral load (VL), and a lower CD4 count were associated with higher NT-proBNP concentrations. In follow-up, among PHIV, a higher admission NT-proBNP concentration was associated with increased cardiovascular mortality (first tertile, 11.5; second tertile, 20; third tertile, 44%; P < .001). Among PHIV, each doubling of NT-proBNP was associated with a 19% increased risk of death. However, among patients living without HIV, each doubling was associated with a 27% increased risk; this difference was attenuated among PHIV with lower VLs and higher CD4 counts. CONCLUSIONS: PHIV with HF had higher admission and discharge NT-proBNP levels, and less change in NT-proBNP concentrations. Among PHIV, VLs and CD4 counts were associated with NT-proBNP concentrations; in follow-up, higher NT-proBNP levels among PHIV were associated with cardiovascular mortality.

Carvedilol Among Patients With Heart Failure With a Cocaine-Use Disorder.

OBJECTIVES: This study sought to assess the safety of carvedilol therapy among heart failure (HF) patients with a cocaine-use disorder (CUD). BACKGROUND: Although carvedilol therapy is recommended among certain patients with HF, the safety and efficacy of carvedilol among HF patients with a CUD is unknown. METHODS: This was a single-center study of hospitalized patients with HF. Cocaine use was self-reported or defined as having a positive urine toxicology. Patients were divided by carvedilol prescription. Subgroup analyses were performed by strata of ejection fraction (EF) ≤40%, 41% to 49%, or ≥50%. Major adverse cardiovascular events (MACE) were defined as cardiovascular mortality and 30-day HF readmission. RESULTS: From a cohort of 2,578 patients hospitalized with HF in 2011, 503 patients with a CUD were identified, among whom 404 (80%) were prescribed carvedilol, and 99 (20%) were not. Both groups had similar characteristics; however, those prescribed carvedilol had a lower LVEF, heart rate, and N-terminal pro-B-type natriuretic peptide concentrations at admission and on discharge, and more coronary artery disease. Over a median follow-up of 19 months, there were 169 MACEs. The MACE rates were similar between the carvedilol and the non-carvedilol groups (32% vs. 38%, respectively; p = 0.16) and between those with a preserved EF (30% vs. 33%, respectively; p = 0.48) and were lower in patients with a reduced EF taking carvedilol (34% vs. 58%, respectively; p = 0.02). In a multivariate model, carvedilol therapy was associated with lower MACE among patients with HF with a CUD (hazard ratio: 0.67; 95% confidence interval; 0.481 to 0.863). CONCLUSIONS: Our findings suggest that carvedilol therapy is safe for patients with HF with a CUD and may be effective among those with a reduced EF.

The Risk for Sudden Cardiac Death Among Patients Living With Heart Failure and Human Immunodeficiency Virus.

OBJECTIVES: The aim of this study was to determine the incidence of sudden cardiac death (SCD) among persons living with human immunodeficiency virus infection (PHIV) with heart failure (HF), who were hospitalized for HF, and the risk factors associated with it. BACKGROUND: HF is associated with an increased risk for SCD. PHIV are at heightened risk for HF. METHODS: This was a retrospective study of 2,578 patients hospitalized with HF from a single academic center, of whom 344 were PHIV. The outcome of interest was SCD. Subgroup analyses were performed by strata of viral load (VL) and left ventricular ejection fraction (LVEF) <35%, 35% to 49%, and ≥50%. RESULTS: Of 2,578 patients with HF, 2,149 (86%) did not have implantable cardioverter-defibrillators; of these, there were 344 PHIV and 1,805 uninfected control subjects. Among PHIV with HF, 313 (91%) were prescribed antiretroviral therapy and 64% were virally suppressed. There were 191 SCDs over a median follow-up period of 19 months. Compared with control subjects, PHIV had a 3-fold increase in SCD (21.0% vs. 6.4%; adjusted odds ratio: 3.0; 95% confidence interval: 1.78 to 4.24). Among PHIV, cocaine use, lower LVEF, absence of beta-blocker prescription, and VL were predictors of SCD. The SCD rate among PHIV with undetectable VL was similar to the rate among uninfected subjects. Similar findings were observed by LVEF strata. Among PHIV with HF without conventional indications for an implantable cardioverter-defibrillator, the rate of SCD was 10% per year. CONCLUSIONS: PHIV hospitalized with HF are at a markedly increased risk for SCD. SCD risk was increased in patients with lower LVEFs, lower CD4 counts, and higher VL.

