Clinical Impact of an Enhanced Recovery Program for Lower-extremity Bypass.

OBJECTIVE: To determine the association of Enhanced Recovery Program (ERP) implementation with length of stay (LOS) and perioperative outcomes after lower-extremity bypass (LEB). BACKGROUND: ERPs have been shown to decrease hospital LOS and improve perioperative outcomes, but their impact on patients undergoing vascular surgery remains unknown. METHODS: Patients undergoing LEB who received or did not receive care under the ERP were included; pre-ERP (January 1, 2016-May 13, 2018) and ERP (May 14, 2018-July 31, 2022). Clinicopathologic characteristics and perioperative outcomes were analyzed. RESULTS: Of 393 patients who underwent LEB [pre-ERP: n = 161 (41%); ERP: n = 232 (59%)], most were males (n = 254, 64.6%), White (n = 236, 60%), and government-insured (n = 265, 67.4%). Pre-ERP patients had higher Body Mass Index (28.8 ± 6.0 vs 27.4 ± 5.7, P = 0.03) and rates of diabetes (52% vs 36%, P = 0.002). ERP patients had a shorter total [6 (3-13) vs 7 (5-14) days, P = 0.01) and postoperative LOS [5 (3-8) vs 6 (4-8) days, P < 0.001]. Stratified by indication, postoperative LOS was shorter in ERP patients with claudication (3 vs 5 days, P = 0.01), rest pain (5 vs 6 days, P = 0.02), and tissue loss (6 vs 7 days, P = 0.03). ERP patients with rest pain also had a shorter total LOS (6 vs 7 days, P = 0.04) and lower 30-day readmission rates (32%-17%, P = 0.02). After ERP implementation, the average daily oral morphine equivalents decreased [median (interquartile range): 52.5 (26.6-105.0) vs 44.12 (22.2-74.4), P = 0.019], while the rates of direct discharge to home increased (83% vs 69%, P = 0.002). CONCLUSIONS: This is the largest single-center cohort study evaluating ERP in LEB, showing that ERP implementation is associated with shorter LOS and improved perioperative outcomes.

FcγRIIB expressed on CD8+ T cells limits responsiveness to PD-1 checkpoint inhibition in cancer.

Checkpoint inhibition using Fc-containing monoclonal antibodies has emerged as a powerful therapeutic approach to augment antitumor immunity. We recently showed that FcγRIIB, the only inhibitory IgG-Fc receptor, is expressed on a population of highly differentiated effector CD8+ T cells in the tumors of mice and humans, raising the possibility that CD8+ T cell responses may be directly modulated by checkpoint inhibitor binding to T cell-expressed FcγRIIB. Here, we show that despite exhibiting strong proliferative and cytokine responses at baseline, human FcγRIIBpos CD8+ T cells exhibited reduced responsiveness to both PD-1 and CTLA-4 checkpoint inhibition as compared with FcγRIIBneg CD8+ T cells in vitro. Moreover, frequencies of FcγRIIBpos CD8+ T cells were reduced after treatment of patients with melanoma with nivolumab in vivo. This reduced responsiveness was FcγRIIB dependent, because conditional genetic deletion of FcγRIIB on tumor-specific CD8+ T cells improved response to checkpoint blockade in B16 and LLC mouse models of cancer. The limited responsiveness of FcγRIIBpos CD8+ T cells was also dependent on an intact Fc region of the checkpoint inhibitor, in that treatment with Fc-devoid anti-PD-1 F(ab) fragments resulted in increased proliferation of FcγRIIBpos CD8+ T cells, without altering the response of FcγRIIBneg CD8+ T cells. Last, the addition of FcγRIIB blockade improved efficacy of PD-1 checkpoint inhibition in mouse models of melanoma, lung, and colon cancer. These results illuminate an FcγRIIB-mediated, cell-autonomous mechanism of CD8+ T cell suppression, which limits the efficacy of checkpoint inhibitors during antitumor immune responses in vivo.

