Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased NF-κB-dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features.

The neoadjuvant rectal score and a novel magnetic resonance imaging based neoadjuvant rectal score are stage independent predictors of long-term outcome in locally advanced rectal cancer.

AIM: Neoadjuvant rectal (NAR) score is an early surrogate for longer-term outcomes in rectal cancer undergoing radiotherapy and resection. In an era of increasing organ preservation, resection specimens are not always available to calculate the NAR score. Post-treatment magnetic resonance imaging (MRI) re-staging of regression is subjective, limiting reproducibility. We explored the potential for a novel MRI-based NAR score (mrNAR) adapted from the NAR formula. METHODS: Locally advanced rectal cancer patients undergoing neoadjuvant therapy (nCRT) and surgery were retrospectively identified between 2008 and 2020 in a single cancer network. mrNAR was calculated by adapting the NAR formula, replacing pathological (p) stages with post-nCRT MR stages (ymr). Cox regression assessed relationships between clinicopathological characteristics, NAR and mrNAR with overall survival (OS) and recurrence-free survival (RFS). RESULTS: In total, 381 NAR and 177 mrNAR scores were calculated. On univariate analysis NAR related to OS (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.33-3.14, p = 0.001) and RFS (HR 2.52, 95% CI 1.77-3.59, p = 0.001). NAR 3-year OS <8 was 95.3%, 8-16 was 88.6% and >16 was 80%. mrNAR related to OS (HR 2.96, 95% CI 1.38-6.34, p = 0.005) and RFS (HR 2.99, 95% CI 1.49-6.00, p = 0.002). 3-year OS for mrNAR <8 was 96.2%, 8-16 was 92.4% and >16 was 78%. On multivariate analysis, mrNAR was a stage-independent predictor of OS and RFS. mrNAR corresponded to NAR score category in only 15% (positive predictive value 0.23) and 47.5% (positive predictive value 0.48) of cases for categories <8 and >16, respectively. CONCLUSIONS: Neoadjuvant rectal score is validated as a surrogate end-point for long-term outcomes. mrNAR categories do not correlate with NAR but have stage-independent prognostic value. mrNAR may represent a novel surrogate end-point for future neoadjuvant treatments that focus on organ preservation.

Hartmann's Pouch Stones and Laparoscopic Cholecystectomy: The Challenges and the Solutions.

BACKGROUND & OBJECTIVE: Hartmann's pouch stones (HPS) encountered during laparoscopic cholecystectomy (LC) may hinder safe dissection of the cystic pedicle or be complicated by mucocele, empyema, or Mirizzi syndrome; distorting the anatomy and increasing the risk of bile duct injury. We studied the incidence, presentations, operative challenges, and outcomes of HPS. METHODS: A cohort study of a prospectively maintained database of LCs and bile duct explorations performed by a single surgeon. Patients were divided into two groups: those with HPS and those without. Patients' demographics, clinical presentation, intra-operative findings, and postoperative outcomes were compared. RESULTS: Of the 5136 patients, 612 (11.9%) had HPS. The HPS group were more likely to present with acute cholecystitis (27.9% vs 5.9%, P = .000) and more patients underwent emergency LC (50.7% vs 41.5%, P = .000). The HPS group had more difficult cholecystectomies, with 46.1% vs 11.8% in the non-HPS group being operative difficulty grade 4 and 5. Mucocele, empyema, and Mirizzi syndrome were more common in the HPS group (24.0% vs 3.7% P = .000, 30.9% vs 3.7% P = .000, 1.8% vs 0.9% P = .000, respectively). There was no significant difference in the open conversion rate or complications. CONCLUSION: HPS increase the difficulty of LC. Surgeons should be aware of their presence and should employ appropriate dissection strategies. Sharp or diathermy dissection should be avoided. Dislodging the stone into the gall bladder, stone removal, swab dissection, and cholangiography are useful measures to avoid ductal injury and reduce the conversion rate.

The effect of concurrent esophageal pathology on bariatric surgical planning.

