A phase IB/IIA study of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of rectovaginal fistulizing Crohn's disease.

BACKGROUND: Crohn-related rectovaginal fistulas are notoriously difficult to treat. Studies of mesenchymal stem cells for the treatment of perianal Crohn fistulizing disease have largely excluded rectovaginal fistulas. The aim of this study was to determine the safety and efficacy of mesenchymal stem cells for refractory rectovaginal fistulizing Crohn disease. METHODS: A phase IB/IIA randomized control trial was performed in a 3:1, single-blinded study. Patients included were adult women with an anovaginal/rectovaginal fistula in the setting of Crohn disease. Seventy-five million mesenchymal stem cells were administered with a 22G needle after curettage and primary closure of the fistula tract at day 0 and month 3. Adverse and serious adverse events were recorded at post-procedure day 1, week 2, week 6, month 3, month 6, and month 12, along with clinical healing, magnetic resonance imaging, and patient-reported outcomes. RESULTS: A total of 19 patients were enrolled and treated-15 treatment and 4 control. There were no adverse or serious adverse events related to mesenchymal stem cell therapy. At 6 months, 50% of the treatment group and 0% of the control had complete clinical and radiographic healing; 91.7% of the treatment group had improvement at 6 months with only one patient having a lack of response, whereas only 50% of the control group had improvement at 6 months. CONCLUSION: Bone marrow-derived mesenchymal stem cells offer a safe alternative treatment approach for rectovaginal fistulas in the setting of Crohn disease. Complete healing was achieved in half of the patients.

Treatment effect of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of fistulizing Crohn's disease are durable at 12 months.

BACKGROUND: Mesenchymal stem cells have been administered via direct injection to treat perianal Crohn's fistulizing disease. We herein sought to determine the safety and durability of treatment response to 12 months with 3 individual phase IB/IIA clinical trials of mesenchymal stem cells for refractory perianal, rectovaginal, and ileal pouch fistulas in the setting of Crohn disease. METHODS: Three phase IB/IIA randomized placebo-controlled single-blinded clinical trials were performed for (1) perianal fistulas, (2) rectovaginal fistula, and (3) ileal pouch in situ with anovaginal and/or perianal fistulas. Bone marrow-derived mesenchymal stem cells (75 million in 7.5 mL) were injected at the time of exam under anesthesia on day 0 and month 3. Outcome measures were adverse events and combined clinical and pelvic magnetic resonance imaging healing at month 6 and month 12. RESULTS: Across all 3 trials, 64 patients were enrolled; 49 were treatment and 15 were control. At 6 months, combined clinical and radiographic healing was achieved in 83.3%, 33.3%, and 30.8% of the perianal, rectovaginal, and pouch fistula treatment cohorts, respectively. At 12 months, the treatment response was durable, with 67.7% of perianal, 37.5% of rectovaginal, and 46.2% of peripouch fistulas maintaining complete clinical and radiographic healing. Two patients in the perianal fistula control cohort achieved combined clinical and radiographic healing at 12 months, whereas 0% of rectovaginal and pouch control patients healed. CONCLUSION: Bone marrow-derived mesenchymal stem cells offer a safe and effective alternative treatment approach for severe perianal, rectovaginal, and peripouch fistulizing Crohn's disease. Treatment results are durable at 12 months.

A Phase I Study of Ex Vivo Expanded Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Pediatric Perianal Fistulizing Crohn's Disease.

