The long weight: association between distressed communities index and long-term weight outcomes following bariatric surgery.

BACKGROUND: Socioeconomic status (SES) is multifactorial, and its effect on post-bariatric weight recurrence is unclear. Distressed Community Index (DCI) is a composite SES score measuring community economic well-being. This study aims to evaluate the effect of DCI on long-term post-bariatric weight outcomes. METHODS: Retrospective analysis of patients undergoing primary laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy between 2015 and 2020 was performed. All weights in the electronic medical record (EMR), including non-bariatric visits, were captured. Patients were stratified into low tier (LT) and high tier (HT) DCI groups. RESULTS: Of 583 patients, 431 (73.9%) were HT and 152 (26.1%) were LT. Average bariatric follow up was 1.78 ± 1.6 years and average postoperative weight in the EMR was 3.96 ± 2.26 years. Rates of bariatric follow up within the last year were similar (13.8% LT vs 16.2% HT, p = 0.47). LT had higher percent total body weight loss (%TWL; 26% LT vs 23% HT, p < 0.01) and percent excess weight loss (%EWL; 62% vs 57%, p = 0.04) at 1 year on univariate analysis. On multivariate linear regression adjusting for baseline characteristics and surgery type, there were no differences in %EWL between groups at 1 year (p = 0.22), ≥ 3 years (p = 0.53) or ≥ 5 years (p = 0.34) postop. While on univariate analysis LT only trended towards greater percentage of patients with > 15% increase from their 1-year weight (33.3% LT vs 21.0% HT, p = 0.06), on multivariate analysis this difference was significant (OR 2.0, LT 95%CI 1.41-2.84). There were no differences in the percentage of patients with > 15% decrease in %EWL from 1 to 3 + years postop between groups (OR 0.98, LT 95% CI 0.72-1.35). CONCLUSIONS: While low tier patients had similar weight loss at 1 year, they were twice as likely to have weight recurrence at ≥ 3 years. Further studies are needed to identify factors contributing to greater weight recurrence among this population.

The impact of maternal bariatric surgery on long-term health of offspring: a scoping review.

While pregnancy post-bariatric surgery has become increasingly common, little is known about whether and how maternal bariatric surgery affects the next generation. This scoping review aimed to collate available evidence about the long-term health of offspring following maternal bariatric surgery. A literature search was conducted using three databases (PubMed, PsycINFO, EMBASE) to obtain relevant human and animal studies. A total of 26 studies were included: 17 were ancillary reports from five "primary" studies (three human, two animal studies) and the remaining nine were "independent" studies (eight human, one animal studies). The human studies adopted sibling-comparison, case-control, and single-group descriptive designs. Despite limited data and inconsistent results across studies, findings suggested that maternal bariatric surgery appeared to (1) modify epigenetics (especially genes involved in immune, glucose, and obesity regulation); (2) alter weight status (unclear direction of alteration); (3) impair cardiometabolic, immune, inflammatory, and appetite regulation markers (primarily based on animal studies); and (4) not affect the neurodevelopment in offspring. In conclusion, this review supports that maternal bariatric surgery has an effect on the health of offspring. However, the scarcity of studies and heterogenous findings highlight that more research is required to determine the scope and degree of such effects. IMPACT: There is evidence that bariatric surgery modifies epigenetics in offspring, especially genes involved in immune, glucose, and obesity regulation. Bariatric surgery appears to alter weight status in offspring, although the direction of alteration is unclear. There is preliminary evidence that bariatric surgery impairs offspring's cardiometabolic, immune, inflammatory, and appetite regulation markers. Therefore, extra care may be needed to ensure optimal growth in children born to mothers with previous bariatric surgery.

The impact of surgical weight loss procedures on the risk of metachronous colorectal neoplasia: the differential effect of surgery type, sex, and anatomic location.

