Endocrine and multiple sclerosis outcomes in patients with autoimmune thyroid events in the alemtuzumab CARE-MS studies.

Background: Alemtuzumab is an effective therapy for relapsing multiple sclerosis. Autoimmune thyroid events are a common adverse event. Objective: Describe endocrine and multiple sclerosis outcomes over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients in the phase 3 CARE-MS I, II, and extension studies who experienced adverse thyroid events. Methods: Endocrine and multiple sclerosis outcomes were evaluated over 6 years. Thyroid event cases, excluding those pre-existing or occurring after Year 6, were adjudicated retrospectively by expert endocrinologists independently of the sponsor and investigators. Results: Thyroid events were reported for 378/811 (46.6%) alemtuzumab-treated patients. Following adjudication, endocrinologists reached consensus on 286 cases (75.7%). Of these, 39.5% were adjudicated to Graves' disease, 2.5% Hashimoto's disease switching to hyperthyroidism, 15.4% Hashimoto's disease, 4.9% Graves' disease switching to hypothyroidism, 10.1% transient thyroiditis, and 27.6% with uncertain diagnosis; inclusion of anti-thyroid antibody status reduced the number of uncertain diagnoses. Multiple sclerosis outcomes of those with and without thyroid events were similar. Conclusion: Adjudicated thyroid events occurring over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients were primarily autoimmune. Thyroid events were considered manageable and did not affect disease course. Thyroid autoimmunity is a common but manageable adverse event in alemtuzumab-treated relapsing multiple sclerosis patients.ClinicalTrials.gov Registration Numbers: CARE-MS I (NCT00530348); CARE-MS II (NCT00548405); CARE-MS Extension (NCT00930553).

A Phase I, First-in-Human, Healthy Volunteer Study to Investigate the Safety, Tolerability, and Pharmacokinetics of CVN424, a Novel G Protein-Coupled Receptor 6 Inverse Agonist for Parkinson's Disease.

CVN424 is a novel small molecule and first-in-class candidate therapeutic to selectively modulate GPR6, an orphan G-protein coupled receptor. Expression of GPR6 is largely confined to the subset of striatal projection neurons that give rise to the indirect (striatopallidal) pathway, important in the control of movement. CVN424 improves motor function in preclinical animal models of Parkinson's disease. Here, we report results of a phase 1, first-in-human study investigating the safety, tolerability, and pharmacokinetics of CVN424 in healthy volunteers. The study (NCT03657030) was randomized, double-blind, and placebo controlled. CVN424 was orally administered in ascending doses to successive cohorts as inpatients in a clinical research unit. Single doses ranged from 1 mg to 225 mg, and repeated (7 day) daily doses were 25, 75, or 150 mg. CVN424 peak plasma concentrations were reached within 2 h post-dose in the fasted state and increased with increasing dose. Dosing after a standardized high-fat meal reduced and delayed the peak plasma concentration, but total plasma exposure was similar. Mean terminal half-life ranged from 30 to 41 h. CVN424 was generally well tolerated: no serious or severe adverse effects were observed, and there were no clinically significant changes in vital signs or laboratory parameters. We conclude that CVN424, a nondopaminergic compound that modulates a novel therapeutic target, was safe and well tolerated. A phase 2 study in patients with Parkinson's disease is underway. SIGNIFICANCE STATEMENT: This is the first-in-human clinical study of a first-in-class candidate therapeutic. CVN424 modulates a novel drug target, GPR6, which is selectively expressed in a pathway in the brain that has been implicated in the motor dysfunction of patients with Parkinson's disease. This study paves the way for investigating this novel mechanism of action in patients with Parkinson's disease.

Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058.