BACKGROUND: Perianal fistulizing Crohn's disease is notoriously difficult to treat. Recent studies of mesenchymal stem cells have demonstrated safety and efficacy of this novel treatment approach. However, no studies to date have included pediatric patients. We sought to determine safety and efficacy of mesenchymal stem cells for pediatric perianal fistulizing Crohn's disease. METHODS: This was a phase I clinical trial to evaluate safety and feasibility of mesenchymal stem cells in pediatric perianal Crohn's patients 13 to 17 years of age. At the time of an exam under anesthesia, following curettage of the fistula tract and closure of the internal opening with absorbable suture, 75 million mesenchymal stem cells were administered with a 22-gauge needle. This was repeated at 3 months if complete clinical and radiographic healing were not achieved. Adverse and serious adverse events at were measured at postprocedure day 1, week 2, week 6, month 3, month 6, and month 12. Clinical healing, radiographic healing per magnetic resonance imaging, and patient-reported outcomes were measured at the same time points. RESULTS: Seven pediatric patients were enrolled and treated (6 male; median age of 16.7 years). There were no adverse or serious adverse events related to the investigational product or injection procedure. At 6 months, 83% had complete clinical and radiographic healing. The perianal Crohn's Disease Activity Index, Wexner incontinence score, and Van Assche score had all decreased at 6 months. CONCLUSIONS: Bone marrow-derived mesenchymal stem cells offer a safe, and likely effective, treatment approach for pediatric perianal fistulizing Crohn's disease.

Interactive Effects of HIV Infection and Cannabis Use on Insula Subregion Functional Connectivity.

Chronic inflammation in the central nervous system is one mechanism through which human immunodeficiency virus (HIV) may lead to progressive cognitive decline. Given cannabis's (CB's) anti-inflammatory properties, use prevalence among people living with HIV (PLWH), and evidence implicating the insula in both, we examined independent and interactive effects of HIV and CB on insular circuitry, cognition, and immune function. We assessed resting-state functional connectivity (rsFC) of three insula subregions among 106 participants across four groups (co-occurring: HIV+/CB+; HIV-only: HIV+/CB-; CB-only: HIV-/CB+; controls: HIV-/CB-). Participants completed a neurocognitive battery assessing functioning across multiple domains and self-reported somatic complaints. Blood samples quantified immune function (T-cell counts) and inflammation (tumor necrosis factor alpha [TNF-α]). We observed interactive HIV × CB effects on rsFC strength between two anterior insula (aI) subregions and sensorimotor cortices such that, CB appeared to normalize altered rsFC among non-using PLWH. Specifically, compared to controls, HIV-only and CB-only groups displayed decreased dorsal anterior insula (DI) - postcentral gyrus rsFC and increased ventral anterior insula (VI) - supplementary motor area rsFC, whereas the co-occurring group displayed DI and VI rsFC more akin to that of controls. Altered DI - postcentral rsFC correlated with decreased processing speed and somatic complaints, but did not significantly correlate with inflammation (TNF-α). These outcomes implicate insula - sensorimotor neurocircuitries in HIV and CB and are consistent with prior work suggesting that CB use may normalize insula functioning among PLWH.

Trajectories of opioid consumption from day of surgery to 28 days postoperatively: a prospective cohort study in patients undergoing abdominal, joint, or spine surgery.

INTRODUCTION: Descriptions of opioid use trajectories and their association with postsurgical pain and opioid consumption are limited. We hypothesized that trajectories of opioid consumption in the first 28 days following surgery would be associated with unique patterns of pain and duration of opioid use. METHODS: A prospective longitudinal cohort of patients undergoing elective inpatient abdominal, joint, or spine surgery between June 2016 and June 2019 was studied. At hospital discharge and every 7 days for 28 days, patients were assessed for pain, analgesic use, pain interference, satisfaction, and side effects. Duration of opioid use was determined for 6 months. The primary analysis used latent class group modeling to identify trajectories of opioid use. RESULTS: Decreasing, high, and persistent opioid trajectories were identified following joint and spine surgery and a decreasing and persistent trajectory following abdominal surgery. Reported pain was greater in the high and persistent trajectories compared with the decreasing use trajectories. Compared with the decreasing opioid trajectory, the median duration of opioid use was increased by 4.5 (95% CI 1 to 22, p<0.01) weeks in persistent opioid use abdominal and by 6 (95% CI 0 to 6, p<0.01) weeks in the high or persistent use joint and spine groups. The odds (95% CI) of opioid use at 6 months in the high or persistent opioid use trajectory was 24.3 (2.9 to 203.4) for abdominal and 3.7 (1.9 to 7.0) for joint or spine surgery compared with the decreasing use trajectory. Morphine milliequivalent per 24 hours of hospitalization was the primary independent predictor of opioid use trajectories. CONCLUSIONS: We observed distinct opioid use trajectories following abdominal and joint or spine surgery that were associated with different patterns of pain and duration of opioid use postoperatively. Prediction of postoperative opioid use trajectory groups may be clinically important for identifying risk of prolonged opioid use.