Patients with prior colorectal polyps are at high risk for metachronous colorectal neoplasia, especially in the presence of obesity. We assessed the impact of 2 common bariatric surgeries, vertical sleeve gastrectomy and roux-n-Y gastric bypass, on the risk of colorectal neoplasia recurrence. This nationally representative analysis included 1183 postbariatric adults and 3193 propensity score-matched controls, who all had prior colonoscopy with polyps and polypectomy. Colorectal polyps reoccurred in 63.8% of bariatric surgery patients and 71.7% of controls at a mean follow-up of 53.1 months from prior colonoscopy. There was a reduced odds of colorectal polyp recurrence after bariatric surgery compared with controls (odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.58 to 0.83). This effect was most pronounced in men (OR = 0.58, 95% CI = 0.42 to 0.79), and post roux-n-Y gastric bypass (OR = 0.57, 95% CI = 0.41 to 0.79). However, the risk of rectal polyps or colorectal cancer remained consistent between groups. This study is the first to our knowledge to show a reduction in risk of polyp recurrence following bariatric surgery.

Venous thromboembolism (VTE) prophylaxis after bariatric surgery: a national survey of MBSAQIP director practices.

BACKGROUND: Venous thromboembolism (VTE) is the most common cause of death following metabolic/bariatric surgery (MBS), with most events occurring after discharge. The available evidence on ideal prophylaxis type, dosage, and duration after discharge is limited. OBJECTIVES: Assess metabolic/bariatric surgeon VTE prophylaxis practices and define existing variability. SETTING: Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP)-accredited centers. METHODS: The members of the ASMBS Research Committee developed and administered a web-based survey to MBSAQIP medical directors and ASMBS members to examine the differences in clinical practice regarding the administration of VTE prophylaxis after MBS. RESULTS: Overall, 264 metabolic/bariatric surgeons (136 medical directors and 128 ASMBS members) participated in the survey. Both mechanical and chemical VTE prophylaxis was used by 97.1% of the participants, knee-high compression devices by 84.7%, enoxaparin (32.4% 40 mg every 24 hours, 22.7% 40 mg every 12 hours, 24.4% adjusted the dose based on body mass index) by 56.5%, and heparin (46.1% 5000 units every 8 hours, 22.6% 5000 units every 12 hours, 20.9% 5000 units once preoperatively) by 38.1%. Most surgeons (81.6%) administered the first dose preoperatively, while the first postoperative dose was given on the evening of surgery by 44% or the next morning by 42.2%. Extended VTE prophylaxis was prescribed for 2 weeks by 38.7% and 4 weeks by 28.9%. CONCLUSIONS: VTE prophylaxis practices vary widely among metabolic/bariatric surgeons. Variability may be related to limited available comparative evidence. Large prospective clinical trials are needed to define optimal practices for VTE risk stratification and prophylaxis in bariatric surgery patients.

Proton pump inhibitor prophylaxis after Roux-en-Y gastric bypass: A national survey of surgeon practices.

BACKGROUND: Proton pump inhibitors (PPIs) are frequently used after Roux-en-Y gastric bypass (RYGB) to prevent marginal ulceration. The optimal duration of PPI treatment after surgery to minimize ulcer development is unclear. OBJECTIVES: Assess bariatric surgeon practice variability regarding postoperative PPI prophylaxis. SETTING: Survey of medical directors of Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program-accredited centers. METHODS: Members of the American Society for Metabolic and Bariatric Surgery research committee developed and administered a web-based anonymous survey in November 2021 to bariatric surgeons of Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program-accredited programs detailing questions related to surgeons' use of PPI after RYGB including patient selection, medication, dosage, and treatment duration. RESULTS: The survey was completed by 112 surgeons (response rate: 52.6%). PPIs were prescribed by 85.4% of surgeons for all patients during their hospitalization, 3.9% for selective patients, and 10.7% not at all. After discharge, 90.3% prescribed PPIs. Pantoprazole was most often used during hospitalization (38.5%), while omeprazole was most prescribed (61.7%) after discharge. The duration of postoperative PPI administration varied; it was 3 months in 43.6%, 1 month in 20.2%, and 6 months in 18.6% of patients. Finally, surgeons' practice setting and case volume were not associated with the duration of prophylactic PPI administration after RYGB. CONCLUSIONS: PPI administration practices vary widely among surgeons after RYGB, which may be related to the limited comparative evidence and guidelines on best duration of PPI administration. Large prospective clinical trials with objective outcome measures are needed to define optimal practices for PPI prophylaxis after RYGB to maximize clinical benefit.

Evaluating the success of American Society of Metabolic and Bariatric Surgery research grants.