Serotonin type-3 receptor (5-HT3R) antagonists show potential as a treatment for cognitive deficits in schizophrenia. CVN058, a brain-penetrant, potent and selective 5-HT3R antagonist, shows efficacy in rodent models of cognition and was well-tolerated in Phase-1 studies. We evaluated the target engagement of CVN058 using mismatch negativity (MMN) in a randomized, double-blind, placebo-controlled, cross-over study. Subjects were stable outpatients with schizophrenia or schizoaffective disorder treated with antipsychotics. Subjects were not permitted to use other 5-HT3R modulators or serotonin reuptake inhibitors. Each subject received a high (150 mg) and low (15 mg or 75 mg) oral dose of CVN058 and placebo in a randomized order across 3 single-day treatment visits separated by at least 1 week. The primary pre-registered outcome was amplitude of duration MMN. Amplitude of other MMN deviants (frequency, intensity, frequency modulation, and location), P50, P300 and auditory steady-state response (ASSR) were exploratory endpoints. 19 of 22 randomized subjects (86.4%) completed the study. Baseline PANSS scores indicated moderate impairment. CVN058 150 mg led to significant improvement vs. placebo on the primary outcome of duration MMN (p = 0.02, Cohen's d = 0.48). A significant treatment effect was also seen in a combined analysis across all MMN deviants (p < 0.001, d = 0.57). Effects on location MMN were independently significant (p < 0.007, d = 0.46). No other significant effects were seen for other deviants, doses or EEG measures. There were no clinically significant treatment related adverse effects. These results show MMN to be a sensitive target engagement biomarker for 5-HT3R, and support the potential utility of CVN058 in correcting the excitatory/inhibitory imbalance in schizophrenia.

Are the current colonoscopy recommendations for interval surveillance in patients with polyps enough? Machine learning-augmented propensity score cohort analysis of 1840 patients.

BACKGROUND: Colonoscopy remains the gold standard for screening and surveillance of colorectal neoplasms, and is associated with a lower risk of colorectal cancer (CRC)-related mortality. The current interval surveillance recommendations in patients with previous adenomas lack sufficient evidence. The prevalence of subsequent adenomas, and especially high-risk adenomas, during surveillance is not well known. METHODS: The primary outcome of this study was to determine the prevalence of polyps upon surveillance colonoscopy in patients who have a history of adenomas on initial average-risk-screening colonoscopy, but then have a normal initial surveillance (second) colonoscopy between 2003 and 2017. This is the first known retrospective cohort study of adenoma detection rate (ADR) with sub-group analysis of patients with serial surveillance colonoscopies by abnormal and high-risk surveillance findings separately by prior abnormal colonoscopies and correct surveillance strategies based on the recent March 2020 updated guidelines. After ADR calculation, machine learning-augmented propensity score adjusted multivariable regression with augmented inverse-probability weighting propensity (AIPW) score analysis was used to assess the relationship between guideline adherence, as well as abnormal and high-risk surveillance findings. RESULTS: A total of 1840 patients with pathologically confirmed adenomas or cancer on an initial average-risk-screening (first) colonoscopy met study criteria. 837 (45.5%) had confirmed adenomas on second colonoscopy, and 1003 (54.5%) had normal findings. Of 837 patients with polyps on both first and second colonoscopy, 423 (50.5%) had adenomas on third colonoscopy. Of the 1003 patients without polyps on second colonoscopy, 406 (40.5%) had confirmed adenomas on third colonoscopy. Guideline adherence was low at 9.18%, though was associated in propensity score adjusted multivariable regression with increased odds of an abnormal third (but not high-risk) colonoscopy, with comparable AIPW results. CONCLUSION: This 14-year study demonstrates the ADR to be > 40% on the third colonoscopy for patients with adenomas on initial screening colonoscopy, who then have a normal second colonoscopy. Through advanced machine learning and propensity score analysis, we showed that correct adherence is associated with higher odds of abnormal, but not high-risk abnormal 3rd colonoscopy, with evidence that high-risk surveillance findings are reduced by providers shortening the time between surveillance colonoscopies in contrast to the guidelines for those for whom there is presumed greater clinical suspicion of eventual cancer. Larger prospective trials are needed to guide optimal surveillance for these patients.

Anastomotic Leak is Increased With Clostridium difficile Infection After Colectomy: Machine Learning-Augmented Propensity Score Modified Analysis of 46 735 Patients.

