Efficacy of Ustekinumab and Vedolizumab Among Postoperative Crohn's Disease Patients as Postoperative Prophylaxis and Rescue Therapy: Real-world Data.

BACKGROUND: Almost half of patients with Crohn's disease (CD) require bowel surgeries in their lifetime. Due to the high risk of postoperative disease recurrence and high rate of previous antitumor necrosis factor (anti-TNF) failure, often alternative therapy options such as ustekinumab (UST) and vedolizumab (VDZ) are used. We aimed to evaluate the efficacy of UST and VDZ among postoperative CD patients as postoperative prophylaxis and rescue therapy. METHODS: Consented CD patients who underwent initial ileocecal resection and were treated with UST and VDZ were included in this study. Demographics, clinical characteristics, health care utilization, endoscopy scores, and surgery outcomes were collected. Postoperative early CD recurrence was defined as a Rutgeerts endoscopic score ≥i2 within the first 2 years. The rescue therapy group was defined as patients who received either UST or VDZ after having Rutgeerts endoscopic score ≥i2 postoperatively. RESULTS: During 2009 to 2019, 98 CD patients were treated with UST or VDZ postoperatively. Postoperative early recurrence rates were 5% (n = 1 out of 20) and 6% (1 out of 15) for the UST and VDZ groups, respectively. Two patients from the UST group and 1 patient from the VDZ group required bowel surgery during follow-up with median drug exposure of 51 (95% confidence interval [CI], 29-61) and 30 (95% CI, 14-63) months, respectively; 55% and 69% of patients had at least 1 point of improvement on postoperative endoscopic Rutgeerts score, respectively, for UST and VDZ. Only 3 out of 40 and 1 out of 23 patients required bowel surgery during follow-up while receiving UST and VDZ as rescue therapy. CONCLUSIONS: Both UST and VDZ were effective as postoperative therapies either as prophylaxis or rescue therapy.

This retrospective 11-year data examines the efficacy of ustekinumab and vedolizumab among postoperative Crohn's disease patients. When utilizing postoperative Rutgeerts score, this study confirms that both ustekinumab and vedolizumab were effective as postoperative therapies either as prophylaxis or rescue therapy.

iGenSig-Rx: an integral genomic signature based white-box tool for modeling cancer therapeutic responses using multi-omics data.

Multi-omics sequencing is poised to revolutionize clinical care in the coming decade. However, there is a lack of effective and interpretable genome-wide modeling methods for the rational selection of patients for personalized interventions. To address this, we present iGenSig-Rx, an integral genomic signature-based approach, as a transparent tool for modeling therapeutic response using clinical trial datasets. This method adeptly addresses challenges related to cross-dataset modeling by capitalizing on high-dimensional redundant genomic features, analogous to reinforcing building pillars with redundant steel rods. Moreover, it integrates adaptive penalization of feature redundancy on a per-sample basis to prevent score flattening and mitigate overfitting. We then developed a purpose-built R package to implement this method for modeling clinical trial datasets. When applied to genomic datasets for HER2 targeted therapies, iGenSig-Rx model demonstrates consistent and reliable predictive power across four independent clinical trials. More importantly, the iGenSig-Rx model offers the level of transparency much needed for clinical application, allowing for clear explanations as to how the predictions are produced, how the features contribute to the prediction, and what are the key underlying pathways. We anticipate that iGenSig-Rx, as an interpretable class of multi-omics modeling methods, will find broad applications in big-data based precision oncology. The R package is available: https://github.com/wangxlab/iGenSig-Rx .

Absolute Configuration of 4-Chloroisoleucine in Cyclolithistide A: An Antifungal Peptide Lactone Discovered in Marine Lithistid Sponges.