BACKGROUND: Since 2004 the American Society of Metabolic and Bariatric Surgery (ASMBS) Foundation has funded competitive proposals by ASMBS members that are administered through the ASMBS Research Committee. These grants are intended to further the knowledge in the field of metabolic and bariatric surgery and support the scholarly growth of its members. OBJECTIVES: The aim of this project was to evaluate the factors associated with grant completion success and barriers encountered by investigators. SETTING: ASMBS. METHODS: Members of the ASMBS Research Committee retrospectively reviewed all awarded research grants since 2004. Information captured included research topic, status of awarded grants, and related publications. Further, a web-based survey of grant recipients was administered exploring the perceived factors of successful completion and barriers encountered. RESULTS: Since 2004, ASMBS members have been awarded 28 research grants funded by the ASMBS Foundation totaling $1,033,000. Fifty-seven percent of awardees responded to the survey. Seventeen projects had been completed at the time of the survey leading to 13 publications, while 11 remain in progress. Seventy percent of non-completed grant recipients indicated that a publication was forthcoming in the next 12 months. Overall, 64% received additional funding. Factors reported to influence successful completion of grants included the effectiveness of the research team, principal investigator (PI) perseverance, PI protected time, institutional support and available resources, and mentorship. Over the last decade, the average time from the award to publication was 2 years. CONCLUSIONS: The research grants awarded by the AMSBS are successful at producing peer reviewed publications at a high rate and often lead to further funding suggesting that they boost the career of their recipients. The identified factors of success can help guide future applicants and the ASMBS Research Committee during its grant selection process.

Exocrine pancreatic insufficiency after bariatric surgery: a bariatric surgery center of excellence experience.

INTRODUCTION: Gastrointestinal symptoms such as diarrhea, bloating, abdominal pain, and nausea are common after bariatric surgery (BS) and can lead to significant morbidity. While many diagnoses can explain these symptoms, post-bariatric exocrine pancreatic insufficiency (EPI) is becoming increasingly recognized as contributor to gastrointestinal symptoms. The frequency and outcomes of EPI after BS are not well understood. We investigated the prevalence and outcomes of EPI over 18 years at a tertiary bariatric referral center. METHODS: A retrospective review of patients who underwent primary or revisional BS from 2002 to 2020 was performed. Patients were included if they were suspected of having EPI or underwent fecal elastase testing (FE-1). EPI diagnosis was defined as positive FE-1 testing or improvement with empiric pancreatic enzyme replacement therapy (PERT). RESULTS: EPI was suspected in 261 patients, and 190 were tested via FE-1 (89.5%) or empirically treated (10.5%). EPI was diagnosed in 79 (41.6%) patients and was associated with older age and lower BMI. Therapeutic PERT was given to 65 patients diagnosed with EPI, and 56 (86.2%) patients reported improved symptoms. Patients who underwent RYGB and BPD-DS were more likely to have EPI than those after SG (47.9% and 70.0% vs 17.4%, p < 0.01). EPI diagnosis was associated with a history chronic pancreatitis. While diarrhea and abdominal pain were the most common symptoms prompting FE-1 testing, no symptoms were significantly associated with EPI. EPI was also associated with abnormal fecal fat results and treatment with bile acid sequestrants, but not small intestinal bacterial overgrowth. CONCLUSION: This study highlights that exocrine pancreatic insufficiency can account to for previously unexplained GI complaints after bariatric surgery. Therefore, bariatric surgery programs should consider this diagnosis in symptomatic patients, especially following RYGB and BPD-DS. Further work to define patient factors that should prompt evaluation, optimal treatment, and prevention is necessary.

Severe Obesity Contributes to Worse Outcomes After Elective Colectomy for Chronic Diverticular Disease.