BACKGROUND: Clostridium difficile infection (CDI) is now the most common cause of healthcare-associated infections, with increasing prevalence, severity, and mortality of nosocomial and community-acquired CDI which makes up approximately one third of all CDI. There are also increased rates of asymptomatic colonization particularly in high-risk patients. C difficile is a known collagenase-producing bacteria which may contribute to anastomotic leak (AL). METHODS: Machine learning-augmented multivariable regression and propensity score (PS)-modified analysis was performed in this nationally representative case-control study of CDI and anastomotic leak, mortality, and length of stay for colectomy patients using the ACS-NSQIP database. RESULTS: Among 46 735 colectomy patients meeting study criteria, mean age was 61.7 years (SD 14.38), 52.2% were woman, 72.5% were Caucasian, 1.5% developed CDI, 3.1% developed anastomotic leak, and 1.6% died. In machine learning (backward propagation neural network)-augmented multivariable regression, CDI significantly increases anastomotic leak (OR 2.39, 95% CI 1.70-3.36; P < .001), which is similar to the neural network results. Having CDI increased the independent likelihood of anastomotic leak by 3.8% to 6.8% overall, and in dose-dependent fashion with increasing ASA class to 4.3%, 5.7%, 7.6%, and 10.0%, respectively, for ASA class I to IV. In doubly robust augmented inverse probability weighted PS analysis, CDI significantly increases the likelihood of AL by 4.58% (95% CI 2.10-7.06; P < .001). CONCLUSIONS: This is the first known nationally representative study on CDI and AL, mortality, and length of stay among colectomy patients. Using advanced machine learning and PS analysis, we provide evidence that suggests CDI increases AL in a dose-dependent manner with increasing ASA Class.

Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial.

BACKGROUND: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline. METHODS: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN-alemtuzumab), followed by additional, as-needed, alemtuzumab. RESULTS: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN-alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN-alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups. CONCLUSION: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups. CLINICALTRIALSGOV IDENTIFIERS: NCT00530348; NCT00548405; NCT00930553.

Caveolin-1-driven membrane remodelling regulates hnRNPK-mediated exosomal microRNA sorting in cancer.

BACKGROUND: Caveolae proteins play diverse roles in cancer development and progression. In prostate cancer, non-caveolar caveolin-1 (CAV1) promotes metastasis, while CAVIN1 attenuates CAV1-induced metastasis. Here, we unveil a novel mechanism linking CAV1 to selective loading of exosomes with metastasis-promoting microRNAs. RESULTS: We identify hnRNPK as a CAV1-regulated microRNA binding protein. In the absence of CAVIN1, non-caveolar CAV1 drives localisation of hnRPNK to multi-vesicular bodies (MVBs), recruiting AsUGnA motif-containing miRNAs and causing their release within exosomes. This process is dependent on the lipid environment of membranes as shown by cholesterol depletion using methyl-ß-cyclodextrin or by treatment with n-3 polyunsaturated fatty acids. Consistent with a role in bone metastasis, knockdown of hnRNPK in prostate cancer PC3 cells abolished the ability of PC3 extracellular vesicles (EV) to induce osteoclastogenesis, and biofluid EV hnRNPK is elevated in metastatic prostate and colorectal cancer. CONCLUSIONS: Taken together, these results support a novel pan-cancer mechanism for CAV1-driven exosomal release of hnRNPK and associated miRNA in metastasis, which is modulated by the membrane lipid environment.

Modified Frailty Index Predicts Postoperative Outcomes in Patients Undergoing Radical Pelvic Surgery.

Patients undergoing radical pelvic surgery such as proctectomy or radical cystectomy are at risk of experiencing a variety of complications. Frailty renders patients vulnerable to adverse events. We hypothesize that frailty measured preoperatively using a validated scoring system correlates with increased likelihood of experiencing Clavien-Dindo grade IV complications and 30-day mortality and may be used as a predictive model for patients preoperatively. The NSQIP database was queried for patients who underwent proctectomy or radical cystectomy from 2008 to 2012. Preoperative frailty was calculated using the 11-point modified frailty index (MFI). Patients were scored based on the presence of indicators and categorized into two groups (<3 or ≥3). Major postoperative morbidities and mortality were identified and analyzed in each group. 10,048 proctectomy and cystectomy patients were identified. The MFI was found to be predictive of both 30-day mortality (P < 0.0001) and Clavien-Dindo grade IV complications (P < 0.0001). Receiver operating characteristic analysis demonstrated improved discriminative power of the MFI with the addition of American Society of Anesthesiologists class for both prediction of complications and 30-day mortality. An MFI score of ≥3 is predictive of postoperative morbidity and mortality. Providers should be encouraged to calculate frailty preoperatively to predict adverse outcomes.