Psychiatric Phenotypes of Pediatric Patients With Seropositive Autoimmune Encephalitis.

OBJECTIVES: Patients with autoimmune encephalitis (AE) often present with symptoms that are broadly characterized as psychiatric or behavioral, yet little attention is given to the precise symptomatology observed. We sought to more fully define the psychiatric symptoms observed in patients with anti-N-methyl-D-aspartate receptor (NMDAR), anti-glutamic-acid-decarboxylase 65 (GAD65), and anti-voltage-gated-potassium-channel complex (VGKC) antibody-mediated AE using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition nomenclature. METHODS: We present a case series (n = 25) using a retrospective chart review of 225 patients evaluated for AE in a tertiary care academic medical center between 2014 and 2018. The included patients were ≤18 years old with anti-NMDAR AE (n = 13), anti-GAD65 AE (n = 7), or anti-VGKC AE (n = 5). The frequency of neuropsychiatric symptoms present at the onset of illness and time to diagnosis were compared across groups. RESULTS: Psychiatric symptoms were seen in 92% of patients in our cohort. Depressive features (72%), personality change (64%), psychosis (48%), and catatonia (32%) were the most common psychiatric symptoms exhibited. On average, patients experienced impairment in ≥4 of 7 symptom domains. No patients had isolated psychiatric symptoms. The average times to diagnosis were 1.7, 15.5, and 12.4 months for anti-NMDAR AE, anti-GAD65 AE, and anti-VGKC AE, respectively (P < .001). CONCLUSIONS: The psychiatric phenotype of AE in children is highly heterogenous. Involving psychiatry consultation services can be helpful in differentiating features of psychosis and catatonia, which may otherwise be misidentified. Patients presenting with psychiatric symptoms along with impairments in other domains should prompt a workup for AE, including testing for all known antineuronal antibodies.

Association of the addition of a transversus abdominis plane block to an enhanced recovery program with opioid consumption, postoperative antiemetic use, and discharge time in patients undergoing laparoscopic bariatric surgery: a retrospective study.

BACKGROUND: Increasing numbers of laparoscopic bariatric surgeries are being performed and enhanced recovery from anesthesia and surgery (ERAS) protocols have been implemented to optimize care for these patients. We evaluated the effects of an anesthesiologist placed preoperative transversus abdominis plane block (TAP) as part of a bariatric surgery ERAS protocol. We hypothesized that an anesthesiologist placed preoperative TAP added to an ERAS protocol following laparoscopic bariatric surgery would reduce total opioid consumption. METHODS: A retrospective cohort of consecutive patients between January 1, 2017 and December 31, 2018 at a single large tertiary care center studied. TAP blocks were added to the ERAS protocol beginning in the second quarter of 2017. The primary outcome was total opioid analgesia use in mg oral morphine equivalents. Secondary outcomes were antiemetics administered and length of hospitalization. Data were analyzed using a generalized linear mixed model adjusted for sociodemographic, surgical, and preoperative risk factors that have been associated with opioid and antiemetic use and length of hospitalization. RESULTS: Five hundred and nine cases were analyzed; TAP blocks were performed in 94/144 (65%) laparoscopic Roux-en-Y gastric bypass (LRYGB) and in 172/365 (47%) laparoscopic sleeve gastrectomy (LSG) patients. Mean (95% CI) adjusted total opioid administered was lower by 11% (1% to 19%, p=0.02), antiemetic drug administration was lower by 15% (-2% to 25%, p=0.06) and discharge time lower by 39% (26% to 48%, p<0.01) following LRYGB in the TAP group. Mean (95% CI) adjusted total opioid administered was lower by 9% (2% to 16%, p<0.01), antiemetic drug administration was lower by 11% (3% to 18%, p<0.01) and discharge time lower by 11% (2% to 18%, p=0.02) following LSG in the TAP group. CONCLUSIONS: TAP blocks added to a laparoscopic bariatric surgery ERAS protocol were associated with decreased total opioid use, number of antiemetic treatments, and length of stay; however, these changes were not likely clinically important. Our findings do not support widespread clinical benefit of TAP use in ERAS protocols for laparoscopic bariatric surgery.