BACKGROUND: Both obesity and chronic diverticular disease (DD) are on the rise. Understanding surgical outcomes for patients with obesity undergoing colectomy for DD is imperative to improve care and minimize complications. Our objective was to investigate the impact of obesity on outcomes after elective colectomy specifically for chronic DD. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database from 2012 to 2018, patients who underwent elective colectomy for chronic DD were grouped into four body mass index categories. Baseline characteristics, surgical approach and procedure, and 30-day morbidity and mortality were assessed. RESULTS: Of 24,559 patients, 21.7% were of normal weight, 35.8% were overweight, 35.9% were obese, and 6.6% were severely obese. Patients with severe obesity were younger, more functionally dependent, and had more comorbidities (all P [Formula: see text] 0.0001). Patients with severe obesity were more likely to have unplanned conversion to open surgery from laparoscopic and robotic approaches (AOR 2.15, 95% CI 1.24-3.70). Obesity class did not significantly affect the type of surgical procedure patients underwent (Hartmann's, colectomy with anastomosis and diversion, or colectomy with primary anastomosis). There were increased odds of any perioperative complications (AOR 1.43, 95% CI 1.19-1.71) and non-home discharge (AOR 2.39, 95% CI 1.59-3.57) in patients with severe obesity compared to normal weight patients. CONCLUSIONS: Obesity is associated with poorer outcomes in patients undergoing elective colectomy for chronic DD. Futures studies to examine the impact of preemptive weight loss to improve outcomes after elective colectomy for chronic sequelae of DD are needed.

Reoperations after sleeve gastrectomy: a dual academic institutional experience.

BACKGROUND: Although laparoscopic sleeve gastrectomy (LSG) is the most common bariatric operation performed worldwide, patients can experience complications and poor outcomes that warrant reoperations. The incidence, indications, and outcomes of reoperations are not well understood. OBJECTIVE: To describe indications and outcomes for reoperations after LSG. SETTING: Two academic, tertiary care hospitals. METHODS: We performed a retrospective observational cohort review of institutional Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program data from 2014-2018 and reviewed charts of all reoperations after LSG. We analyzed demographics, preoperative symptoms and work-up, and postoperative outcomes. RESULTS: Fifty-seven reoperations after LSG represented 3.0% of 1965 bariatric cases performed. Most LSGs (56.1%) were performed outside our academic centers. Median time to reoperation and follow-up were 2.63 and 1.2 years, respectively. Conversion to gastric bypass was the most common reoperation (77.2%). More than half of the patients (52.6%) had multiple indications for reoperation. Reflux was the most common primary indication for reoperation (47.3%), followed by incisural strictures (20.1%), inadequate weight loss (17.5%), and leak/fistulae (12.2%). Reoperations were most successful when performed for reflux (92.5%) and oral intolerance from strictures (92%), whereas only 71.4% of leak/fistulas resolved. Surgery for inadequate weight loss resulted in total weight loss of 24.7 ± 10.1%. Complications occurred in 36.2% of cases but varied by indication. CONCLUSION: Symptoms and complications after LSG can persist, and patients may require reoperation. Reoperations can successfully treat the primary indications for reoperation and should be offered, but they have higher complication rates than initial operations.

Exploring the Relationship Between Bariatric Surgery and Inflammatory Bowel Disease: A Systematic Review.

Background: Obesity affects over 40% of Americans. Bariatric surgery is an increasingly popular and well-studied method to achieve weight loss, improve metabolic homeostasis, and resolve obesity-related comorbid conditions. While the impact of bariatric surgery on weight loss and metabolic health has been extensively studied, there is an increasing body of literature characterizing the impact of bariatric surgery on gastrointestinal health and inflammation. Inflammatory bowel disease (IBD) leads to inflammation in both the small and large intestine, and leads to significant patient morbidity. Similar to obesity, the incidence of IBD is also rising. Patients with IBD and obesity may seek bariatric surgery. The impact of bariatric surgery on IBD is not well understood, but critical to understand for optimal patient care. Herein, we review the currently available literature on the impact of bariatric surgery on IBD including common trends, discrepancies in findings, and remaining knowledge gaps in need of further study. Methods: A systematic review of the PubMed/MEDLINE database using PRISMA guidelines was performed. Results: We identified 12 manuscripts discussing de novo IBD after bariatric surgery and 16 studying bariatric surgery in patients with pre-existing IBD. Overall, bariatric surgery appears to be safe in patients with pre-existing IBD but may increase the risk of developing de novo IBD. Conclusions: Further research into optimal surgical approaches, patient selection, and mechanisms on how bariatric surgery impacts IBD is needed.

Treatment of achalasia in the bariatric surgery population: a systematic review and single-institution experience.