Cyclolithistide A is a peptide lactone isolated from marine lithistid sponges. Its entire structure, including absolute configurations, has been reported except the relative and absolute configurations of its characteristic residue, 4-chloroisoleucine (4-CIle). We synthesized four isomers of 4-CIle from furfural-derived N-Boc imine and propionaldehyde. Analysis of the acid hydrolysate of cyclolithistide A and the synthetic samples of 4-CIle after derivatization with l- and d-FDAA permitted us to propose the absolute configuration of the 4-chloroisoleucine residue in cyclolithistide A as 2S,3R,4R.

Tumor Intrinsic Subtypes and Gene Expression Signatures in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Pooled Analysis of CALGB 40601, NeoALTTO, and NSABP B-41 Trials.

Importance: Biologic features may affect pathologic complete response (pCR) and event-free survival (EFS) after neoadjuvant chemotherapy plus ERBB2/HER2 blockade in ERBB2/HER2-positive early breast cancer (EBC). Objective: To define the quantitative association between pCR and EFS by intrinsic subtype and by other gene expression signatures in a pooled analysis of 3 phase 3 trials: CALGB 40601, NeoALTTO, and NSABP B-41. Design, Setting, and Participants: In this retrospective pooled analysis, 1289 patients with EBC received chemotherapy plus either trastuzumab, lapatinib, or the combination, with a combined median follow-up of 5.5 years. Gene expression profiling by RNA sequencing was obtained from 758 samples, and intrinsic subtypes and 618 gene expression signatures were calculated. Data analyses were performed from June 1, 2020, to January 1, 2023. Main Outcomes and Measures: The association of clinical variables and gene expression biomarkers with pCR and EFS were studied by logistic regression and Cox analyses. Results: In the pooled analysis, of 758 women, median age was 49 years, 12% were Asian, 6% Black, and 75% were White. Overall, pCR results were associated with EFS in the ERBB2-enriched (hazard ratio [HR], 0.45; 95% CI, 0.29-0.70; P < .001) and basal-like (HR, 0.19; 95% CI, 0.04-0.86; P = .03) subtypes but not in luminal A or B tumors. Dual trastuzumab plus lapatinib blockade over trastuzumab alone had a trend toward EFS benefit in the intention-to-treat population; however, in the ERBB2-enriched subtype there was a significant and independent EFS benefit of trastuzumab plus lapatinib vs trastuzumab alone (HR, 0.47; 95% CI, 0.27-0.83; P = .009). Overall, 275 of 618 gene expression signatures (44.5%) were significantly associated with pCR and 9 of 618 (1.5%) with EFS. The ERBB2/HER2 amplicon and multiple immune signatures were significantly associated with pCR. Luminal-related signatures were associated with lower pCR rates but better EFS, especially among patients with residual disease and independent of hormone receptor status. There was significant adjusted HR for pCR ranging from 0.45 to 0.81 (higher pCR) and 1.21-1.94 (lower pCR rate); significant adjusted HR for EFS ranged from 0.71 to 0.94. Conclusions and relevance: In patients with ERBB2/HER2-positive EBC, the association between pCR and EFS differed by tumor intrinsic subtype, and the benefit of dual ERBB2/HER2 blockade was limited to ERBB2-enriched tumors. Immune-activated signatures were concordantly associated with higher pCR rates and better EFS, whereas luminal signatures were associated with lower pCR rates.

A Secreted BBE-Like Enzyme Acting as a Drug-Binding Efflux Carrier Confers Microbial Self-Resistance to Mitomycin C.

The berberine bridge enzyme (BBE)-like flavoproteins have attracted continuous attention for their capability to catalyze various oxidative reactions. Here we demonstrate that MitR, a secreted BBE-like enzyme, functions as a special drug-binding efflux protein evolved from quinone reductase. Moreover, this protein provides self-resistance to its hosts toward the DNA-alkylating agent mitomycin C with a distinctive strategy, featured by independently performing drug binding and efflux.

iGenSig-Rx: an integral genomic signature based white-box tool for modeling cancer therapeutic responses using multi-omics data.