Proportion of alemtuzumab-treated patients converting from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis over 6 years.

BACKGROUND: Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies. OBJECTIVE: Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies. METHODS: Patients (N = 811) were analyzed post hoc for secondary progressive MS conversion. Optimal conversion definition: Expanded Disability Status Scale (EDSS) score ≥4, pyramidal functional system score ≥2, and confirmed progression over ≥3 months including confirmation within the functional system leading to progression, independent of relapse. RESULTS: Over 6.2 years median follow-up, 20 alemtuzumab-treated patients converted (Kaplan-Meier estimate, 2.7%; 95% confidence interval, 1.8%-4.2%). Sensitivity analysis accounting for dropouts showed similar results (3%), as did analyses using alternative definitions with different EDSS thresholds and/or confirmation periods, and analysis of core study subcutaneous interferon beta-1a-treated patients who received alemtuzumab in the extension. Patients converting to secondary progressive MS were older, and had higher EDSS scores and greater brain lesion volumes at baseline, but did not need additional alemtuzumab or other therapies. CONCLUSIONS: The 6-year conversion rate to secondary progressive MS was low for alemtuzumab-treated patients, supporting further study of the role alemtuzumab may play in reducing risk of secondary progression.ClinicalTrials.gov identifiers: NCT00530348, NCT00548405, NCT00930553.

Immune thrombocytopenia in alemtuzumab-treated MS patients: Incidence, detection, and management.

BACKGROUND: Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk. OBJECTIVE: To examine ITP incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials. METHODS: CAMMS223 and Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion. RESULTS: Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 [2.0%]; alemtuzumab 24 mg, 9 [3.3%]) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials. CONCLUSION: Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.

Impact of alemtuzumab on health-related quality of life over 6 years in CARE-MS II trial extension patients with relapsing-remitting multiple sclerosis.

BACKGROUND: In CARE-MS II (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; NCT00548405), alemtuzumab (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved health-related quality of life (HRQL) outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis (RRMS) patients over 2 years. Patients completing CARE-MS II could enter a 4-year extension study (NCT00930553). OBJECTIVE: The aim of this study is to assess 6-year HRQL outcomes in alemtuzumab-treated CARE-MS II patients, including those with highly active disease (HAD). METHODS: During extension, patients could receive additional alemtuzumab for clinical/magnetic resonance imaging (MRI) activity or other disease-modifying therapies per investigator's discretion. Assessments include Functional Assessment of Multiple Sclerosis (FAMS), 36-Item Short-Form Health Survey (SF-36), and EQ-5D visual analog scale (EQ-VAS). RESULTS: Alemtuzumab-treated patients improved or stabilized all HRQL measures over 6 years with significant improvements from baseline at all time points on EQ-VAS and for up to 5 years on FAMS, SF-36 MCS, and SF-36 PCS. Alemtuzumab-treated patients with HAD showed significant improvements versus baseline at Year 2 on all HRQL measures, and significant improvements versus SC IFNB-1a on SF-36 PCS and EQ-VAS; however, the improvements did not reach the threshold for clinical relevance. CONCLUSION: Alemtuzumab-treated CARE-MS II patients improved or stabilized HRQL versus baseline over 6 years. This is the first study to show long-term HRQL benefits in patients with HAD.

CDCP1 enhances Wnt signaling in colorectal cancer promoting nuclear localization of ß-catenin and E-cadherin.