BACKGROUND: Although the link between achalasia and morbid obesity is unclear, the reported prevalence is 0.5-1% in this population. For bariatric surgery patients, optimal type and timing of achalasia intervention is uncertain. METHODS: Patient charts from a single academic institution were retrospectively reviewed. Between 2012 and 2019, 245 patients were diagnosed with achalasia, 13 of whom underwent bariatric surgery and were included. Patients were divided into two groups depending on the timing of their achalasia diagnosis and bariatric surgery. Groups were compared in terms of type and timing of intervention as well as treatment response. RESULTS: Group 1 included 4 patients diagnosed with achalasia before bariatric surgery. Three had laparoscopic Heller myotomy (LHM) and 1 had a per oral endoscopic myotomy (POEM). These patients had laparoscopic gastric bypass (LGB) within 5 years of achalasia diagnosis. Postoperatively, 1 had severe reflux with regurgitation necessitating radiofrequency energy application to the lower esophageal sphincter. All had relief from dysphagia. Group 2 included 9 patients diagnosed with achalasia after bariatric surgery. Achalasia subtypes were evenly distributed. Initial operations were: 5 LGB, 2 laparoscopic sleeve gastrectomy (LSG), 1 duodenal switch (DS), 1 lap band. One LSG patient was converted to LGB concurrently with LHM. On average, achalasia was diagnosed 8.3 years after bariatric surgery. Achalasia interventions included: 1 pneumatic dilation, 1 Botox injection, 1 POEM, 6 LHM. While LHM was the most common procedure, 4 of 6 patients experienced recurrent dysphagia, one of whom required esophagectomy. CONCLUSIONS: Achalasia is a challenging problem in the bariatric surgery population. Recurrent symptoms are common. Patients treated for achalasia after bariatric surgery tended to have worse symptom resolution than those diagnosed prior to bariatric surgery. Additional prospective studies are needed to elucidate whether interventions for achalasia should be performed concurrently or in a particular sequence for optimal results.

Roux-en-Y gastric bypass is a safe and effective option that improves major Co-Morbidities associated with obesity in an older, veteran population.

BACKGROUND: Though over one-third of veterans suffer from obesity and its associated comorbidities, bariatric surgery (deleted: is seldom offered) is less commonly offered than in other populations. METHODS: We reviewed surgical outcomes using CPRS/Vista data of ("deleted 308) 315 Roux-en-Y gastric bypass (RYGB) cases performed at a major VA Medical Center (1995-2017). RESULTS: Patients were 69% male, with an average age 52 (65% over 50), and were followed for an average of 8 years; 158 (51%) underwent laparoscopic surgery, and the remaining open. Outcomes were: 30-day mortality- Open: 1.3%, Lap: 0%; anatomic leak-open: 0.3%, Lap: 0%. A total of 32 (10%) Clavien-Dindo ≥3 complications occurred. At 5 and 15 years, average BMI decreased from 47 preoperatively to 33.3 and 31 respectively, while excess body weight loss was 68%, and 80%, respectively. Co-morbidity resolution rates were between 70 and 80% diabetes, sleep apnea, hyperlipidemia, GERD, (delete - hypertension), and NASH. CONCLUSIONS: RYGB offers sustained, long-term weight loss with significant resolution of major comorbidities in older veterans, with acceptably low morbidity and mortality.

Low-dose cyclophosphamide improves survival in a murine treatment model of sepsis.

Sepsis is a complex medical condition characterized by a systemic inflammatory response in the setting of infection. We hypothesized that combining antibiotics plus an immunosuppressant would protect against the morbidity and mortality of polymicrobial sepsis in mice better than would antibiotics alone. We used a murine cecal-ligation-and-puncture model in which mice were treated either with imipenem plus cyclophosphamide or imipenem alone. Titration to a low cyclophosphamide dose revealed that combination therapy increased survival by 20% compared with imipenem alone (56% vs. 36%, P < 0.001). To investigate the mechanism by which combination therapy did this, we reviewed quantitative and qualitative markers of the systemic immune response, end-organ damage, and the local immune response at the site of injury. Cyclophosphamide treatment was not associated with depletion of peripheral leukocytes or differences in pulmonary damage. However, mice that received combination therapy had higher plasma granulocyte colony-stimulating factor levels than did those treated with antibiotics alone. In addition, mice treated with cyclophosphamide had higher levels of bacterial colonization in intestinal Peyer's patch lymph nodes at 72 h after the septic insult. Intraperitoneal macrophage phenotypes and phagocytosis activity did not differ between groups. We conclude that the inflammatory response plays a significant role in the mortality of polymicrobial sepsis and that the regulation of this element is both feasible and beneficial in this disease model.