Multi-omics sequencing is expected to become clinically routine within the next decade and transform clinical care. However, there is a paucity of viable and interpretable genome-wide modeling methods that can facilitate rational selection of patients for tailored intervention. Here we develop an integral genomic signature-based method called iGenSig-Rx as a white-box tool for modeling therapeutic response based on clinical trial datasets with improved cross-dataset applicability and tolerance to sequencing bias. This method leverages high-dimensional redundant genomic features to address the challenges of cross-dataset modeling, a concept similar to the use of redundant steel rods to reinforce the pillars of a building. Using genomic datasets for HER2 targeted therapies, the iGenSig-Rx model demonstrates stable predictive power across four independent clinical trials. More importantly, the iGenSig-Rx model offers the level of transparency much needed for clinical application, allowing for clear explanations as to how the predictions are produced, how the features contribute to the prediction, and what are the key underlying pathways. We expect that iGenSig-Rx as a class of biologically interpretable multi-omics modeling methods will have broad applications in big-data based precision oncology. The R package is available: https://github.com/wangxlab/iGenSig-Rx. NOTE: the Github website will be released upon publication and the R package is available for review through google drive: https://drive.google.com/drive/folders/1KgecmUoon9-h2Dg1rPCyEGFPOp28Ols3?usp=sharing.

First report of Epicoccum nigrum causing brown leaf spot of sweet cherry (Prunus avium) in China.

Sweet cherry (Prunus avium L.) has become an important economic fruit in China, mainly produced in Shandong Province. In recent years, the planting area of Aba Prefecture in Sichuan Province has increased. In June 2022, sweet cherry brown leaf spot was found in a cherry plantation (100ha) in Wenchuan County (30°54'50.21″N, 103°24'49.10″E), with an incidence of 50 - 70%. The symptoms appeared as brown circular spots on the leaf, gradually expanding until multiple lesions coalesced to form large irregular brown spots; eventually entire leaves were killed. To isolate the causal pathogens, 10 diseased trees were randomly selected from an orchard, one diseased leaf was taken from each tree, and samples (4×4 mm2) were cut from the border between diseased and healthy tissues of 10 diseased leaves, surface sterilized with 75% ethanol for 30 sec, washed three times with sterilized water, dried on sterilized filter paper and placed on potato dextrose agar (PDA). After 5d at 25℃, five morphologically similar colonies were obtained, colony appears yellow fluffy and released a large amount of red-orangepigment. Microscopy revealed circular to ovoid, verrucose, and multicellular conidia measuring 20×25 µm diameter (n = 30) were produced on the mycelia. The morphological characteristics were consistent with the description of Epicoccum nigrum (Lima et al 2011). To further identify the strains, the internal transcribed spacer (ITS), ß-tubulin, and RNA polymerase second largest subunit (RPB2) gene regions were amplified with ITS1/ITS4 , Bt2a/Bt2b, and 5f2/7cr (White et al. 1990; Glass and Donaldson 1995; Sung et al. 2007), respectively. BLAST analysis revealed that the ITS, ß-tubulin, and RPB2 sequences were 99.2%, 100% and 99.6% homologous, with those of E. nigrum (KU204750.1, OL782123.1, and MW602294.1), respectively. The sequences of the five isolates were identical; and those of representative strain TY3 were deposited in GenBank (ITS, OP410968; ß-tubulin, OR502448; RPB2, OP484927). Maximum likelihood phylogenetic analyses were performed for the combined data set with ITS , ß-tubulin and RPB2 using MEGA6 under the Tamura-Nei model (Tamura et al. 1993). Isolate TY3 clustered with E. nigrum type strain CBS 505.85. The pathogenicity of TY3 was tested on 10 sweet cherry trees aged 3 years (there were about 50 leaves per plant). Five plants were sprayed with 50 mL of spore suspension (1×105 spores/mL), while the controls (Five plants) were sprayed with 50 mL of sterile water. All plants were in closed plastic bags to maintain high humidity, placed in a greenhouse, and incubated at 25℃with a 12-h photoperiod. Twelve days after inoculation, 35% of the inoculated leaves showed lesions; that were consistent with those observed in the field, and the control group was asymptomatic. To confirm Koch´s postulates, two isolates were taken from the margins of leaf lesions and both were confirmed to be E. nigrum based on morphological observations and molecular identification using ITS ß-tubulin, and RPB2 sequences. This is the first report of brown leaf spot caused by E. nigrum on P. avium in China. This discovery needs to be considered in developing and implementing disease management programs in sweet cherry production.