In the presence of esophageal pathology, there is risk of worse outcomes after laparoscopic adjustable gastric banding (LAGB) and sleeve gastrectomy (SG). This study reviewed how an esophageal workup affected a bariatric operative plan in patients with concurrent esophageal pathology. We retrospectively reviewed patients planning bariatric surgery referred with significant reflux, dysphagia, and hiatal hernia (>3 cm) to determine how and why a thorough esophageal workup changed a bariatric operative plan. We identified 79 patients for analysis from 2009 to 2013. In 10/41 patients (24.3%) planning LAGB and 5/9 patients planning SG (55.5%), a Roux was preferred because of severe symptoms of reflux and aspiration, dysphagia, manometric abnormalities (aperistaltic or hypoperistaltic esophagus with low mean wave amplitudes), large hiatal hernia (>5 cm), and/or presence of Barrett's esophagus. Patients without these characteristics had a decreased risk of foregut symptoms after surgery. We recommend a thorough esophageal workup in bariatric patients with known preoperative esophageal pathology. The operative plan might need to be changed to a Roux to prevent adverse outcomes including dysphagia, severe reflux, or suboptimal weight loss. An esophageal workup may improve surgical decision making and improve patient outcomes.

A systematic review on the quality of life benefits after percutaneous coronary intervention in the elderly.

AIMS: Percutaneous coronary intervention (PCI) is being increasingly performed on elderly patients with acceptable peri-procedural outcomes and long-term survival. We aim to systematically review the health-related quality of life (HRQOL) following PCI in the elderly which is an important measure of procedural success. METHODS: A systematic review of clinical studies before September 2012 was performed to identify HRQOL in the elderly after PCI. Strict inclusion and exclusion criteria were applied. Quality appraisal of each study was also performed using pre-defined criteria. HRQOL results were synthesised through a narrative review with full tabulation of results of all included studies. RESULTS: Elderly patients have significant improvements in cardiovascular well-being. Early HRQOL appears improved from baseline, but recovery in physical health may be slower than in younger patients. HRQOL is comparable to an age-matched general population and younger patients undergoing PCI. Conservative management is not able to offer the same HRQOL benefits. Coronary artery bypass graft surgery may be superior to PCI in the very elderly. Significant heterogeneity and bias exists. Lack of appropriate data precluded meta-analysis. CONCLUSION: HRQOL after PCI in the elderly can improve for at least 1 year across a broad range of health domains, and is comparable to an age-matched general population and younger patients undergoing PCI. Given a limited number of articles and patients included, more prospective studies are needed to better identify the benefits for elderly patients.

A systematic review on the quality of life benefits after aortic valve replacement in the elderly.

BACKGROUND: Surgical aortic valve replacement is being increasingly performed in elderly patients with good perioperative outcomes and long-term survival. Evidence is limited on health-related quality of life after aortic valve replacement, which is an important measure of operative success in the elderly. METHODS: A systematic review of clinical studies after January 2000 was performed to identify health-related quality of life in the elderly after aortic valve replacement. Strict inclusion and exclusion criteria were applied. Quality appraisal of each study also was performed using predefined criteria. Health-related quality of life results were synthesized through a narrative review with full tabulation of the results of all included studies. RESULTS: Health-related quality of life improvements were shown across most or all domains in different health-related quality of life instruments. Elderly patients experienced marked symptomatic improvement. Health-related quality of life was equivalent or superior to both an age-matched population and younger patients undergoing identical procedures. There were excellent functional gains after surgery, but elderly patients remain susceptible to geriatric issues and mood problems. Concomitant coronary artery bypass did not affect health-related quality of life. There was a diverse range of study designs, methods, and follow-up times that limited direct comparison between studies. CONCLUSIONS: Aortic valve replacement results in significant health-related quality of life benefits across a broad range of health domains in elderly patients. Age alone should not be a precluding factor for surgery. Data are heterogeneous and mostly retrospective. We recommend future studies based on consistent guidelines provided in this systematic review.

Left bundle branch block without concordant ST changes is rarely associated with acute coronary occlusion.