Biliary tract cancers: current knowledge, clinical candidates and future challenges.

Biliary tract cancers (BTCs) are rare with poor prognosis. Due to the advent of genomic sequencing, new data have emerged regarding the molecular makeup of this disease. To add to the complexity, various subtypes also harbor a varied genetic composition. The commonly mutated genes associated with this cancer are KRAS, EGFR, IDH, FGFR and BAP1. Various clinical studies are looking at targeting these genetic mutations. Another therapeutic area of note is the potential for the use of immunotherapy in patients with BTC. Although BTC may be a result of chronic inflammation, this does not necessarily translate into increased immunogenicity. This literature review discusses the diverse molecular and immune-related pathways in patients with BTC and their potential therapeutic implications.

Heart failure and adverse heart failure outcomes among persons living with HIV in a US tertiary medical center.

BACKGROUND: Persons living with HIV (PLHIV) have an increased risk of heart failure (HF). However, little is known about outcomes among PLHIV with HF. The study aim was to compare HF outcomes among PLHIV with HF versus individuals without HIV with HF. METHODS: Our cohort included 2,308 individuals admitted with decompensated HF. We compared baseline characteristics, 30-day HF readmission, and cardiovascular (CV) and all-cause mortality. Within PLHIV, we assessed outcomes stratified between CD4 count and viral load (VL), and tested the association between traditional and HIV-specific parameters with 30-day HF readmission. RESULTS: There were 374 (16%) PLHIV with HF. Among PLHIV, 92% were on antiretroviral therapy and 63% had a VL <200 copies/mL. Groups were similar with respect to age, sex, race/ethnicity, and CV risk factors. In follow-up, PLHIV had increased 30-day HF readmission (49% vs 32%) and CV (26% vs 13.5%) and all-cause mortality rates (38% vs 22%). Among PLHIV, cocaine use, HIV-specific parameters (CD4, VL), and coronary artery disease were predictors of 30-day HF readmission. Specifically, among PLHIV, those with detectable VL had higher 30-day HF readmission and CV mortality, whereas PLHIV with undetectable VL had a similar 30-day HF readmission rate and CV mortality to uninfected controls with HF. Similar outcomes were observed across strata of left ventricular ejection fraction and by CD4. CONCLUSIONS: PLHIV with a low CD4 count or detectable VL have an increased 30-day HF readmission rate as well as increased CV and all-cause mortality. In contrast, PLHIV with a higher CD4 count and undetectable VL have similar HF outcomes to uninfected controls.

Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis.

BACKGROUND: Sorafenib has demonstrated survival benefit in first-line treatment of advanced hepatocellular carcinoma (HCC); utility of sorafenib in patients with advanced HCC and Child-Pugh B (CP-B) liver function remains a subject of debate. METHODS: A systematic review identified studies using first-line sorafenib in patients with advanced HCC and CP-A/B liver function. Meta-regression analysis comprising linear regression was conducted to explore the association between the baseline factors and overall survival (OS). Differences between efficacy/safety and tolerability parameters were explored using meta-analysis. RESULTS: Thirty studies (12 Asian) comprising 8678 patients (August 2002 - September 2012) were included (four randomised controlled trials, 26 cohort studies). Median age was 61 years and 83% were men. Hepatitis B/C status was positive in 35%/22%, respectively. The CP status was available for 8577 patients (99%); CP-A, 79% and CP-B, 19%. Median OS on sorafenib for entire cohort was 7.2 months; 8.8 months in CP-A and 4.6 months in CP-B. Multivariable meta-regression analysis showed significant negative association between OS and proportion of patients with the Eastern Cooperative Oncology Group performance status 2 (P = 0.04) and CP-B liver function (P = 0.001). Among four studies reporting multivariable comparison of the CP status, CP-B was associated with significantly worse OS (P < 0.001). There were no differences in the response rate to sorafenib between patients with CP-A (4.6%) and CP-B (4.2%) liver function. Safety and tolerability were similar; 35% of patients with CP-A/B liver function developed grade III/IV adverse events (P = 0.7). Meta-regression analysis showed similar rates of treatment discontinuation without progression (P = 0.31) and treatment-related death (P = 0.94) in patients with CP-B liver function. CONCLUSION: CP-B liver function (versus CP-A) is associated with worse OS (but the similar response rate, safety and tolerability of first-line sorafenib, is unlikely to be clinically meaningful).