Safety and Efficacy of Laparoscopic Access in a Surgical Training Program.

Our study evaluated outcomes of laparoscopic access in a surgical residency program and identified variables associated with adverse outcomes. Following IRB approval, we reviewed prospectively collected data from consecutive laparoscopic surgeries from a single surgeon August 2008 to November 2011. Descriptive statistics were generated, and successful and unsuccessful access techniques were compared using the t test, Fisher exact test, and χ test of independence, with P<0.05 considered significant. Five hundred consecutive laparoscopic surgeries were evaluated; the average patient age was 47 years and 55% of patients were female. The most common procedures included laparoscopic cholecystectomy (29%), laparoscopic ventral hernia (15%), laparoscopic appendectomy (12%), laparoscopic colon/small bowel (11%), and laparoscopic inguinal hernia (10%). Successful laparoscopic access was obtained in 98% of patients. The most common access techniques were umbilical stalk technique (57%) and Veress followed by optical trocar technique (29%). The complication rate was 7% and included multiple access attempts in 3.4%, attending physician having to take over access in 1.6%, bleeding/solid organ injury in 0.8%, insufflating peritoneum in 0.6%, and bowel injury in 0.2%. There was a significant relationship between entry technique and failure rate. Open cutdown away from umbilicus had a higher failure rate than other techniques (P=0.0002). There was also a significant relationship between type of surgery and failure rate of technique, with laparoscopic ventral hernia and laparoscopic small bowel cases having the highest failure rate (P=0.005). We observed no difference in success rate based on age, sex, race, previous surgery, and resident training level (P>0.05). Laparoscopic access using appropriate techniques can be safely performed in a residency training program. Laparoscopic ventral hernia and small bowel procedures for obstruction can be difficult cases to obtain access, and surgeons should be able to use multiple strategies to obtain access.

The effect of watchful waiting on the management and treatment of inguinal hernias in a community setting.

A landmark study by Fitzgibbons et al. reported the safety of watchful waiting in men with minimally symptomatic inguinal hernias. The extent to which this study has changed practice patterns is unknown. The purpose of our study was to survey physicians caring for patients with hernia in our community to determine if the Fitzgibbons report impacted their medical practices. We sent an electronic survey containing questions regarding physician background and familiarity with the 2006 New England Journal of Medicine report on watchful waiting to physicians in our community. The online survey was accessed by 77 physicians; 74 completed the survey. Of 74 participants, surgeons accounted for 15 per cent, family/internal medicine 42 per cent, and 13 other specialties 43 per cent. Nonsurgeons were less familiar with the Fitzgibbons report. All surgeons had heard of the study, and 73 per cent had read it compared with 3 per cent of nonsurgeons. In nonsurgeon physicians, 38 per cent preferred letting patients with inguinal hernia decide treatment after counseling, 30 per cent sent all patients to a surgeon, and 25 per cent sent only symptomatic patients to a surgeon. Surgeons let patients decide after counseling in 73 per cent and chose watchful waiting for asymptomatic patients/offered surgery to symptomatic patients in 27 per cent. Based on our survey, Fitzgibbons' watchful waiting report does not appear to have significantly impacted practice and referral patterns in our community, although the watchful waiting strategy outlined in the study is practiced. Our study illustrates the challenge of translating research outcomes into clinical practice. Further research on ways to disseminate important surgical information to nonsurgeons seems warranted.

Oncoplastic surgery and radiation therapy for breast conservation: early outcomes.