Investigating glycemic control in patients undergoing lower extremity bypass within an enhanced recovery pathway at a single institution.

BACKGROUND: Enhanced recovery pathways (ERPs) aim to lower perioperative stress to facilitate recovery. Limited fasting combined with carbohydrate loading is a common ERP element. The effect of limited fasting has not been elucidated in patients with diabetes. Given the known deleterious effects of poor glycemic control in the perioperative period, such as increased rates of surgical site infection, the associations of preoperative limited fasting with perioperative glycemic control and early outcomes after lower extremity bypass (LEB) were investigated. METHODS: A single institutional retrospective review of patients who underwent infrainguinal LEB from 2016 to 2022 was performed. The ERP was initiated in May 2018. Patients were stratified by diabetes diagnosis and preoperative hemoglobin A1C (HbA1C) levels. Perioperative glycemic control was compared between the limited fasting and traditional fasting patients (nil per os at midnight). Limited fasting was defined as a clear liquid diet until 2 hours before surgery with recommended carbohydrate loading consisting of 400 cc of a clear sports drink (approximately 30 g of carbohydrates). All limited fasting patients were within the ERP. Early perioperative hyperglycemia (EPH) was defined as blood glucose of >180 mg/dL within the first 24 hours of surgery. Perioperative outcomes such as surgical site infection, readmission, reinterventions, and complications were also compared. RESULTS: A total of 393 patients were included (limited fasting patients N = 135; traditional fasting patients N = 258). A trend toward EPH was seen in all limited fasting groups. Evaluating limited fasting within diabetic patients revealed that 74.5% of limited fasting-diabetic patients had EPH compared with 49.6% of traditional fasting-diabetic patients (P = .001). When stratified by the HbA1C level, a significantly higher rate of EPH was seen in the HbA1c >8.0% groups, with 90.5% in the limited fasting patients compared with 67.9% in traditional fasting patients (P = .05). Limited fasting-diabetic patients experience a longer postoperative length of stay at 5.0 days (interquartile range: 3, 9) vs 4.0 days (2, 6) in nondiabetic patients (P = .016). CONCLUSIONS: ERP limited fasting was associated with early perioperative hyperglycemia after LEB, particularly in patients with HbA1C >8.0%. Due to the high prevalence of diabetic patients undergoing LEB under ERP, the role of limited fasting and common glycemic elements of ERP may need to be re-evaluated in this subpopulation.

Acral Lentiginous Melanoma: A United States Multi-Center Substage Survival Analysis.

BACKGROUND: Acral lentiginous melanoma is associated with worse survival than other subtypes of melanoma. Understanding prognostic factors for survival and recurrence can help better inform follow-up care. OBJECTIVES: To analyze the clinicopathologic features, melanoma-specific survival, and recurrence-free survival by substage in a large, multi-institutional cohort of primary acral lentiginous melanoma patients. METHODS: Retrospective review of the United States Melanoma Consortium database, a multi-center prospectively collected database of acral lentiginous melanoma patients treated between January 2000 and December 2017. RESULTS: Of the 433 primary acral lentiginous melanoma patients identified (median [range] age: 66 [8-97] years; 53% female, 83% white), 66% presented with stage 0-2 disease and the median time of follow-up for the 392 patients included in the survival analysis was 32.5 months (range: 0-259). The 5-year melanoma-specific survivals by stage were 0 = 100%, I = 93.8%, II = 76.2%, III = 63.4%, IIIA = 80.8%, and IV = 0%. Thicker Breslow depth ((HR) = 1.13; 95% CI = 1.05-1.21; P < .001)) and positive nodal status ((HR) = 1.79; 95% CI = 1.00-3.22; P = .050)) were independent prognostic factors for melanoma-specific survival. Breslow depth ((HR = 1.13; 95% CI = 1.07-1.20; P < .001), and positive nodal status (HR = 2.12; 95% CI = 1.38-3.80; P = .001) were also prognostic factors for recurrence-free survival. CONCLUSION: In this cohort of patients, acral lentiginous melanoma was associated with poor outcomes even in early stage disease, consistent with prior reports. Stage IIB and IIC disease were associated with particularly low melanoma-specific and recurrence-free survival. This suggests that studies investigating adjuvant therapies in stage II patients may be especially valuable in acral lentiginous melanoma patients.