Identification and characterization of a strong constitutive promoter stnYp for activating biosynthetic genes and producing natural products in streptomyces.

BACKGROUND: Streptomyces are well known for their potential to produce various pharmaceutically active compounds, the commercial development of which is often limited by the low productivity and purity of the desired compounds expressed by natural producers. Well-characterized promoters are crucial for driving the expression of target genes and improving the production of metabolites of interest. RESULTS: A strong constitutive promoter, stnYp, was identified in Streptomyces flocculus CGMCC4.1223 and was characterized by its effective activation of silent biosynthetic genes and high efficiency of heterologous gene expression. The promoter stnYp showed the highest activity in model strains of four Streptomyces species compared with the three frequently used constitutive promoters ermEp*, kasOp*, and SP44. The promoter stnYp could efficiently activate the indigoidine biosynthetic gene cluster in S. albus J1074, which is thought to be silent under routine laboratory conditions. Moreover, stnYp was found suitable for heterologous gene expression in different Streptomyces hosts. Compared with the promoters ermEp*, kasOp*, and SP44, stnYp conferred the highest production level of diverse metabolites in various heterologous hosts, including the agricultural-bactericide aureonuclemycin and the antitumor compound YM-216391, with an approximately 1.4 - 11.6-fold enhancement of the yields. Furthermore, the purity of tylosin A was greatly improved by overexpressing rate-limiting genes through stnYp in the industrial strain. Further, the yield of tylosin A was significantly elevated to 10.30 ± 0.12 g/L, approximately 1.7-fold higher than that of the original strain. CONCLUSIONS: The promoter stnYp is a reliable, well-defined promoter with strong activity and broad suitability. The findings of this study can expand promoter diversity, facilitate genetic manipulation, and promote metabolic engineering in multiple Streptomyces species.

Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor-Positive Breast Cancer.

PURPOSE: The 21-gene recurrence score (RS) assay quantifies the likelihood of distant recurrence in women with estrogen receptor-positive, lymph node-negative breast cancer treated with adjuvant tamoxifen. The relationship between the RS and chemotherapy benefit is not known. METHODS: The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy-treated patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial. Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS. RESULTS: A total of 651 patients were assessable (227 randomly assigned to tamoxifen and 424 randomly assigned to tamoxifen plus chemotherapy). The test for interaction between chemotherapy treatment and RS was statistically significant (P = .038). Patients with high-RS (≥ 31) tumors (ie, high risk of recurrence) had a large benefit from chemotherapy (relative risk, 0.26; 95% CI, 0.13 to 0.53; absolute decrease in 10-year distant recurrence rate: mean, 27.6%; SE, 8.0%). Patients with low-RS (< 18) tumors derived minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% CI, 0.46 to 3.78; absolute decrease in distant recurrence rate at 10 years: mean, -1.1%; SE, 2.2%). Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit. CONCLUSION: The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor-positive breast cancer, but also predicts the magnitude of chemotherapy benefit.

Trioxacarcin A Interactions with G-Quadruplex DNA Reveal Its Potential New Targets as an Anticancer Agent.