PURPOSE: To analyze a multidisciplinary community experience with oncoplastic breast surgery (OBS) and postoperative radiation therapy (RT). METHODS: The records of 79 patients with localized breast cancer who underwent OBS+RT were reviewed. OBS included immediate reconstruction and contralateral mammoreduction. All patients had negative surgical margins. Whole-breast RT was delivered without boost. A subset of 44 patients agreed to complete a validated quality of life survey pre-RT, post-RT, 6 months after RT, and at final follow-up assessing cosmesis and treatment satisfaction. RESULTS: Sixty-seven patients (85%) were white. Median age was 62 years. Median interval between OBS and RT start was 9.6 weeks. Median RT dose was 46 Gy. Fourteen patients (18%) developed surgical toxicities before RT. Five patients (6%) developed RT toxicities. Physician rating of cosmesis post-RT was: 3% excellent, 94% good, and 4% fair. Cosmesis was rated as excellent or good by 87% of patients pre-RT, 82% post-RT, 75% at 6 months, and 88% at the final follow-up. Treatment satisfaction was rated as "total" or "somewhat" by 97% of patients pre-RT, 93% post-RT, 75% at 6 months, and 96% at final follow-up. No significant relation was found between patient or treatment-related factors and toxicity. Local control is 100% at median follow-up of 2.9 years. CONCLUSIONS: OBS followed by RT resulted in acceptable toxicity and favorable physician-rated cosmesis in this large community series. Patients' ratings of cosmesis and treatment satisfaction were initially high, decreasing at 6 months, returning near baseline at final follow-up.

Assessing resident performance and training of colonoscopy in a general surgery training program.

BACKGROUND: Recently, the adequacy of endoscopy training in general surgery residency programs has been questioned. Efforts to improve resident endoscopic training and to judge competency are ongoing but not well studied. We assessed resident performance using two assessment tools in colonoscopy in a general surgery residency program. METHODS: Prospectively collected data were reviewed from consecutive colonoscopies by a single surgeon: September 2008 to June 2011. Colonoscopies performed without residents were excluded. Data included patient demographics, procedural data, and outcomes. Following the colonoscopy, residents were graded by the attending surgeon using up two different assessment tools. Descriptive statistics were calculated and outcomes were compared. RESULTS: Colonoscopies were performed by residents in 100 patients. Average age was 52 (range, 22-79) years. Females made up 66 % of patients, and 63 % were Caucasian. Postgraduate level (PG-Y) 3 level residents performed 72 % of colonoscopies. The average resident participation was 73 % of the procedure. Biopsies were performed in 35 %; adenomatous polyps were found in 17 % and invasive cancer in 1 %. Bowel preparation was deemed good in 76 % of patients. Colonoscopy was completed in 90 % of patients. Reasons for incomplete exam were technical (7 patients), inability to pass a stricture (2 patients), and poor prep (1 patient). For completed full colonoscopies, the average time to reach the cecum was 22 min, and withdrawal time was 13 min. Resident assessments were made in 89 of the colonoscopies using 2 separate assessment tools. There were no mortalities; the morbidity rate was 3 %. Morbidities included a perforation related to a biopsy requiring surgery and partial colectomy, a postpolypectomy bleed requiring repeat colonoscopy with clipping of the bleeding vessel, and a patient with transient bradycardia requiring atropine during the procedure. CONCLUSIONS: Using objective assessment tools, overall resident skill and knowledge in performing colonoscopy appears to improve based on increasing PG-Y level, although this was not evident with all categories measured. Methods to assess competency continue to evolve and should be the focus of future research.

Use and indications of human acellular dermis in ventral hernia repair at a community hospital.

Background. To evaluate the use, indications, and short-term outcomes for human acellular dermis. Methods. We retrospectively reviewed patients having human acellular dermis placed for ventral hernia repair from January 2008 through October 2009. Demographic information, operative details, and outcomes of patients with and without recurrences were compared; a P value <0.05 was considered significant. Results. 115 patients met inclusion criteria. The average age was 60 years (range, 24-89). The technique of repair included primary repair with overlay of mesh in 76%, bridge repair in 13%, and underlay in 11%. Average cost of mesh per operation was $3,709 (range $191-10,630). Open repairs were performed in 90% of patients with addition of component separation in 12%. At an average of 13 months, 58 patients were available for followup (50%), with a 47% recurrence rate. The morbidity rate was 48% and the mortality rate was 2%. Technique of repair was the only significant risk factor for recurrence with bridge repairs associated with a higher rate of recurrence (P < 0.05). Conclusions. The use of biologic grafts for ventral hernia repair is becoming more popular especially in clean cases. Although followup is limited, there remains a high recurrence rate associated with the use of human acellular dermis.