Incidence, Predictors, and Outcomes of Implantable Cardioverter-Defibrillator Discharge Among People Living With HIV.

Background People living with HIV ( PHIV ) are at an increased risk for sudden cardiac death, and implantable cardioverter-defibrillators ( ICDs ) prevent SCD . There are no data on the incidence, predictors, and effects of ICD therapies among PHIV . Methods and Results We compared ICD discharge rates between 59 PHIV and 267 uninfected controls. For PHIV , we tested the association of traditional cardiovascular risk factors and HIV -specific parameters with an ICD discharge and then tested whether an ICD discharge among PHIV was associated with cardiovascular mortality or an admission for heart failure. The indication for ICD insertion was similar among groups. Compared with controls, PHIV with an ICD were more likely to have coronary artery disease and to use cocaine. In follow-up, PHIV had a higher ICD discharge rate (39% versus 20%; P=0.001; median follow-up period, 19 months). Among PHIV , cocaine use, coronary artery disease, QRS duration, and higher New York Heart Association class were associated with an ICD discharge. An ICD discharge had a prognostic effect, with a subsequent 1.7-fold increase in heart failure admission and a 2-fold increase in cardiovascular mortality, an effect consistent across racial/ethnic and sex categories. Conclusions ICD discharge rates are higher among PHIV compared with uninfected controls. Among PHIV , cocaine use and New York Heart Association class are associated with increased ICD discharge, and an ICD discharge is associated with a subsequent increase in admission for heart failure and cardiovascular mortality.

Protease Inhibitors and Cardiovascular Outcomes in Patients With HIV and Heart Failure.

BACKGROUND: Incident heart failure (HF) is increased in persons with human immunodeficiency virus (PHIV). Protease inhibitors (PIs) are associated with adverse cardiac remodeling and vascular events; however, there are no data on the use of PIs in PHIV with HF. OBJECTIVES: This study sought to compare characteristics, cardiac structure, and outcomes in PHIV with HF who were receiving PI-based versus non-PI (NPI) therapy. METHODS: This was a retrospective single-center study of all 394 antiretroviral therapy-treated PHIV who were hospitalized with HF in 2011, stratified by PI and NPI. The primary outcome was cardiovascular (CV) mortality, and the secondary outcome was 30-day HF readmission rate. RESULTS: Of the 394 PHIV with HF (47% female, mean age 60 ± 9.5 years, CD4 count 292 ± 206 cells/mm3), 145 (37%) were prescribed a PI, whereas 249 (63%) were prescribed NPI regimens. All PI-based antiretroviral therapy contained boosted-dose ritonavir. PHIV who were receiving a PI had higher rates of hyperlipidemia, diabetes mellitus, and coronary artery disease (CAD); higher pulmonary artery systolic pressure (PASP); and lower left ventricular ejection fraction. In follow-up, PI use was associated with increased CV mortality (35% vs. 17%; p < 0.001) and 30-day HF readmission (68% vs. 34%; p < 0.001), effects seen in all HF types. Predictors of CV mortality included PI use, CAD, PASP, and immunosuppression. Overall, PIs were associated with a 2-fold increased risk of CV mortality. CONCLUSIONS: PI-based regimens in PHIV with HF are associated with dyslipidemia, diabetes, CAD, a lower left ventricular ejection fraction, and a higher PASP. In follow-up, PHIV with HF who are receiving a PI have increased CV mortality and 30-day HF readmission.

Biliary Tract Cancer: Implicated Immune-Mediated Pathways and Their Associated Potential Targets.

