Utility of a Third Heplisav-B Dose in Patients With Inflammatory Bowel Disease Without Immunity After 2-Dose Heplisav-B Vaccination.

INTRODUCTION: Hepatitis B virus (HBV) vaccination is recommended in patients with inflammatory bowel disease (IBD). Although the 2-dose Heplisav-B vaccine has proven effective, more than 20% of patients with IBD do not seroconvert. We prospectively evaluated the effectiveness of a third Heplisav-B dose in patients with IBD lacking HBV immunity despite 2-dose vaccination. METHODS: Adults with IBD who had received 2-dose Heplisav-B vaccination between 2018 and 2023 were identified. Seroconversion was defined as hepatitis B surface antibody (HBsAb) ≥ 10 IU/L measured at ≥4 weeks after vaccination. Patients who did not seroconvert were prospectively offered a third Heplisav-B dose, followed by repeat HBsAb measurement. Demographic, clinical, medication, and vaccination data were compared between those who did and did not seroconvert. RESULTS: Of 192 patients identified, 71.9% (138/192) seroconverted after 2-dose Heplisav-B vaccination. The 54 patients (28.1%) who did not seroconvert were more likely to be male, have diabetes, chronic kidney disease, or elevated Charlson Comorbidity Index. Of the 54 patients, 30 (55.6%) elected to receive a third Heplisav-B dose, with 56.7% (17/30) achieving seroconversion (median HBsAb titer 376 IU/L, IQR 47-1,000 IU/L) despite a median intervaccination time of 416 days (IQR 90.8-667.8). No differences were noted between patients who did vs did not seroconvert after third-dose vaccination. DISCUSSION: In patients with IBD lacking HBV immunity despite 2-dose Heplisav-B vaccination, administration of a third dose resulted in a 56.7% seroconversion rate. Our results suggest that administration of an additional Heplisav-B dose may be an effective strategy in patients lacking immunity despite primary 2-dose vaccination.

Electronic Health Record Burden Among Gastroenterology Providers Associated With Subspecialty and Training.

INTRODUCTION: Use of the electronic health record (EHR) has become increasingly widespread. Higher EHR burden is associated with burnout, but this has not been specifically investigated among gastroenterology (GI) providers. METHODS: We retrospectively collected measures of EHR use for outpatient GI providers during a 6-month period. We compared metrics across provider sex, subspecialty, and training (physicians vs nonphysician providers [NPPs]). RESULTS: Data collected represented more than 16,000 appointments from 41 providers across the Division of Gastroenterology and Hepatology. Inflammatory bowel disease (IBD) and hepatology specialists spent more time per appointment in the EHR, clinical review, and outside regular hours compared with other subspecialists. NPPs spent more EHR time than physicians. DISCUSSION: IBD and hepatology specialists and NPPs may have disproportionally high EHR burden. More work is needed to understand differences in provider workload to combat burnout.

Tofacitinib for Biologic-Experienced Hospitalized Patients With Acute Severe Ulcerative Colitis: A Retrospective Case-Control Study.

BACKGROUND & AIMS: Despite rescue therapy, more than 30% of patients with acute severe ulcerative colitis (ASUC) require colectomy. Tofacitinib is a rapidly acting Janus kinase inhibitor with proven efficacy in ulcerative colitis. Tofacitinib may provide additional means for preventing colectomy in patients with ASUC. METHODS: A retrospective case-control study was performed evaluating the efficacy of tofacitinib induction in biologic-experienced patients admitted with ASUC requiring intravenous corticosteroids. Tofacitinib patients were matched 1:3 to controls according to gender and date of admission. Using Cox regression adjusted for disease severity, we estimated the 90-day risk of colectomy. Rates of complications and steroid dependence were examined as secondary outcomes. RESULTS: Forty patients who received tofacitinib were matched 1:3 to controls (n = 113). Tofacitinib was protective against colectomy at 90 days compared with matched controls (hazard ratio [HR], 0.28, 95% confidence interval [CI], 0.10-0.81; P = .018). When stratifying according to treatment dose, 10 mg three times daily (HR, 0.11; 95% CI, 0.02-0.56; P = .008) was protective, whereas 10 mg twice daily was not significantly protective (HR, 0.66; 95% CI, 0.21-2.09; P = .5). Rate of complications and steroid dependence were similar between tofacitinib and controls. CONCLUSIONS: Tofacitinib with concomitant intravenous corticosteroids may be an effective induction strategy in biologic-experienced patients hospitalized with ASUC. Prospective trials are needed to identify the safety, optimal dose, frequency, and duration of tofacitinib for ASUC.