TIGIT regulates apoptosis of risky memory T cell subsets implicated in belatacept-resistant rejection.

Belatacept confers increased patient and graft survival in renal transplant recipients relative to calcineurin inhibitors, but is associated with an increased rate of acute rejection. Recent immunophenotypic studies comparing pretransplant T cell phenotypes of patients who reject versus those who remain stable on belatacept identified three potential "risky" memory T cell subsets that potentially underlie belatacept-resistant rejection: CD4+ CD28+ TEM , CD8+ CD28null , and CD4+ CD57+ PD1- subsets. Here, we compared key phenotypic and functional aspects of these human memory T cell subsets, with the goal of identifying additional potential targets to modulate them. Results demonstrate that TIGIT, an increasingly well-appreciated immune checkpoint receptor, was expressed on all three risky memory T cell subsets in vitro and in vivo in the presence of belatacept. Coculture of human memory CD4+ and CD8+ T cells with an agonistic anti-TIGIT mAb significantly increased apoptotic cell death of all three risky memory T cell subsets. Mechanistically, TIGIT-mediated apoptosis of risky memory T cells was dependent on FOXP3+ Treg, suggesting that agonism of the TIGIT pathway increases FOXP3+ Treg suppression of human memory T cell populations. Overall, these data suggest that TIGIT agonism could represent a new therapeutic target to inhibit belatacept-resistant rejection during transplantation.

The Impact of Obesity on Surgically Treated Locoregional Melanoma.

BACKGROUND: The impact of obesity on early-stage melanoma is poorly understood. We examined the impact of overweight and obesity on clinical outcomes in locoregional melanoma. METHODS: Adults who underwent surgery at Emory University Healthcare between 2010 and 2017 for clinically stage I-II cutaneous melanoma, with known stage, height, and weight at the time of presentation, were identified. The relationship between body mass index (BMI) and clinicopathologic characteristics was assessed. RESULTS: Of 1756 patients, 584 were obese (33.2%; BMI ≥ 30), 658 were overweight (37.5%; BMI ≥ 25 and < 30), and 514 were normal weight (29.3%; BMI < 25). Demographics associated with obesity included male sex (odds ratio [OR] 2.6, 95% confidence interval [CI] 2.1-3.3; p < 0.001) and lower income (OR 1.5, 95% CI 1.2-1.9; p = 0.003). Melanomas in obese patients were thicker (2.0 ± 0.2 mm) than in overweight (1.7 ± 0.1 mm) or normal-weight patients (1.4 ± 0.1 mm; p = 0.002). Ulceration, mitoses, BRAF status, and sentinel lymph node (SLN) status were not affected by obesity. In multivariable analysis, obesity independently predicted increased odds of pathologic stage II melanoma (vs. stage 0 or I; OR 1.9, 95% CI 1.4-2.7, p = 0.001), but not pathologic stage III melanoma (p > 0.05). At 33 months' median follow-up, obesity was not an independent predictor of stage-specific overall survival (p > 0.05). CONCLUSION: Obese patients are nearly twice as likely as their normal-weight peers to present with thicker melanomas, but they have similar stage-specific overall survival and SLN positivity. Obesity may promote more aggressive growth of the primary tumor, and barriers to preventive care in obese patients may exacerbate later-stage presentation.

FcγRIIB is a T cell checkpoint in antitumor immunity.