The TGR5 receptor mediates bile acid-induced itch and analgesia.

Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucine-enkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide- and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.

Active cathepsins B, L, and S in murine and human pancreatitis.

Cathepsins regulate premature trypsinogen activation within acinar cells, a key initial step in pancreatitis. The identity, origin, and causative roles of activated cathepsins in pancreatic inflammation and pain are not defined. By using a near infrared-labeled activity-based probe (GB123) that covalently modifies active cathepsins, we localized and identified activated cathepsins in mice with cerulein-induced pancreatitis and in pancreatic juice from patients with chronic pancreatitis. We used inhibitors of activated cathepsins to define their causative role in pancreatic inflammation and pain. After GB123 administration to mice with pancreatitis, reflectance and confocal imaging showed significant accumulation of the probe in inflamed pancreas compared with controls, particularly in acinar cells and macrophages, and in spinal cord microglia and neurons. Biochemical analysis of pancreatic extracts identified them as cathepsins B, L, and S (Cat-B, Cat-L, and Cat-S, respectively). These active cathepsins were also identified in pancreatic juice from patients with chronic pancreatitis undergoing an endoscopic procedure for the treatment of pain, indicating cathepsin secretion. The cathepsin inhibitor K11777 suppressed cerulein-induced activation of Cat-B, Cat-L, and Cat-S in the pancreas and ameliorated pancreatic inflammation, nocifensive behavior, and activation of spinal nociceptive neurons. Thus pancreatitis is associated with an increase in the active forms of the proteases Cat-B, Cat-L, and Cat-S in pancreatic acinar cells and macrophages, and in spinal neurons and microglial cells. Inhibition of cathepsin activation ameliorated pancreatic inflammation and pain. Activity-based probes permit identification of proteases that are predictive biomarkers of disease progression and response to therapy and may be useful noninvasive tools for the detection of pancreatic inflammation.

In-transit intramammary sentinel lymph nodes from malignant melanoma of the trunk.

OBJECTIVE: Our goal was to determine the incidence and outcomes of intramammary in-transit sentinel lymph nodes (IMSLN) from primary malignant melanoma (MM) of the trunk. We hypothesize that regional metastasis to the breast from anterior trunk MM also occurs via the lymphatic system to these intramammary in-transit sentinel lymph nodes. BACKGROUND: MM is the most common solid tumor metastasis to the breast. The mechanism of intramammary (IM) metastasis is generally attributed to hematogenous rather than lymphatic spread. METHODS: We retrospectively reviewed medical records from all patients who underwent selective sentinel lymph node dissection at the UCSF Melanoma Center from 1993 to 2008 after the approval of UCSF Committee on Human Research. Of the 1911 cases, we found 614 patients with primary MM located on the trunk, and queried their medical records for in-transit SLN and SLNs in the breast. Data from preoperative lymphoscintigraphy, intraoperative lymphatic mapping, operative notes, and pathology and clinic notes were gathered. RESULTS: Of the 1911 patients with MM, 169 (8.9%) and 420 (22.0%) had anterior and posterior trunk lesions, respectively, and 25 patients (1.3%) with flank lesions (lateral abdominal wall below the rib cage, above the iliac crest). Of the anterior trunk population, 18 patients had in-transit SLNs. The vast majority of these patients (14 of 18, 77.8%) had in-transit IMSLN. Of patients with posterior trunk melanoma, 27 patients had in-transit nodes with 1 patient having IMSLNs. Of patients with flank melanomas, 3 patients had in-transit nodes with 1 patient having IMSLNs. Interestingly, all patients with IMSLNs had primary lesions located inferior to the breasts. Two of the 16 patients with IMSLNs had micrometastasis to IMSLN; 1 patient died and the other currently is disease free 4 years after initial SLND. Four of the 32 patients with non-IM in-transit nodes had micrometastases to these in-transit nodes. Of all patients with trunk melanomas, 4 patients had micrometastases to axillary SLNs (AxSLNs). Three of the 4 patients with positive AxSLNs also had positive in-transit nodes whereas only half of the patients with positive in-transit SLNs had positive AxSLNs. CONCLUSIONS: IMSLNs exist in the breast. Our results establish an anatomic basis for lymphatic metastasis to the breast from primary cutaneous melanoma mainly from the anterior trunk inferior to the breasts. For anterior trunk melanomas, IMSLNs should not be overlooked during SLND as they may harbor micrometastasis.