Efficacy of Induction Therapy With High-Intensity Tofacitinib in 4 Patients With Acute Severe Ulcerative Colitis.

As many as 25% of patients diagnosed with ulcerative colitis are hospitalized with an episode of acute severe ulcerative colitis (ASUC).1 The standard of care for patients hospitalized with ASUC relies on rapid induction with intravenous (IV) corticosteroids. Up to 30% of patients do not respond to corticosteroids alone.2 Rescue therapy with infliximab or cyclosporine has been shown to reduce rates of colectomy to 20% by 90 days.3,4 This still represents a significant rate of treatment failure, which leads to an unplanned and irreversible surgery. In recent years, increasing numbers of patients admitted with ASUC have already failed infliximab therapy, highlighting the need for additional treatment options for these patients. Tofacitinib is a rapidly acting, oral, small-molecule Janus kinase inhibitor that was recently approved by the Food and Drug Administration for treatment of ulcerative colitis.5 We present the first reported use of off-label, high-intensity tofacitinib in 4 patients admitted to our institution with ASUC predicted to fail medical management.

Radiofrequency Ablation with an Enhanced-Irrigation Flexible-Tip Catheter versus a Standard-Irrigation Rigid-Tip Catheter.

BACKGROUND: The flexible-tip irrigated ablation catheter Cool Flex™ (St. Jude Medical, St. Paul, MN, USA) was introduced to enhance cooling of the catheter-tissue interface and to conform to endocardial surface with better contact. Little is known about the performance of such catheter design compared to the widely used rigid-tip catheters. METHODS: In a thigh muscle preparation, ablation using the flexible-tip and rigid-tip catheters was performed in seven pigs across a range of ablation settings and catheter orientation. Postprocedure, the thigh muscle was stained with 2,3,5-triphenyltetrazolium-chloride injected into the femoral artery. The muscle was excised, fixed with formalin, and examined grossly. RESULTS: A total of 196 lesions (95 flexible tip, 101 rigid tip) were evaluated. The flexible-tip catheter was associated with enhanced cooling of catheter-tissue interface (31.1 ± 3.3°C vs 36.3 ± 3.7°C, P = 0.0001) in both perpendicular and nonperpendicular catheter orientations. This allowed more energy delivery (37.3 ± 8.9 W vs 33.7 ± 8.1 W, P = 0.004) to targeted tissue and resulted in larger lesions (median 194.7 [interquartile range: 113.1-333.8] mm(3) vs 170.9 [88.7-261.6] mm(3) , P = 0.03) than the rigid-tip catheter with larger maximum diameter (11.1 ± 2.6 mm vs 10.3 ± 2.1 mm, P = 0.03) and larger diameter at tissue surface (10.3 ± 2.4 mm vs 9.6 ± 1.7 mm, P = 0.01). Catheter orientation during ablation affected the efficiency of rigid-tip but not the flexible-tip catheter. The use of the flexible-tip catheter was associated with significantly less char formation on tissue (none vs 5.1% with rigid tip, P = 0.009). CONCLUSION: The Cool Flex™ catheter performed better than a rigid-tip catheter with enhanced cooling, larger ablation lesions, and no charring of targeted tissue.

Metformin Is Associated With Improved Inflammatory Bowel Disease Outcomes in Patients With Type 2 Diabetes Mellitus: A Propensity-Matched Cohort Study.

BACKGROUND: Metformin exerts anti-inflammatory properties through a positive effect on oxidative stress, gut barrier integrity, and the gut microbiota. Our aim was to evaluate the influence of metformin on inflammatory bowel disease (IBD) outcomes in patients with type 2 diabetes mellitus (T2DM). METHODS: We conducted a retrospective cohort study using the TriNetX database in patients with IBD and T2DM who initiated metformin vs oral hypoglycemics or insulin (control cohort) between August 31, 2002, and August 31, 2022. One-to-one propensity score matching was performed. Primary outcomes were need for intravenous (IV) steroid use or IBD-related surgery within 1, 2, and 3 years after metformin initiation. RESULTS: Our cohorts included 1323 patients with ulcerative colitis (UC) (mean age 58.7 ±â€…12.2 years, 50.1% female, 77.3% White) and 1278 patients with Crohn's disease (CD) (mean age 56.3 ±â€…12.6 years, 58.2% female, 76.5% White). At 1 year, patients with UC and CD were less likely to require IV steroids (UC: adjusted odds ratio [aOR], 0.45; 95% confidence interval [CI], 0.34-0.59; P < .01; CD: aOR, 0.67; 95% CI, 0.53-0.85; P < .01). The decreased need for IV steroids persisted in all metformin groups at 2 and 3 years. Patients with CD were at a lower risk for IBD-related surgery at year 1 (aOR, 0.5; 95% CI, 0.31-0.81; P < .01), and this finding persisted at 3 years (aOR, 0.62; 95% CI, 0.43-0.89; P < .01). Metformin did not affect risk for surgery in patients with UC. CONCLUSIONS: Patients with IBD and T2DM on metformin had a decreased likelihood of worse IBD outcomes.