In the setting of cancer, T cells upregulate coinhibitory molecules that attenuate TCR signaling and lead to the loss of proliferative capacity and effector function. Checkpoint inhibitors currently in clinical use have dramatically improved mortality from melanoma yet are not effective in all patients, suggesting that additional pathways may contribute to suppression of tumor-specific CD8+ T cell responses in melanoma. Here, we show that FcγRIIB, an inhibitory Fc receptor previously thought to be exclusively expressed on B cells and innate immune cells, is upregulated on tumor-infiltrating effector CD8+ T cells in an experimental melanoma model and expressed on CD8+ T cells in patients with melanoma. Genetic deficiency of Fcgr2b resulted in enhanced tumor-infiltrating CD8+ T cell responses and significantly reduced tumor burden. Adoptive transfer experiments of Fcgr2b-/- tumor antigen-specific T cells into FcγRIIB-sufficient hosts resulted in an increased frequency of tumor-infiltrating CD8+ T cells with greater effector function. Finally, FcγRIIB was expressed on CD8+ memory T cells isolated from patients with melanoma. These data illuminate a cell-intrinsic role for the FcγRIIB checkpoint in suppressing tumor-infiltrating CD8+ T cells.

The Devil's in the Details: Discrepancy Between Biopsy Thickness and Final Pathology in Acral Melanoma.

PURPOSE: We hypothesized that initial biopsy may understage acral lentiginous melanoma (ALM) and lead to undertreatment or incomplete staging. Understanding this possibility can potentially aid surgical planning and improve primary tumor staging. METHODS: A retrospective review of primary ALMs treated from 2000 to 2017 in the US Melanoma Consortium database was performed. We reviewed pathology characteristics of initial biopsy, final excision specimens, surgical margins, and sentinel lymph node biopsy (SLNB). RESULTS: We identified 418 primary ALMs (321 plantar, 34 palmar, 63 subungual) with initial biopsy and final pathology results. Median final thickness was 1.8 mm (range 0.0-19.0). There was a discrepancy between initial biopsy and final pathology thickness in 180 (43%) patients with a median difference of 1.6 mm (range 0.1-16.4). Final T category was increased in 132 patients (32%), including 47% of initially in situ, 32% of T1, 39% of T2, and 28% of T3 lesions. T category was more likely to be increased in subungual (46%) and palmar (38%) melanomas than plantar (28%, p = 0.01). Among patients upstaged to T2 or higher, 71% had ≤ 1-cm margins taken. Among the 27 patients upstaged to T1b or higher, 8 (30%) did not have a SLNB performed, resulting in incomplete initial staging. CONCLUSIONS: In this large series of ALMs, final T category was frequently increased on final pathology. A high index of suspicion is necessary for lesions initially in situ or T1 and consideration should be given to performing additional punch biopsies, wider margin excisions, and/or SLNB.

Diabetes development after distal pancreatectomy: results of a 10 year series.

BACKGROUND: Limited literature is available on the postoperative development of impaired glucose tolerance (IGT) and new-onset diabetes mellitus (NODM) following Distal Pancreatectomy (DP). We aimed to study the post-surgical clinical evolution of IGT/DM and its association with preoperative glycemic profiles of patients undergoing DP. METHODS: Pre- and postoperative glycemic laboratories were measured in patients undergoing DP by the senior author from 2007-2017. Multivariate risk factor analysis was performed to determine risk factors for new-onset IGT/DM after DP. Kaplan-Meier curves were constructed for development of NODM postoperatively. RESULTS: Of 216 included patients, n = 63, n = 68 and n = 85 were preoperatively diagnosed with no-diabetes (No-DM), pre-diabetes (Pre-DM), and diabetes (DM), respectively. At 2-year follow-up, n = 37, n = 80 and n = 99 were classified as No-DM, Pre-DM or DM, respectively. Pre-diabetics had a higher risk of developing postoperative dysglycemia (RR 2.230, 95% CI 1.732-2.870, p = 0.001). Preoperative OGTT>130, HbA1c >6.0, and chronic pancreatitis were risk factors for postoperative DM. CONCLUSION: 40% of patients undergoing DP were unaware of their dysglycemic status (pre-DM or DM) pre-operatively. At 2-year follow-up, 36% non-diabetic and 57% pre-diabetic patients had developed NODM. Appropriate pre-operative diabetic assessment is warranted for all patients undergoing pancreatic resections.