Solid organ injury grading in trauma: accuracy of grading by surgical residents.

The American Association for the Surgery of Trauma developed an Organ Injury Scale for management of patients with splenic, kidney, or liver injuries. Despite widespread use of the guidelines, the person who determines the injury grade varies among institutions. Our purpose was to determine the accuracy and interobserver agreement between surgical residents and a radiologist in grading solid organ injuries. We retrospectively reviewed patients with solid organ injuries from January 2009 to May 2010 and compared the grade of solid organ injuries by a single resident with grades by a single blinded radiologist using a paired t test, analysis of variance, or Kruskal-Wallis. Computed tomography scans of 58 patients with splenic injuries, 43 with liver injuries, and 16 with kidney injuries were reviewed. Average grades for splenic injuries were 2.5 and 2.4 (radiologist/resident); liver injuries, 2.6 and 2.1; and kidney injuries, 2.7 and 2.8. There were no significant differences in grading by the radiologist and resident for splenic and kidney injuries; however, equal values were only achieved in 43 and 38 per cent, respectively. There was a significant difference (average rating difference 0.54, P = 0.0002) in grading between the radiologist and resident for liver injuries with only 35 per cent having equal values and the radiologist grading on average 0.5 points higher than the resident. No demographic, injury, or outcome variables were significantly associated with interobserver variability (P > 0.05). Despite a significant difference for liver injury grading, interobserver agreement between residents and a single radiologist was low. Clinical implications and the impact on outcomes related to interobserver variations require further study.

After-hours urgent and emergent surgery in the elderly: outcomes and prognostic factors.

Surgeons are becoming increasingly involved in the care of elderly patients. The purpose of this project was to evaluate contemporary outcomes of emergent surgeries performed after hours in elderly patients and to determine any risk factors for poor outcome. We retrospectively reviewed patients 80 years or older undergoing an urgent or emergent surgery at our medical center from 6 pm to 6 am from October 2006 through July 2009. Comparisons were made between survivors and nonsurvivors using Wilcoxon rank sum and Fisher exact test when indicated. P < 0.05 was considered significant. During the study period, 59 patients met inclusion criteria; the average age was 84 years (range, 80 to 102 years). A total of 70 procedures were performed; the most common were colectomy (18), small bowel resection (13), lysis of adhesions (9), and gastric surgery (8). The majority of patients were female (68%) with 47 per cent and 53 per cent of patients undergoing emergent and urgent surgery, respectively. Sixty-seven complications occurred in 38 patients; the morbidity rate was 64 per cent, and the mortality rate was 25 per cent. The only studied factors significantly associated with mortality were higher American Society of Anesthesiologists score (P = 0.004), increased intravenous fluids (P = 0.03), decreased intraoperative urine output (P = 0.03), and the need for intraoperative blood (P = 0.003). After-hours urgent and emergent surgery in the elderly has a high morbidity and mortality rate. We identified several risk factors for a poor prognosis that may be useful to the surgeon when discussing the patient's prognosis with the family.

Noscapine alters microtubule dynamics in living cells and inhibits the progression of melanoma.

Cellular microtubules, polymers of tubulin, alternate relentlessly between phases of growth and shortening. We now show that noscapine, a tubulin-binding agent, increases the time that cellular microtubules spend idle in a paused state. As a result, most mammalian cell types observed arrest in mitosis in the presence of noscapine. We demonstrate that noscapine-treated murine melanoma B16LS9 cells do not arrest in mitosis but rather become polyploid followed by cell death, whereas primary melanocytes reversibly arrest in mitosis and resume a normal cell cycle after noscapine removal. Furthermore, in a syngeneic murine model of established s.c. melanoma, noscapine treatment resulted in an 85% inhibition of tumor volume on day 17 when delivered by gavage compared with untreated animals (P