Trioxacarcin (TXN) A was reported to be an anticancer agent through alkylation of dsDNA. G-quadruplex DNA (G4-DNA) is frequently formed in the promoter regions of oncogenes and the ends of telomerase genes, considered as promising drug targets for anticancer therapy. There are no reports about TXN A interactions with G4-DNA. Here, we tested TXN A's interactions with several G4-DNA oligos with parallel, antiparallel, or hybrid folding, respectively. We demonstrated that TXN A preferred to alkylate one flexible guanine in the loops of parallel G4-DNA. The position of the alkylated guanine is in favor of interactions of G4-DNA with TXN A. The structure of TXN A covalently bound RET G4-DNA indicated that TXN A alkylation on RET G4-DNA stabilizes the G4-DNA conformation. These studies opened a new window of how TXN A interacted with G4-DNA, which might hint a new mode of its function as an anticancer agent.

Pathologic Complete Response and Individual Patient Prognosis After Neoadjuvant Chemotherapy Plus Anti-Human Epidermal Growth Factor Receptor 2 Therapy of Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer.

PURPOSE: The achievement of pathologic complete response (pCR) is strongly prognostic for event-free survival (EFS) and overall survival (OS) in patients with early breast cancer (EBC), and adapting postneoadjuvant therapy improves long-term outcomes for patients with HER2-positive disease not achieving pCR. We sought to investigate prognostic factors for EFS and OS among patients with and without pCR after neoadjuvant systemic treatment consisting of chemotherapy plus anti-HER2 therapy. MATERIALS AND METHODS: We used individual data from 3,710 patients randomly assigned in 11 neoadjuvant trials for HER2-positive EBC with ≥100 patients enrolled, available data for pCR, EFS, and OS, and follow-up ≥3 years. We assessed baseline clinical tumor size (cT) and clinical nodal status (cN) as prognostic factors using stratified (by trial and treatment) Cox models separately for hormone receptor-positive versus hormone receptor-negative disease, and for patients who had pCR (pCR+; ypT0/is, ypN0) versus patients who did not achieve a pCR (pCR-). RESULTS: The median follow-up overall was 61.2 months. In pCR+ patients, cT and cN were significant independent prognostic factors for EFS, whereas only cT was a significant predictor for OS. In pCR- patients, cT, cN, and hormone receptor status were significant independent predictors for both EFS and OS. Regardless of hormone receptor status, cT, and cN, the 5-year EFS/OS rates were higher in pCR+ patients than in pCR- patients. In most subsets with regards to hormone receptor and pCR status, cT and cN were independent prognostic factors for both EFS and OS, including pCR+ patients. CONCLUSION: These results confirm that patients achieving pCR have far better survival outcomes than patients who do not. The traditional poor prognostic features, namely tumor size and nodal status, remain important even after a pCR.

Long-term outcomes of dual vs single HER2-directed neoadjuvant therapy in NSABP B-41.

BACKGROUND: The primary aim of this randomized neoadjuvant trial in operable, HER2-positive breast cancer, was to determine the efficacy on pathologic complete response (pCR) of substituting lapatinib (L) for trastuzumab (T) or adding L to T, in combination with weekly paclitaxel (WP) following AC. Results on pCR were previously reported. Here, we report data on planned secondary endpoints, recurrence-free interval (RFI) post-surgery, and overall survival (OS). METHODS: All patients received standard AC q3 weeks × 4 cycles followed by WP (80 mg/m2) on days 1, 8, and 15, q28 days × 4 cycles. Concurrently with WP, patients received either T (4 mg/kg load, then 2 mg/kg) weekly until surgery, L (1250 mg) daily until surgery, or weekly T plus L (750 mg) daily until surgery. Following surgery, all patients received T to complete 52 weeks of HER2-targeted therapy. 522 of 529 randomized patients had follow-up. Median follow-up was 5.1 years. RESULTS: RFI at 4.5 years was 87.2%, 79.4% (p = 0.34; HR = 1.37; 95% CI 0.80, 2.34), and 89.4% (p = 0.37; HR = 0.70; 0.37, 1.32) for arms T, L, and TL, respectively. The corresponding five-year OS was 94.8%, 89.1% (p = 0.34; HR = 1.46; 0.68, 3.11), and 95.8% (p = 0.25; HR = 0.58; 0.22, 1.51), respectively. Patients with pCR had a much better prognosis, especially in the ER-negative cohort: RFI (HR = 0.23, p < 0.001) and OS (HR = 0.28, p < 0.001). CONCLUSIONS: Although pCR, RFI, and OS were numerically better with the dual combination and less with L, the differences were not statistically significant. However, achievement of pCR again correlated with improved outcomes, especially remarkable in the ER-negative subset. CLINICAL TRIALS REGISTRATION: NCT00486668.