BACKGROUND: The Sgarbossa score has been used to identify acute myocardial infarction on ECG in the presence of LBBB but has relied on elevated CK-MB for validation rather than angiographic evidence of vessel occlusion. METHODS: We determined (a) the presence or absence of Sgarbossa criteria with concordant (S-con) or discordant (S-dis) ST changes, (b) the presence of acute coronary occlusion or likely recent occlusion on angiography and (c) the biochemical evidence of myocardial infarction (Troponin T >0.10 µg/L, Troponin I >1.0 µg/L) in patients field-triaged with suspected AMI and LBBB. RESULTS: Between April 2004 and March 2009, 102 patients had field ECGs transmitted by paramedics for triage--8 with S-con, 26 with S-dis and 68 with LBBB alone. Acute coronary occlusion was present in 8/8 with S-con but none of the S-dis or LBBB alone patients, and in all 8 S-con patients reperfusion resulted in resolution of S-con changes. Likely culprit lesions with TIMI 3 flow were found in 3 S-dis patients but stenting did not result in resolution of S-dis. LBBB did not resolve in any patient. Troponin was elevated in 26 patients--11 with occlusion or likely culprit lesions, 15 with non-ischaemic causes. CONCLUSIONS: In the absence of S-con, LBBB is not associated with acute coronary occlusion and should not be used as criteria for reperfusion therapy in myocardial infarction.

The STEDMAN project: biophysical, biochemical and metabolic effects of a behavioral weight loss intervention during weight loss, maintenance, and regain.

The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body composition, metabolic rate, hormones, and 80 intermediary metabolites measured by mass spectrometry. In 27 obese adults in a behavioral weight loss intervention, median weight decreased 13.9 lb over the first 6 months, then reverted towards baseline by 12 months. Insulin resistance (HOMA) was partially ameliorated in the first 6 months and showed sustained improvement at 12 months despite weight regain. Ghrelin increased with weight loss and reverted to baseline, whereas leptin and PYY fell at 6 months and remained persistently low. NPY levels did not change. Factors possibly contributing to sustained improvement in insulin sensitivity despite weight regain include adiponectin (increased by 12 months), IGF-1 (increased during weight loss and continued to increase during weight regain), and visceral fat (fell at 6 months but did not change thereafter). We observed a persistent reduction in free fatty acids, branched chain amino acids, and related metabolites that may contribute to improved insulin action. These findings provide evidence for sustained benefits of weight loss in obese humans and insights into mechanisms.

Expectant management of the asymptomatic gallbladder at Roux-en-Y gastric bypass.

BACKGROUND: Because of the claim that about one third of patients develop gallstones within 6 months of Roux-en-Y gastric bypass (RYGB), many have recommended preoperative ultrasonography for all patients and/or prophylactic cholecystectomy (CCY), or ursodiol to prevent stone formation. METHODS: Prospective data were collected from 1391 consecutive patients followed up for > or = 6 months after RYGB (2000-2005) to assess our practice of not routinely removing the gallbladder and not administering ursodiol. RESULTS: Of the 1391 patients, 334 (24%) had undergone CCY before RYGB. Of the remaining 1057 asymptomatic patients, 516 had undergone preoperative ultrasonography. Stones were identified in 99 (19%), sludge in 5 (0.97%), and polyps in 6 (1.1%). Of the 984 patients with gallbladders left in situ after RYGB, only 80 (8.1%) became symptomatic and required delayed CCY. The average excess weight loss at the delayed CCY was 65%. The risk of undergoing delayed CCY seemed to be restricted to the first 29 months after RYGB, because none of 165 patients followed up for 30-144 months required CCY. CONCLUSION: Although CCY should be performed whenever symptoms mandate, the value of routine preoperative ultrasonography and CCY was not apparent from the results of our study. Waiting until symptoms develop might simplify the operative procedure because of the significant weight loss that should have occurred after RYGB. Using an expectant approach, most patients undergoing RYGB will not require CCY.

Surgical revision of loop ("mini") gastric bypass procedure: multicenter review of complications and conversions to Roux-en-Y gastric bypass.