Cathepsin S is activated during colitis and causes visceral hyperalgesia by a PAR2-dependent mechanism in mice.

BACKGROUND & AIMS: Although proteases control inflammation and pain, the identity, cellular origin, mechanism of action, and causative role of proteases that are activated during disease are not defined. We investigated the activation and function of cysteine cathepsins (Cat) in colitis. METHODS: Because protease activity, rather than expression, is regulated, we treated mice with fluorescent activity-based probes that covalently modify activated cathepsins. Activated proteases were localized by tomographic imaging of intact mice and confocal imaging of tissues, and were identified by electrophoresis and immunoprecipitation. We examined the effects of activated cathepsins on excitability of colonic nociceptors and on colonic pain, and determined their role in colonic inflammatory pain by gene deletion. RESULTS: Tomography and magnetic resonance imaging localized activated cathepsins to the inflamed colon of piroxicam-treated il10(-/-) mice. Confocal imaging detected activated cathepsins in colonic macrophages and spinal neurons and microglial cells of mice with colitis. Gel electrophoresis and immunoprecipitation identified activated Cat-B, Cat-L, and Cat-S in colon and spinal cord, and Cat-S was preferentially secreted into the colonic lumen. Intraluminal Cat-S amplified visceromotor responses to colorectal distension and induced hyperexcitability of colonic nociceptors, which required expression of protease-activated receptor-2. Cat-S deletion attenuated colonic inflammatory pain induced with trinitrobenzene sulfonic acid. CONCLUSIONS: Activity-based probes enable noninvasive detection, cellular localization, and proteomic identification of proteases activated during colitis and are potential diagnostic tools for detection of predictive disease biomarkers. Macrophage cathepsins are activated during colitis, and Cat-S activates nociceptors to induce visceral pain via protease-activated receptor-2. Cat-S mediates colitis pain and is a potential therapeutic target.

Serine proteases mediate inflammatory pain in acute pancreatitis.

Acute pancreatitis is a life-threatening inflammatory disease characterized by abdominal pain of unknown etiology. Trypsin, a key mediator of pancreatitis, causes inflammation and pain by activating protease-activated receptor 2 (PAR(2)), but the isoforms of trypsin that cause pancreatitis and pancreatic pain are unknown. We hypothesized that human trypsin IV and rat P23, which activate PAR(2) and are resistant to pancreatic trypsin inhibitors, contribute to pancreatic inflammation and pain. Injections of a subinflammatory dose of exogenous trypsin increased c-Fos immunoreactivity, indicative of spinal nociceptive activation, but did not cause inflammation, as assessed by measuring serum amylase and myeloperoxidase activity and by histology. The same dose of trypsin IV and P23 increased some inflammatory end points and caused a more robust effect on nociception, which was blocked by melagatran, a trypsin inhibitor that also inhibits polypeptide-resistant trypsin isoforms. To determine the contribution of endogenous activation of trypsin and its minor isoforms, recombinant enterokinase (ENK), which activates trypsins in the duodenum, was administered into the pancreas. Intraductal ENK caused nociception and inflammation that were diminished by polypeptide inhibitors, including soybean trypsin inhibitor and a specific trypsin inhibitor (type I-P), and by melagatran. Finally, the secretagogue cerulein induced pancreatic nociceptive activation and nocifensive behavior that were reversed by melagatran. Thus trypsin and its minor isoforms mediate pancreatic pain and inflammation. In particular, the inhibitor-resistant isoforms trypsin IV and P23 may be important in mediating prolonged pancreatic inflammatory pain in pancreatitis. Our results suggest that inhibitors of these isoforms could be novel therapies for pancreatitis pain.