Re-Evaluation of Pathologic Complete Response as a Surrogate for Event-Free and Overall Survival in Human Epidermal Growth Factor Receptor 2-Positive, Early Breast Cancer Treated With Neoadjuvant Therapy Including Anti-Human Epidermal Growth Factor Receptor 2 Therapy.

PURPOSE: Pathologic complete response (pCR) has prognostic importance and is frequently used as a primary end point, but doubts remain about its validity as a surrogate for event-free survival (EFS) and overall survival (OS) in human epidermal growth factor receptor 2 (HER2)-positive, early breast cancer. METHODS: We obtained individual-patient data from randomized trials of neoadjuvant anti-HER2 therapy that enrolled at least 100 patients, had data for pCR, EFS, and OS, and a median follow-up of at least 3 years. We quantified the patient-level association between pCR (defined as ypT0/Tis ypN0) and both EFS and OS using odds ratios (ORs, with ORs >1.00 indicating a benefit from achieving a pCR). We quantified the trial-level association between treatment effects on pCR and on EFS and OS using R2 (with values above 0.75 considered as indicating strong associations). RESULTS: Eleven of 15 eligible trials had data for analysis (3,980 patients, with a median follow-up of 62 months). Considering all trials, we found strong patient-level associations, with ORs of 2.64 (95% CI, 2.20 to 3.07) for EFS and 3.15 (95% CI, 2.38 to 3.91) for OS; however, trial-level associations were weak, with an unadjusted R2 of 0.23 (95% CI, 0 to 0.66) for EFS and 0.02 (95% CI, 0 to 0.17) for OS. We found qualitatively similar results when grouping trials according to different clinical questions, when analyzing only patients with hormone receptor-negative disease, and when using a more stringent definition of pCR (ypT0 ypN0). CONCLUSION: Although pCR may be useful for patient management, it cannot be considered as a surrogate for EFS or OS in neoadjuvant trials of HER2-positive, operable breast cancer.

Dihydrofolate reductase-like protein inactivates hemiaminal pharmacophore for self-resistance in safracin biosynthesis.

Dihydrofolate reductase (DHFR), a housekeeping enzyme in primary metabolism, has been extensively studied as a model of acid-base catalysis and a clinic drug target. Herein, we investigated the enzymology of a DHFR-like protein SacH in safracin (SAC) biosynthesis, which reductively inactivates hemiaminal pharmacophore-containing biosynthetic intermediates and antibiotics for self-resistance. Furthermore, based on the crystal structure of SacH-NADPH-SAC-A ternary complexes and mutagenesis, we proposed a catalytic mechanism that is distinct from the previously characterized short-chain dehydrogenases/reductases-mediated inactivation of hemiaminal pharmacophore. These findings expand the functions of DHFR family proteins, reveal that the common reaction can be catalyzed by distinct family of enzymes, and imply the possibility for the discovery of novel antibiotics with hemiaminal pharmacophore.

Peripheral Blood Monocytosis Is Associated With Long-Term Disease Severity in Pediatric-Onset Inflammatory Bowel Disease.