Our study shows that metformin is associated with decreased risk of corticosteroids in patients with ulcerative colitis and Crohn's disease and decreased risk of surgery in patients with Crohn's disease.

Inflammation is an independent risk factor for colonic neoplasia in patients with ulcerative colitis: a case-control study.

BACKGROUND & AIMS: An association between inflammatory activity and colorectal neoplasia (CRN) has been documented in patients with ulcerative colitis (UC). However, previous studies did not address the duration of inflammation or the effects of therapy on risk for CRN. We investigated the effects of inflammation, therapies, and characteristics of patients with UC on their risk for CRN. METHODS: We collected data from 141 patients with UC without CRN (controls) and 59 matched patients with UC who developed CRN (cases), comparing disease extent and duration and patients' ages. We used a new 6-point histologic inflammatory activity (HIA) scale to score biopsy fragments (n = 4449). Information on medications, smoking status, primary sclerosing cholangitis, and family history of CRN were collected from the University of Chicago Inflammatory Bowel Disease Endoscopy Database. Relationships between HIA, clinical features, and CRN were assessed by conditional logistic regression. RESULTS: Cases and controls were similar in numbers of procedures and biopsies, exposure to steroids or mesalamine, smoking status, and family history of CRN. They differed in proportion of men vs women, exposure to immune modulators, and primary sclerosing cholangitis prevalence. In univariate analysis, HIA was positively associated with CRN (odds ratio [OR], 2.56 per unit increase; P = .001), whereas immune modulators (including azathioprine, 6-mercaptopurine, and methotrexate) reduced the risk for CRN (OR, 0.35; P < .01). HIA was also associated with CRN in multivariate analysis (OR, 3.68; P = .001). CONCLUSIONS: In a case-control study, we associated increased inflammation with CRN in patients with UC. Use of immune modulators reduced the risk for CRN, indicating that these drugs have chemoprotective effects. On the basis of these data, we propose new stratified surveillance and treatment strategies to prevent and detect CRN in patients with UC.

Clostridium difficile Infection in Patients with Ulcerative Colitis Treated with Tofacitinib in the Ulcerative Colitis Program.

BACKGROUND: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Patients with inflammatory bowel disease are susceptible to Clostridium difficile infection (CDI). Here, we evaluate CDI in the tofacitinib UC clinical program. METHODS: Events from 4 randomized, placebo-controlled studies (phase [P] 2 or P3 induction [NCT00787202; NCT01465763; NCT01458951], P3 maintenance [NCT01458574]) and an open-label, long-term extension (OLE) study (NCT01470612), were analyzed as 3 cohorts: Induction (P2/P3 induction), Maintenance (P3 maintenance), and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, and OLE studies; including final data from the OLE study, as of August 24, 2020). Proportions and incidence rates (unique patients with events per 100 patient-years of exposure) of CDI were evaluated. RESULTS: The overall cohort comprised 1157 patients who received ≥1 dose of tofacitinib 5 or 10 mg BID, with a total of 2814.4 patient-years of tofacitinib exposure and up to 7.8 years of treatment. A total of 82.6% of patients received predominantly tofacitinib 10 mg BID. In the induction, maintenance, and overall cohorts, 3 (2 tofacitinib treated, 1 placebo treated), 3 (all placebo treated), and 9 patients had CDI, respectively; the overall cohort incidence rate was 0.31 (95% confidence interval, 0.14-0.59). CDI were all mild-moderate in severity and resolved with treatment in 8 patients. Six of 9 patients continued tofacitinib treatment without interruption. Two patients had events reported as serious due to hospitalization. Two patients were receiving corticosteroids when the CDI occurred. CONCLUSION: CDIs among patients with UC receiving tofacitinib were infrequent, cases were mild-moderate in severity, and most resolved with treatment.