Elevated CUB-domain containing protein 1 (CDCP1) is predictive of colorectal cancer (CRC) recurrence and poor patient survival. While CDCP1 expression identifies stem cell populations that mediate lung metastasis, mechanisms underlying the role of this cell surface receptor in CRC have not been defined. We sought to identify CDCP1 regulated processes in CRC using stem cell populations, enriched from primary cells and cell lines, in extensive in vitro and in vivo assays. These experiments, demonstrating that CDCP1 is functionally important in CRC tumor initiation, growth and metastasis, identified CDCP1 as a positive regulator of Wnt signaling. Detailed cell fractionation, immunoprecipitation, microscopy, and immunohistochemical analyses demonstrated that CDCP1 promotes translocation of the key regulators of Wnt signaling, ß-catenin, and E-cadherin, to the nucleus. Of functional importance, disruption of CDCP1 reduces nuclear localized, chromatin-associated ß-catenin and nuclear localized E-cadherin, increases sequestration of these proteins in cell membranes, disrupts regulation of CRC promoting genes, and reduces CRC tumor burden. Thus, disruption of CDCP1 perturbs pro-cancerous Wnt signaling including nuclear localization of ß-catenin and E-cadherin.

Efficacy of alemtuzumab over 6 years in relapsing-remitting multiple sclerosis patients who relapsed between courses 1 and 2: Post hoc analysis of the CARE-MS studies.

BACKGROUND: Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen. OBJECTIVE: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers). METHODS: Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension. RESULTS: Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%). CONCLUSION: Early relapsers' outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit. CLINICALTRIALS.GOV REGISTRATION NUMBERS: CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553.

Patient-derived Orthotopic Xenograft Models for Human Urothelial Cell Carcinoma and Colorectal Cancer Tumor Growth and Spontaneous Metastasis.

Cancer patients have poor prognoses when lymph node (LN) involvement is present in both high-grade urothelial cell carcinoma (HG-UCC) of the bladder and colorectal cancer (CRC). More than 50% of patients with muscle-invasive UCC, despite curative therapy for clinically-localized disease, will develop metastases and die within 5 years, and metastatic CRC is a leading cause of cancer-related deaths in the US. Xenograft models that consistently mimic UCC and CRC metastasis seen in patients are needed. This study aims to generate patient-derived orthotopic xenograft (PDOX) models of UCC and CRC for primary tumor growth and spontaneous metastases under the influence of LN stromal cells mimicking the progression of human metastatic diseases for drug screening. Fresh UCC and CRC tumors were obtained from consented patients undergoing resection for HG-UCC and colorectal adenocarcinoma, respectively. Co-inoculated with LN stromal cell (LNSC) analog HK cells, luciferase-tagged UCC cells were intra-vesically (IB) instilled into female non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, and CRC cells were intra-rectally (IR) injected into male NOD/SCID mice. Tumor growth and metastasis were monitored weekly using bioluminescence imaging (BLI). Upon sacrifice, primary tumors and mouse organs were harvested, weighed, and formalin-fixed for Hematoxylin and Eosin and immunohistochemistry staining. In our unique PDOX models, xenograft tumors resemble patient pre-implantation tumors. In the presence of HK cells, both models have high tumor implantation rates measured by BLI and tumor weights, 83.3% for UCC and 96.9% for CRC, and high distant organ metastasis rates (33.3% detected liver or lung metastasis for UCC and 53.1% for CRC). In addition, both models have zero mortality from the procedure. We have established unique, reproducible PDOX models for human HG-UCC and CRC, which allow for tumor formation, growth, and metastasis studies. With these models, testing of novel therapeutic drugs can be performed efficiently and in a clinically-mimetic manner.

Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis.

BACKGROUND: Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population. OBJECTIVE: Describe instances of autoimmune nephropathy in alemtuzumab-treated MS patients. METHODS: Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use. RESULTS: As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti-glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria. CONCLUSION: Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely.

The Role of Bowel Preparation in Colorectal Surgery: Results of the 2012-2015 ACS-NSQIP Data.