There is a well-established link between biliary tract cancers (BTC) and chronic inflammatory conditions such as primary sclerosing cholangitis, chronic cholecystitis, chronic cholelithiasis, liver fluke-associated infestations, and chronic viral hepatic infections. These associated risk factors highlight the potential for development of immune-modulatory agents in this poor-prognostic disease group with limited treatment options. Clinical trials have evaluated the role of immune cells, inflammatory biomarkers, vaccines, cytokines, adoptive cell therapy, and immune checkpoint inhibitors in patients with BTC. Although these have demonstrated the importance of the immune environment in BTC, currently none of the immune-based therapies have been approved for use in this disease group. The role of immunomodulatory agents is a developing field and has yet to find its way 'from bench to bedside' in BTC.

Sleep Apnea and Heart Failure With a Reduced Ejection Fraction Among Persons Living With Human Immunodeficiency Virus.

Background: Sleep apnea (SA) is common and has prognostic significance among broad groups of patients with heart failure (HF). There are no data characterizing the presence, associations, and prognostic significance of SA among persons living with human immunodeficiency virus (PLHIV) with HF. Methods: We conducted a single-center study of PLHIV with HF with reduced ejection fraction (HFrEF; left ventricular ejection fraction [LVEF] <50%) and analyzed the relationship of SA with 30-day HF hospital readmission rate. Results: Our cohort included 1124 individuals admitted with HFrEF; 15% were PLHIV, and 92% were on antiretroviral therapy. SA was noted in 28% of PLHIV and 26% of uninfected controls. Compared to uninfected controls with HFrEF and SA, PLHIV with HFrEF and SA had a lower body mass index, lower LVEF, a higher pulmonary artery systolic pressure (PASP), were more likely to have obstructive rather than central SA (P < .05 for all). In a multivariable model, PASP, low CD4 count, high viral load (VL), and SA parameters (apnea-hypopnea index, CPAP use and duration) were predictors of 30-day HF readmission rate. Each 1-hour increase in CPAP use was associated with a 14% decreased risk of 30-day HF readmission among PLHIV. Conclusions: Compared to uninfected controls, PLHIV were more likely to have obstructive SA than central SA. Apnea severity, low CD4 count, high VL, and cocaine use were positively associated with 30-day HF hospital readmission rate, whereas CPAP use and increased duration of CPAP use conferred protection.

Quantification and Determination of Normal 123I-Meta Iodobenzylguanidine Heart-to-Mediastinum Ratio (HMR) from Cardiac SPECT/CT and Correlation with Planar HMR.

Assessment of cardiac 123I-meta iodobenzylguanidine (123I-mIBG) uptake relies on the heart-to-mediastinum ratio (HMR) derived from planar images. We have developed novel semiautomated quantitative methodologies for assessing HMR from SPECT images using a dedicated cardiac multipinhole SPECT/CT system and determined the lower limit of normal (LLN) SPECT-derived HMR and the correlation to planar-derived HMR. Methods: Twenty-one healthy volunteers were injected with 123I-mIBG and imaged using 2 different cameras. Planar images were acquired using a conventional SPECT camera equipped with parallel hole collimators, and hybrid SPECT/CT images were acquired using a dedicated cardiac SPECT system with 19 pinhole collimators interfaced with 64-slice CT. Planar HMR was calculated as per standard guidelines (manual traditional method) and elliptic region-of-interest (Elip-ROI) and region-growing (RG-ROI) techniques. SPECT HMR was quantified using a new method that incorporates various cardiac and mediastinal segmentation schemes in which upper and lower limits of the heart were determined from CT and the left ventricular ROI, and mean counts were calculated using Elip-ROI and RG-ROI techniques. Mean counts in mediastinal ROI were computed from a fixed volume in 3 different regions: upper mediastinum (UM), lower mediastinum (LM), and contralateral lung (CL). HMRs were processed by 2 observers, and reproducibility was assessed by intraclass correlation coefficient and Bland-Altman analysis. Results: Planar HMR calculated using the RG-ROI method showed highest intra- and interobserver levels of agreement compared with Elip-ROI and manual traditional methods. SPECT HMR calculated on the basis of UM, LM, and CL background regions showed excellent intra- and interobserver agreement. SPECT HMR with UM resulted in highest correlation (R = 0.91) with planar HMR compared with that with LM (R = 0.74) and CL (R = 0.73). The LLN of SPECT HMR with UM and that of planar HMR was calculated as 5.5 and 1.6, respectively. The normal values of SPECT-derived HMR and planar-derived HMR were correlated linearly. Conclusion: We reconfirmed the previous planar HMR threshold and determined SPECT LLN HMR for SPECT. Planar HMR can be estimated from SPECT HMR via a simple linear regression equation, allowing use of the new cardiac-dedicated SPECT camera for 123I-mIBG imaging.