The incidence of Clostridium difficile infection in the tofacitinib ulcerative colitis clinical program was evaluated. C. difficile infection among patients with ulcerative colitis receiving tofacitinib were infrequent; cases were mild­moderate in severity, and most resolved with treatment.

Association of C-reactive Protein and Partial Mayo Score With Response to Tofacitinib Induction Therapy: Results From the Ulcerative Colitis Clinical Program.

BACKGROUND: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). These post hoc analyses assessed associations between C-reactive protein (CRP), partial Mayo score (PMS), and efficacy outcomes during tofacitinib induction in UC. METHODS: Patients received tofacitinib 10 mg twice daily (BID) in an 8-week, phase 2 induction study and 2 identical, 8-week, phase 3 induction studies (OCTAVE Induction 1&2); induction nonresponders (IndNR) received an additional 8 weeks of tofacitinib 10 mg BID in an open-label, long-term extension study. Associations between CRP and PMS, and efficacy outcomes (clinical response, clinical remission, endoscopic improvement, and endoscopic remission) were analyzed using univariate and multivariable logistic regression and receiver operating characteristic curves. RESULTS: Changes from baseline in the logarithm of CRP ([log]CRP) and PMS at week 4 were associated with clinical response at week 8 (univariate: per unit, odds ratio [OR], 0.55 [95% confidence interval (CI), 0.48-0.62]; and 0.42 [0.37-0.47], respectively). Among IndNR, change from baseline in PMS at week 8 was associated with clinical response at week 16 (univariate: per unit, OR, 0.59; 95% CI, 0.46-0.75). C-reactive protein at week 4 (area under the curve [AUC] > 0.6) and PMS at weeks 2 and 4 (AUC, > 0.7) generally exhibited predictive value for week 8 efficacy outcomes. CONCLUSIONS: Patients who achieved clinical response at week 8 had larger decreases in CRP and PMS at week 4 than patients who did not. IndNR who achieved clinical response at week 16 with extended tofacitinib induction had a larger decrease in PMS at week 8 vs those who did not. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01470612.

Early decreases in partial Mayo score and C-reactive protein were found to be associated with achieving efficacy outcomes following tofacitinib 10 mg twice daily induction therapy in the ulcerative colitis clinical program.

Resuscitating the Socratic Method: Student and Faculty Perspectives on Posing Probing Questions During Clinical Teaching.

PURPOSE: Teaching by way of asking questions is a time-honored practice that has taken on the negative connotation of "pimping" among medical students and has made some faculty hesitant to ask students questions during clerkship rotations. Yet, quantitative studies exploring student perspectives on this practice are limited. This study aimed to solicit student and faculty views and investigate faculty perceptions of students' preferences. METHOD: Students who completed their internal medicine clerkship during the 2017-2018 academic year (n = 165) and were from the 2020 graduating class and their supervising faculty (n = 144) at the University of Michigan Medical School were asked to complete a Likert response survey in April 2019. The survey solicited perspectives on questions probing medical knowledge posed to students by faculty. Surveys were constructed using an iterative process, and data were analyzed using t tests and linear regressions. RESULTS: A total of 140 (85%) students and 112 (78%) faculty participated. Of those, 125 (89%) students and 109 (97%) faculty agreed that probing questions are valuable for student education, but only 73 (65%) faculty perceived that students agreed with this statement (P < .001). In addition, 115 (82%) students preferred to be asked too many questions than none at all. Fifty-five (39%) students agreed that they feel humiliated when they answer a question incorrectly. However, only 7 (5%) students agreed that faculty ask questions to humiliate them, and only 20 (14%) preferred that faculty stop asking questions if they answer a question incorrectly. CONCLUSIONS: Students valued probing questions more than faculty perceived, which argues against a withdrawal from the Socratic teaching method in the clinical arena. The students' experience of humiliation when answering incorrectly requires further study and perhaps can be tempered by more explicit framing of the role of the questioning process.

Quantifying Clinical Opportunities at the Navy Trauma Training Center.