Development of Diabetes after Pancreaticoduodenectomy: Results of a 10-Year Series Using Prospective Endocrine Evaluation.

BACKGROUND: Limited literature is available on the development of impaired glucose tolerance and diabetes mellitus after pancreaticoduodenectomy. The primary aim was to define the diabetic phenotype and correlate preoperative glycemic laboratory results to new-onset diabetes after pancreaticoduodenectomy. STUDY DESIGN: In this prospective study, perioperative fasting and postprandial (oral glucose tolerance test) plasma glucose, glycated hemoglobin, insulin, and c-peptide were measured in consecutive patients undergoing pancreaticoduodenectomy by the senior author from 2006 to 2017. American Diabetes Association definitions were used for glycemic classifications. Multivariate risk factor analysis was performed. RESULTS: Of 774 identified patients, 371 diabetics were excluded and 403 patients were included: 167 and 236 were preoperatively classified as nondiabetic and prediabetic, respectively. The incidence rates of diabetes at 120 months post pancreaticoduodenectomy were 9.0% (nondiabetics), 22.0% (prediabetics), and 16.6% (overall). Patients in whom diabetes developed demonstrated a 3-fold larger difference between oral glucose tolerance test and fasting glucose (Δ), and 2-fold larger Δinsulin and Δc-peptide values. Tiered multivariate analysis identified glycated hemoglobin >5.4% with a relative risk (RR) of 2.944 (p = 0.047) as an independent predictor of impaired glucose tolerance and diabetes mellitus. Analysis of patients stratified by preoperative classification identified fasting glucose >95 mg/dL (nondiabetics, RR 1.925; p = 0.002), and glycated hemoglobin ≥5.4% (prediabetics, RR 3.125; p = 0.040) as independent risk factors for diabetes. Compared with nondiabetics, prediabetics classified by any laboratory results demonstrated an RR of 2.471 (p = 0.001) for diabetes developing postoperatively. There was no association between primary pathology, advancing age, or BMI and increased risk of diabetes development. CONCLUSIONS: Diabetes will develop after pancreaticoduodenectomy in approximately 16.6% of patients. A preoperative glycated hemoglobin >5.4% independently predicts new-onset diabetes. Pre- and postoperative endocrine analysis remains paramount for proper patient risk stratification.

Value of Dedicated Research Time for IMGs in Obtaining Surgical Residency Training Positions: A 10-Year Review of Applicants from a Medical College in Pakistan.

OBJECTIVE: International Medical Graduates (IMGs) secured greater than 10% of all general surgery (GS) residency positions in the US during the past decade. The Match process remains competitive, with a significant number of IMGs performing dedicated research before residency application. The impact of such research remains largely unknown. We aimed to provide an objective analysis of the impact of dedicated research time on obtaining a categorical GS residency position. DESIGN: Data for National Resident Matching Program Match results from 2008-2017 was compiled from annual Match lists of the Aga Khan University, Medical College (Karachi, Pakistan). Medical graduates provided this information voluntarily each year. Data was exported to Microsoft Excel and used for descriptive and statistical analysis using SPSS. Candidates were divided into quasi-experimental groups based on their preference for direct application (no-research group, n = 64) or research prior to Match (research group, n = 20). RESULTS: A total of 84 IMG applicants matched into GS residency positions in the US within the past decade. Amongst these, 18 matched directly into categorical positions while 66 applicants secured preliminary spots. A total of 37 (56%) preliminary candidates eventually secured categorical GS residency positions. Research group applicants had an overall 85% (n = 17) success rate of obtaining a categorical position, while no-research group had a 59% (n = 39) success rate (chi-square test, p = 0.04). Success rate was 69% (n = 38) for male applicants and 57% (n = 17) for female applicants. Median time to a categorical position was 4 years (2-6) for the research group and 3 years (1-6) for the no-research group. CONCLUSIONS: Our quasi-experimental study demonstrated a higher success rate for Aga Khan University, Medical College applicants with significant research background in the US, compared to those who did not. Better social integration, enhanced mentorship available during research, overcoming of cultural and linguistic barriers and a perception as better qualified candidate can be some factors contributing to higher success rates.