Targeting the Epidermal Growth Factor Receptor in Addition to Chemotherapy in Patients with Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Overexpression of epidermal growth factor receptors (EGFR) occurs in >90% of pancreatic ductal adenocarcinomas (PDACs) and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced (LA)/metastatic PDAC. Efficacy, safety and tolerability of EGFR-targeted therapy were explored using meta-analysis of randomised controlled trials (RCTs). Meta-regression was utilised to explore factors associated with improved prognosis (all studies) and benefit from EGFR-targeted therapy (RCTs). Twenty-eight studies (7 RCTs and 21 cohort studies) comprising 3718 patients were included. The addition of EGFR-targeted treatment to chemotherapy did not improve progression-free (pooled hazard ratio (HR): 0.90, p = 0.15) or overall survival (HR: 0.94, p = 0.18). EGFR-targeted therapy was associated with increased treatment-related deaths (pooled odds ratio (OR): 5.18, p = 0.007), and grade (G)3/4 rash (OR: 4.82, p = 0.03). There was a borderline significant increase in G3/4 diarrhoea (OR: 1.75, p = 0.06), but no effect on treatment discontinuation without progression (OR: 0.87, p = 0.25). Neither G3/4 rash nor diarrhoea were associated with increased survival benefit from EGFR-targeted therapy. The effect of EGFR-targeted therapy on overall survival (OS) appeared greater in studies with a greater proportion of LA rather than metastatic patients (R = -0.69, p < 0.001). Further studies in unselected patients with advanced PDAC are not warranted. The benefit from EGFR inhibitors may be limited to patient subgroups not yet clearly defined.

Beyond EGFR and ALK inhibition: unravelling and exploiting novel genetic alterations in advanced non small-cell lung cancer.

During the last decade, thoracic oncology has witnessed an unprecedented outburst of knowledge regarding molecular biology of non small-cell lung cancer (NSCLC). The implementation of high-throughput sequencing analysis and genomic technologies has led to the identification of novel molecular events that characterize NSCLC transformation and may represent critical oncogenic drivers amenable to targeted therapy. Among these, the presence of activating mutations of the epidermal growth factor receptor (EGFR) gene and of chromosomic rearrangements in the anaplastic-lymphoma kinase (ALK) proto-oncogene, have been the first well characterized genetic alterations with corresponding targeted agents to enter the clinical arena. Nevertheless, in the recent years a number of other oncogenic drivers beyond EGFR and ALK inhibition have emerged as novel molecular targets with potential therapeutic implications, including mutations in the genes KRAS, BRAF, HER2, PI3KCA and DDR2, as well as ROS1 and RET rearrangements and MET, HER2 and FGFR1 gene amplifications. The aim of this review is to provide comprehensive information on the novel therapeutic targets identified by recent preclinical evidence and to discuss developments in molecular treatments targeting these oncogenic drivers or actionable mutations beyond EGFR and ALK in advanced NSCLC.

The role of chemotherapy in the modern management of melanoma.

The last 4 years have seen dramatic changes in the treatment of advanced melanoma, largely based on advances in targeted therapy and immunotherapy. This article examines the role of chemotherapy in the modern management of melanoma. We examine the evidence for promising new agents and discuss their position in the sequencing of treatment options for patients with advanced disease. In addition, we discuss the combination of chemotherapy with targeted treatments and immune therapies. Finally, we discuss future areas of research for ensuring that we maximize the potential of all agents available to us and identify new, effective treatments.