BACKGROUND: The claim that the "mini"-gastric bypass (MGB) procedure with its loop gastrojejunostomy is safer and equally effective to the Roux-en-Y gastric bypass (RYGB) procedure has been promoted before validation. Rumors of unreported complications and the accuracy of follow-up are additional concerns. This study was undertaken to identify MGB patients who require or required revisional surgery at 5 hospitals within the region of the United States where the MGB procedure originated to assess the claim that revision to RYGB is rarely needed. METHODS: The databases of 5 medical centers were retrospectively searched to identify patients undergoing surgical revision after a MGB procedure, all of which had been done elsewhere. RESULTS: A total of 32 patients were identified who presented with complications after undergoing an MGB procedure and required or require revisional surgery. The complications included gastrojejunostomy leak in 3, bile reflux in 20, intractable marginal ulcer in 5, malabsorption/malnutrition in 8, and weight gain in 2. Of the 32 patients, 21 required conversion to RYGB and an additional 5 have planned revisions in the future. Also, 2 patients were treated with Braun enteroenterostomies and 4 required 1 or more abdominal explorations. CONCLUSIONS: The results of this preliminary review have confirmed that MGB does require revision in some patients and that conversion to RYGB is a common form of revision. A national registry to record the complications and number of revisions is proposed to gain insight into the need for revision after MGB and other nontraditional bariatric procedures.

Effect of eucaloric high- and low-sucrose diets with identical macronutrient profile on insulin resistance and vascular risk: a randomized controlled trial.

The long-term impact of dietary carbohydrate type, in particular sucrose, on insulin resistance and the development of diabetes and atherosclerosis is not established. Current guidelines for the healthy population advise restriction of sucrose intake. We investigated the effect of high- versus low-sucrose diet (25 vs. 10%, respectively, of total energy intake) in 13 healthy subjects aged 33 +/- 3 years (mean +/- SE), BMI 26.6 +/- 0.9 kg/m(2), in a randomized crossover design with sequential 6-week dietary interventions separated by a 4-week washout. Weight maintenance, eucaloric diets with identical macronutrient profiles and fiber content were designed. All food was weighed and distributed. Insulin action was assessed using a two-step euglycemic clamp; glycemic profiles were assessed by the continuous glucose monitoring system and vascular compliance by pulse-wave analysis. There was no change in weight across the study. Peripheral glucose uptake and suppression of endogenous glucose production were similar after each diet. Glycemic profiles and measures of vascular compliance did not change. A rise in total and LDL cholesterol was observed. In this study, a high-sucrose intake as part of an eucaloric, weight-maintaining diet had no detrimental effect on insulin sensitivity, glycemic profiles, or measures of vascular compliance in healthy nondiabetic subjects.

The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) weight loss project: Rationale and design.

This paper outlines the rationale and design of the Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) weight loss project, in which detailed biologic profiling of three hundred and fifty obese individuals (body mass index (BMI): 30-50 kg/m(2)) will be conducted as they lose weight via seven distinct interventions. These profiles will be compared to those of fifty normal, healthy, control participants (BMI: 18.5-24.9 kg/m(2)). The interventions include the following: Roux-en-Y gastric bypass surgery, dietary interventions of differing macronutrient composition and diverse pharmacologic interventions. Outcome variables include eight conventional metabolites and CRP measured by standard clinical chemistry techniques, twenty hormones of energy balance and fuel homeostasis measured by radioimmunoassay (RIA) or by enzyme-linked Immunosorbent assay (ELISA), ten pro- and anti-inflammatory cytokines measured using Luminex xMAP technology, one hundred and one intermediary metabolites measured by targeted mass-spectrometry-based methods, and physiologic variables such as body composition measured by dual energy X-ray absorptiometry (DEXA), air displacement plethysmography, and abdominal computerized tomography (CT), insulin sensitivity measured by intravenous glucose tolerance test (IV-GTT) and metabolic rate measured by indirect calorimetry. Results from this study will expand our knowledge of the biology of obesity and weight regulation and may lead to targeted strategies for its treatment and control.