Low conversion rate during minimally invasive major hepatectomy: Ten-year experience at a high-volume center.

BACKGROUND: Minimally invasive approaches for major hepatectomy have been marred by significant rates of conversion and associated morbidity. This study aimed to determine risk factors for conversion as well as postoperative morbidity in patients undergoing minimally invasive right-sided hepatectomy (MIRH). METHODS: Data for patients undergoing MIRH between 2008 and 2017 at Emory University were reviewed. Risk factors for conversion were determined using multivariate regression analysis. Outcomes of conversion patients were compared with those who underwent successful MIRH or elective open surgery. RESULTS: Unplanned conversion occurred in 7 (6.25%) of 112 patients undergoing MIRH. Primary reason for conversion was difficult dissection secondary to inflammation and severe adhesions. No preoperative clinical factor was identified that predicted conversions. Converted cases had higher EBL and pRBC transfusion compared to non-converted cases however morbidity was similar to those undergoing primary open surgery. CONCLUSION: Difficult dissection and adhesions remained the only clinically applicable parameter leading to unplanned conversions. While these did offset benefits of a successful minimally invasive approach, it did not increase risk of postoperative complications compared with planned open surgery.

Risk of appendicitis in patients with incidentally discovered appendicoliths.

BACKGROUND: An appendicolith-related appendiceal obstruction leading to appendicitis is a commonly encountered surgical emergency that has clear evidence-based management plans. However, there is no consensus on management of asymptomatic patients when appendicoliths are found incidentally. The objective of this study was to determine the risk of appendicitis in patients with an incidental finding of the appendicolith. METHODS: A retrospective matched cohort study of patients with appendicolith discovered incidentally on computed tomographic scan from January 2008 to December 2014 at our institution was completed. The size and position of the appendicolith were ascertained. The study group was matched by age and gender to a control group. Both groups were contacted and interviewed regarding development of appendicitis. RESULTS: In total, 111 patients with appendicolith were successfully contacted and included in the study. Mean age was found to be 38 ± 15 y with 36 (32%) of the study population being females. Mean length of appendix was 66 ± 16 mm, and mean width was 5.8 ± 0.9 mm. Mean size of the appendicolith was 3.6 ± 1.1 mm (1.4-7.8 mm). Fifty-eight percent of appendicoliths was located at the proximal end or whole of appendix, 31% at mid area, and 11% at the distal end of appendix. All patients of the study and control groups were contacted, and at a mean follow-up of 4.0 ± 1.7 y, there was no occurrence of acute appendicitis in either group. CONCLUSIONS: Patients with incidentally discovered appendicolith on radiological imaging did not develop appendicitis. Hence, the risk of developing acute appendicitis for these patients does not seem higher than the general population.

Hookworm infestation as a cause of melena and severe anaemia in farmer.

Hookworm infections remain a major cause of morbidity in the developing world. Prevalence is highest in agricultural areas, where use of waste water for irrigation and poor hygiene increases infection rates among farmers. Infections present with gastrointestinal symptoms and chronic anaemia, and there are usually no signs of overt blood loss. The following report describes a case of melena in a middle-aged farmer, where the diagnosis of hookworm infestation was delayed due to the unusual presentation. The patient underwent multiple blood transfusions before referral to the Aga Khan University Hospital (AKUH), Karachi and was managed conservatively with mebendazole at our hospital after exclusion of other possible causes of gastrointestinal bleeding. This case highlights the importance of considering hookworm infestations as a cause of melena in the older age group, where other critical differentials such as peptic ulcer disease and occult malignancy may result in delay in initiation of treatment and a significant financial burden on the patient.