OBJECTIVE: To analyze potential benefits with regards to infectious complications with combined use of mechanical bowel preparation (MBP) and ABP in elective colorectal resections. BACKGROUND: Despite recent literature suggesting that MBP does not reduce infection rate, it still is commonly used. The use of oral antibiotic bowel preparation (ABP) has been practiced for decades but its use is also controversial. METHODS: Patients undergoing elective colorectal resection in the 2012 to 2015 American College of Surgeons National Surgical Quality Improvement Program cohorts were selected. Doubly robust propensity score-adjusted multivariable regression was conducted for infectious and other postoperative complications. RESULTS: A total of 27,804 subjects were analyzed; 5471 (23.46%) received no preparation, 7617 (32.67%) received MBP only, 1374 (5.89%) received ABP only, and 8855 (37.98%) received both preparations. Compared to patients receiving no preparation, those receiving dual preparation had less surgical site infection (SSI) [odds ratio (OR) = 0.39, P < 0.001], organ space infection (OR = 0.56, P ≤ 0.001), wound dehiscence (OR = 0.43, P = 0.001), and anastomotic leak (OR = 0.53, P < 0.001). ABP alone compared to no prep resulted in significantly lower rates of surgical site infection (OR = 0.63, P = 0.001), organ space infection (OR = 0.59, P = 0.005), anastomotic leak (OR = 0.53, P = 0.002). MBP showed no significant benefit to infectious complications when used as monotherapy. CONCLUSIONS: Combined MBP/ABP results in significantly lower rates of SSI, organ space infection, wound dehiscence, and anastomotic leak than no preparation and a lower rate of SSI than ABP alone. Combined bowel preparation significantly reduces the rates of infectious complications in colon and rectal procedures without increased risk of Clostridium difficile infection. For patients undergoing elective colon or rectal resection we recommend bowel preparation with both mechanical agents and oral antibiotics whenever feasible.

Disease-free Survival and Local Recurrence for Laparoscopic Resection Compared With Open Resection of Stage II to III Rectal Cancer: Follow-up Results of the ACOSOG Z6051 Randomized Controlled Trial.

OBJECTIVE: To determine the disease-free survival (DFS) and recurrence after the treatment of patients with rectal cancer with open (OPEN) or laparoscopic (LAP) resection. BACKGROUND: This randomized clinical trial (ACOSOG [Alliance] Z6051), performed between 2008 and 2013, compared LAP and OPEN resection of stage II/III rectal cancer, within 12 cm of the anal verge (T1-3, N0-2, M0) in patients who received neoadjuvant chemoradiotherapy. The rectum and mesorectum were resected using open instruments for rectal dissection (included hybrid hand-assisted laparoscopic) or with laparoscopic instruments under pneumoperitoneum. The 2-year DFS and recurrence were secondary endpoints of Z6051. METHODS: The DFS and recurrence were not powered, and are being assessed for superiority. Recurrence was determined at 3, 6, 9, 12, and every 6 months thereafter, using carcinoembryonic antigen, physical examination, computed tomography, and colonoscopy. In all, 486 patients were randomized to LAP (243) or OPEN (243), with 462 eligible for analysis (LAP = 240 and OPEN = 222). Median follow-up is 47.9 months. RESULTS: The 2-year DFS was LAP 79.5% (95% confidence interval [CI] 74.4-84.9) and OPEN 83.2% (95% CI 78.3-88.3). Local and regional recurrence was 4.6% LAP and 4.5% OPEN. Distant recurrence was 14.6% LAP and 16.7% OPEN.Disease-free survival was impacted by unsuccessful resection (hazard ratio [HR] 1.87, 95% CI 1.21-2.91): composite of incomplete specimen (HR 1.65, 95% CI 0.85-3.18); positive circumferential resection margins (HR 2.31, 95% CI 1.40-3.79); positive distal margin (HR 2.53, 95% CI 1.30-3.77). CONCLUSION: Laparoscopic assisted resection of rectal cancer was not found to be significantly different to OPEN resection of rectal cancer based on the outcomes of DFS and recurrence.

Infection risk with alemtuzumab decreases over time: pooled analysis of 6-year data from the CAMMS223, CARE-MS I, and CARE-MS II studies and the CAMMS03409 extension study.