INTRODUCTION: Military-Civilian partnerships (MCPs), such as the Navy Trauma Training Center, are an essential tool for training military trauma care providers. Despite Congressional and military leadership support, sparse data exist to quantify participants' clinical opportunities in MCPs. These preliminary data from an ongoing Navy Trauma Training Center outcomes study quantify clinical experiences and compare skill observation to skill performance. MATERIALS AND METHODS: Participants completed clinical logs after each patient encounter to quantify both patients and procedures they were involved with during clinical rotations; they self-reported demographic data. Data analyses included descriptive statistics and chi-square statistics to compare skills observed to skills performed between the first and second half of the 21-day course. RESULTS: A sample of 47 Navy personnel (30 corpsmen, 10 nurses, 3 physician assistants, 4 physicians) completed 551 clinical logs. Most logs (453/551) reflected experiences in the emergency department, where corpsmen and nurses each spent 102.0 hours, and physician assistants and physicians each spent 105.4 hours. Logs completed per participant ranged from 1 to 31, (mean = 8). No professional group was more likely than others to complete the clinical logs. Completion rates varied by cohort, both overall and by clinical role. Of emergency department logs, 39% reflected highest acuity patients, compared with 21% of intensive care unit logs, and 61% of operating room logs. Penetrating trauma was reported on 16.5% of logs. Primary and secondary trauma assessments were the most commonly reported clinical opportunities, followed by obtaining intravenous access and administration of analgesic medications. With few exceptions, logs reflected skill observation versus skill performance, a ratio that did not change over time. CONCLUSION: Prospective real-time data of actual clinical activity is a crucial measure of the success of MCPs. These preliminary data provide a beginning perspective on how these experiences contribute to maintaining a skilled military medical force.

Preliminary Data on Trauma Knowledge, Confidence, and Stress During Navy Trauma Training.

INTRODUCTION: The Navy Trauma Training Center (NTTC) is a military-civilian partnership that provides advanced trauma training for application across the range of military operations while exposing military medical personnel to high-volume and high-acuity trauma. Few published data evaluate the outcomes of military-civilian partnerships, including NTTC. The purpose of this study is to evaluate the knowledge, confidence, and stress of NTTC participants before, at mid-point, and after completion of the program. Participants include corpsmen (HM), nurses (RNs), physician assistants (PAs), and physicians (MDs). MATERIALS AND METHODS: These are preliminary data from an ongoing prospective, observational study with repeated measures. Included are participants that complete NTTC training. Pre-training measures include a demographic questionnaire, trauma knowledge test, Confidence survey, and the Perceived Stress Scale. These same instruments are completed at mid-training and at the conclusion of the NTTC curriculum. Data were analyzed using paired t-tests and linear mixed models. RESULTS: The sample was composed of 83 participants (49 HM, 18 RNs, 4 PAs, and 12 MDs. Knowledge and confidence increased from baseline to post-NTTC for each clinical role (P < .05). Stress for all roles was low and stable over time (P > .05). CONCLUSIONS: These preliminary data suggest that, as expected, trauma-related knowledge and confidence increase significantly with training at NTTC. Stress was low and stable over time. These data from a small sample of participants indicate NTTC training is increasing participants' trauma knowledge and confidence to care for trauma casualties. Continued collection of data in the ongoing study will allow us to determine whether these early findings persist in the overall study sample and may help inform the optimal length of training needed.

The peri-appendiceal red patch in ulcerative colitis: review of the University of Chicago experience.

BACKGROUND: Previous case series have described patients with a limited extent of ulcerative colitis (UC) and an area in the cecum with focal activity surrounding the appendiceal orifice ["peri-appendiceal red patch" (PARP)]. The clinical significance and prognostic implications of this finding are unknown. We used a tertiary care center database to review the clinical characteristics of UC patients with PARP. METHODS: Patients with a clinical diagnosis of UC, less than pancolitis, and in whom a PARP was described were identified and clinical characteristics were reviewed at the University of Chicago. RESULTS: Of the 622 UC patients, 367 did not have pancolitis. Twenty-nine (7.9%) patients had endoscopically described PARP. Of the 29 patients, 23 (79%) were male, eight had a history of smoking, and none had prior appendectomy. Twenty of 30 (67%) exams that obtained biopsies showed that the histologic activity in the PARP paralleled the activity of the distal colitis. Of the patients, 24 of 29 had a median of 8 years follow-up (range 2-16 years), and these patients had a disease duration of median 12 years (range 0.08-22 years). Eleven of 21 patients with endoscopic follow-up had progression of the extent of disease. CONCLUSIONS: We have confirmed the association of peri-appendiceal inflammation in a subset of patients with the otherwise clinical features of UC. The lack of appendectomy, male preponderance, and parallel histologic activity to the distal colitis are important observations that warrant further investigation into the potential relationship of PARP and UC.