Binge eating, quality of life and physical activity improve after Roux-en-Y gastric bypass for morbid obesity.

BACKGROUND: Severe obesity has been associated with disordered eating, impaired quality of life (QoL), and decreased physical activity. This study examines changes in these variables 6 months after Roux-en-Y gastric bypass (RYGBP). METHODS: 40 morbidly obese patients were evaluated at baseline and at 6 months after RYGBP on the following measures: Binge Eating Scale, Three Factor Eating Questionnaire, Impact of Weight on Quality of Life-Lite (IWQoL-Lite), and the Baseline Questionnaire of Activity. RESULTS: 6 months after RYGBP, weight loss averaged 26.7%, and scores on measures of disordered eating, weight-related QoL, and physical activity showed statistically significant improvement from baseline. At the time of follow-up, 100% of participants achieved a score on the Binge Eating Scale that indicated no binge eating problems, and weight-related QoL scores approached those obtained by a reference sample of community volunteers. There were also improvements in the level of self-reported physical activity and television watching behavior. CONCLUSIONS: RYGBP resulted in significant improvements in disordered eating, weight-related QoL, and physical activity in addition to weight loss.

Sporadic gastric carcinoid tumor laparoscopically resected: a case report.

Sporadic gastric carcinoid tumors are relatively infrequent malignancies of the stomach. Tumors measuring less than 1 cm can sometimes be safely removed endoscopically; however, larger neoplasias require surgical ablation. The present case report represents a gastric carcinoid tumor laparoscopically resected in a patient with a history of hematemesis. The tumor was first marked endoscopically with India ink, which facilitated subsequent localization of the area to be resected. Laparoscopic resection of the mass was without complication, and the pathology study confirmed the preoperative diagnosis and negativity of the margins. In patients who present with masses that are not amended for endoscopic resection, sporadic gastric carcinoid tumors can be resected laparoscopically.

Chronic myeloid leukemia with an e13a3 BCR-ABL fusion: benign course responsive to imatinib with an RT-PCR advisory.

A case of a patient with chronic myeloid leukemia whose cells expressed an e13a3 (b2a3) variant BCR-ABL p210 mRNA is presented. The variant splice was detected by a qualitative reverse transcriptase polymerase chain reaction using primers complementary to BCR exon 13 (b2) and ABL exon 3 (a3). The patient responded well to imatinib and achieved a complete cytogenetic response.

A review of laparoscopy for non-obstetric-related surgery during pregnancy.

PURPOSE: Similar to the general population, parturients (and their fetuses) could benefit from the reduced manipulation associated with laparoscopy. The purpose of this article is to review the current state of knowledge (both clinical and experimental) with respect to the fetal effects of maternal laparoscopy for non-obstetric-related surgery during pregnancy. METHODS: Human and experimental animal results are examined, and we present preliminary data from our own laboratory. CONCLUSIONS: Future experiments are proposed to further develop and refine standards of care for general surgeons and obstetricians who are presented with gravid females in abdominal distress.

Specific killing of Ph+ chronic myeloid leukemia cells by a lentiviral vector-delivered anti-bcr/abl small hairpin RNA.

Chronic myeloid leukemia (CML) is characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 t(9;22)(q34;q11) that causes fusion of the bcr and abl genes. Transcription and splicing of the fusion gene generate two major splice variants of the bcr/abl transcript that encode an oncoprotein with tyrosine kinase activity. We have taken advantage of lentiviral vectormediated delivery of anti-bcr/abl short hairpin RNAs (shRNA) to downregulate the bcr/abl transcript in Philadelphia chromosome-positive (Ph+) K562 leukemia cells. This downregulation caused complete inhibition of proliferation of these cells and was accompanied by >90% inhibition of the bcr/abl transcript and p210 protein. These results demonstrate the feasibility of using a lentiviral vector to stably transduce therapeutic shRNAs into leukemia cells for the potential ex vivo purging of Ph+ cells in an autologous hematopoietic cell transplant setting. Furthermore, the robust expression of the shRNAs from our lentiviral vector suggests that this system could be generally useful for the expression of other shRNAs.