BACKGROUND: Reduced MS disease activity with alemtuzumab versus subcutaneous interferon beta-1a (SC IFNB-1a) in core phase 2/3 studies was accompanied by increased incidence of infections that were mainly nonserious and responsive to treatment. Alemtuzumab efficacy was durable over 6 years. OBJECTIVE: To evaluate infections over 6 years in alemtuzumab-treated patients. METHODS: Three randomized trials (CAMMS223, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I, and CARE-MS II) compared two courses of alemtuzumab 12 mg with SC IFNB-1a 44 µg in patients with active relapsing-remitting MS. An extension study (CAMMS03409) provided further evaluation and as-needed alemtuzumab retreatment. RESULTS: Infections occurred more frequently with alemtuzumab 12 mg than SC IFNB-1a during Years 1 (58.7% vs 41.3%) and 2 (52.6% vs 37.7%), but declined for alemtuzumab-treated patients in Years 3 (46.6%), 4 (42.8%), 5 (40.9%), and 6 (38.1%). Serious infections were uncommon (1.0%-1.9% per year). Infections were predominantly (>95%) mild to moderate and included upper respiratory tract infections, urinary tract infections, and mucocutaneous herpetic infections. Prophylactic acyclovir reduced herpetic infections. Lymphocyte counts after alemtuzumab therapy did not predict infection risk. CONCLUSION: Infections with alemtuzumab were mostly mild to moderate and decreased over time, consistent with preservation of components of protective immunity.

Impact of a Novel Surgical Wound Protection Device on Observed versus Expected Surgical Site Infection Rates after Colectomy Using the National Surgical Quality Improvement Program Risk Calculator.

BACKGROUND: Surgical site infection (SSI) remains a persistent and morbid problem in colorectal surgery. A novel surgical device that combines barrier surgical wound protection and continuous surgical wound irrigation was evaluated in a cohort of elective colorectal surgery patients. A retrospective analysis was performed comparing rates of SSI observed in a prospective cohort study with the predicted rate of SSI using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) Risk Calculator. PATIENTS AND METHODS: A prospective multi-center study of colectomy patients was conducted using a study device for surgical site retraction and protection, as well as irrigation of the incision. Patients were followed for 30 days after the surgical procedure to assess for SSI. After completion of the study, patients' characteristics were inserted into the ACS-NSQIP Risk Calculator to determine the predicted rate of SSI for the given patient population and compared with the observed rate in the study. RESULTS: A total of 108 subjects were enrolled in the study. The observed rate of SSI in the prospective study using the novel device was 3.7% (4/108). The predicted rate of SSI in the same patient population utilizing the ACS-NSQIP Risk Calculator was estimated to be 9.5%. This demonstrated a 61% difference (3.7% vs. 9.5%, p = 0.04) in SSI from the NSQIP predicted rate with the use of the irrigating surgical wound protection and retraction device. CONCLUSIONS: These data suggest the use of a novel surgical wound protection device seems to reduce the rate of SSIs in colorectal surgery.

Clopidogrel bisulfate (Plavix) does not increase bleeding complications in patients undergoing rubber band ligation for symptomatic hemorrhoids.

BACKGROUND: The incidence of postprocedural bleeding in patients undergoing rubber band ligation (RBL) for symptomatic internal hemorrhoids while taking clopidogrel bisulfate is unknown. To determine the postprocedural bleeding risk of RBL for patients taking clopidogrel compared with age- and sex-matched controls. MATERIALS AND METHODS: This is a retrospective case-controlled cohort study analyzing data from 2005 to 2013 conducted at a single tertiary care academic center. The study included a total of 80 rubber bands placed on 41 patients taking clopidogrel bisulfate and 72 bands placed on 41 control patients not taking clopidogrel matched for age and sex. The 30-d rates of significant and insignificant bleeding events after RBL were recorded. A bleeding event was considered significant if the patient required admission to the hospital, transfusion of blood products, or additional procedures to stop the bleeding. Insignificant bleeding was defined as passage of blood or clots per rectum with spontaneous cessation and no need for additional intervention. RESULTS: There was no significant difference in the number of bleeding events per band placed in the clopidogrel group when compared with the control group (3.75% versus 2.78%, P = 0.7387). The rate of significant (2.5% versus 1.39%, P = 0.6244) and insignificant bleeding events (1.25% versus 1.39%, P = 0.9399) was also similar between the two groups. Two significant bleeding events occurred in the clopidogrel group requiring intervention: cauterization in one patient and colonoscopy and transfusion in the other. CONCLUSIONS: The risk of a bleeding complication after RBL for hemorrhoids does not appear to be increased in patients taking clopidogrel. Our results support the practice of continuing clopidogrel bisulfate in the periprocedural period as the associated risk of thrombosis is greater than the risk of bleeding.