An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase.

Autoregulatory domains found within kinases may provide more unique targets for chemical inhibitors than the conserved ATP-binding pocket targeted by most inhibitors. The kinase Pak1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. Pak1 activators relieve this autoinhibition and initiate conformational rearrangements and autophosphorylation events leading to kinase activation. We developed a screen for allosteric inhibitors targeting Pak1 activation and identified the inhibitor IPA-3. Remarkably, preactivated Pak1 is resistant to IPA-3. IPA-3 also inhibits activation of related Pak isoforms regulated by autoinhibition, but not more distantly related Paks, nor >200 other kinases tested. Pak1 inhibition by IPA-3 in live cells supports a critical role for Pak in PDGF-stimulated Erk activation. These studies illustrate an alternative strategy for kinase inhibition and introduce a highly selective, cell-permeable chemical inhibitor of Pak.

Nuances of the psychogastroenterology patient: A predictive model for gastrointestinal quality of life improvement.

BACKGROUND: Gastrointestinal conditions are multifactorial in nature, and certain patients can benefit greatly from brain-gut psychotherapies delivered by mental health professionals who specialize in psychogastroenterology. This study aimed to identify features associated with improvements in GI-specific quality of life scores following behavioral health interventions (BHI). The second aim was to create a psychogastroenterology referral care pathway incorporating identified characteristics for greatest benefit from GI-specific behavioral therapy. METHODS: We performed a prospective observational study of 101 (63 women; median age, 45 years) gastroenterology patients referred for psychogastroenterology consultation at a single center. Patients attended an average of seven sessions with a single GI psychologist where evidence-based brain-gut psychotherapies were employed. GI-specific quality of life (IBS-QOL) and psychological distress (BSI-18) were assessed before and after BHI. Patients completed self-reported questionnaires. We performed a multivariable analysis to determine predictors associated with IBS-QOL score improvement. KEY RESULTS: A total of 53 (52.5%) patients experienced improvement in IBS-QOL score. Patients with improved IBS-QOL scores had significantly higher baseline BSI general domain T-scores (61.9 vs. 56.9, P = 0.002). Female gender (odds ratio [OR], 3.2), pretreatment BSI somatization T-score ≥63 (OR, 3.7), and a diagnosis of depression (OR, 4.2) were associated with greater odds of IBS-QOL score improvement following BHI. CONCLUSIONS AND INFERENCES: We identified factors associated with response to GI-specific BHI to aid in optimizing the utilization of psychogastroenterology services and provide referring providers with information to inform treatment recommendations. Female patients with disorders of gut-brain interaction (DGBIs), high somatization, and depression should be considered a priority for brain-gut psychotherapies.

Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer.

PURPOSE: This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP). PATIENTS AND METHODS: Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2. RESULTS: World Health Organization (WHO)-modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively. CONCLUSION: This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.

Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status.

The rest/activity circadian cycle has been used as a reference for chemotherapy administration at specific times to improve tolerability and efficacy. Because cancer processes may be associated with alterations of circadian rhythms, the rest/activity cycle was monitored noninvasively to assess its relationship with tumor response, survival, and quality of life in 200 patients with metastatic colorectal cancer. Patients wore an actigraph, a wristwatch that records the number of accelerations per minute, for 3 days before receiving chronomodulated chemotherapy. The circadian rhythms in activity were estimated by two robust parameters: the autocorrelation coefficient at 24 h (r24), and the dichotomy index (I

Mechanism of action for the cytotoxic effects of the nitric oxide prodrug JS-K in murine erythroleukemia cells.

The nitric oxide (NO) prodrug JS-K, a promising anti-cancer agent, consists of a diazeniumdiolate group necessary for the release of NO as well as an arylating ring. In this study, we research the mechanism by which JS-K kills a murine erythroleukemia cell line and determine the roles of NO and arylation in the process. Our studies indicate that JS-K inhibits the PI 3-kinase/Akt and MAP kinase pathways. This correlates with the activation of the tumor suppressor FoxO3a and increased expression of various caspases, leading to apoptosis. The arylating capability of JS-K appears to be sufficient for inducing these biological effects. Overall, these data suggest that JS-K kills tumor cells by arylating and inactivating signaling molecules that block the activation of a tumor suppressor.