OBJECTIVES: Peripheral blood monocytosis (PBM) is a marker of increased disease severity in adults with inflammatory bowel diseases (IBDs). We sought to determine whether PBM serves as a prognostic biomarker in patients with pediatric-onset IBD for a more aggressive long-term disease course when followed into adulthood. METHODS: Patients with pediatric-onset inflammatory bowel disease were identified within an adult tertiary care center, within a consented, prospectively collected natural history disease registry, to compare clinical outcomes between patients with and without PBM from the years 2009 to 2019. Patients demonstrating elevation in PBM at any time defined membership and long-term clinical trajectories were compared with pediatric-onset patients without PBM. RESULTS: A total of 581 patients with IBD, diagnosed by 18 years of age, were identified for inclusion, of which 440 patients were diagnosed with Crohn disease and 141 with ulcerative colitis. Monocytosis was detected by complete blood cell counts in 40.1% of patients. PBM was associated with steroid and biologic exposure, number of IBD-related surgeries, and increased health care utilization. Multivariate logistic regression analyses, accounting for elevation of inflammatory markers and other values associated with acute disease activity as well as steroid use, showed persistently increased odds of biologic exposure, emergency department visits, and hospitalizations, but not surgeries, after detection of monocytosis. CONCLUSIONS: Within patients with pediatric-onset IBD, the sub-cohort with PBM had associated worse clinical outcomes and other markers of increased disease severity.

Granuloma Presence at Initial Surgery Predicts Need for Repeat Surgery Independent of Rutgeerts Score in Crohn's Disease.

BACKGROUND: Approximately half of Crohn's disease (CD) patients experience recurrence and need for repeat resections, highlighting need for prognostic biomarkers. Presence of epithelioid granuloma on surgical tissue and high Rutgeerts endoscopic score are associated with postoperative CD clinical recurrence. We sought to evaluate presence of epithelioid granuloma at first surgery and Rutgeerts score as a combined risk assessment for CD surgical recurrence. METHODS: Our study included consented CD patients who underwent initial ileocecal resection and were prospectively followed postoperatively. From 2009 to 2019, 418 CD patients underwent initial ileocecal resection with >4 years of follow-up, including postoperative endoscopic assessment (Rutgeerts score). RESULTS: Postoperative CD patients were grouped based on granuloma presence (30.6%; n = 128) or absence (69.4%; n = 290). Endoscopic recurrence (defined as Rutgeerts score ≥i2) was similar between the granuloma (26%) and no granuloma (25%) groups, respectively (P = .82). Patients with granuloma and CD endoscopic recurrence at first postoperative endoscopy had higher number of bowel surgeries compared with all other groups (no granuloma or CD endoscopic recurrence, P = .007; no granuloma but CD endoscopic recurrence present, P = .04; granuloma present and no CD endoscopic recurrence, P = .04). Epithelioid granuloma presence was associated with 1.65 times higher risk of subsequent surgery independently from first postoperative endoscopic recurrence Rutgeerts score. CONCLUSIONS: Granuloma presence on initial surgical histology is immediately available and identifies high-risk CD patients who may benefit from early postoperative treatment, and these precision intervention trials are warranted.

This study shows the presence of epithelioid granuloma as a risk factor for repeat Crohn's disease­related surgery, which is independent of first postoperative Rugteerts score. These 11-year observational data provide a risk factor that is immediately available after surgery and identifies high-risk CD patients who may benefit from early postoperative treatment.

A series of two-sample non-parametric tests for quantile residual life time.

Quantile residual lifetime (QRL) is of significant interest in many clinical studies as an easily interpretable quantity compared to other summary measures of survival distributions. In cancer or other chronic diseases, treatments are often compared based on the distributions or quantiles of the residual lifetime. Thus a common problem of interest is to test the equality of the QRL between two populations. In this paper, we propose two classes of tests to compare two QRLs; one class is based on the difference between two estimated QRLs, and the other is based on the estimating function of the QRL, where the estimated QRL from one sample is plugged into the QRL-estimating-function of the other sample. We outline the asymptotic properties of these test statistics. Simulation studies demonstrate that the proposed tests produced Type I errors closer to the nominal level and are superior to some existing tests based on both Type I error and power. Our proposed test statistics are also computationally less intensive and more straightforward compared to tests based on the confidence intervals. We applied the proposed methods to a randomized multicenter phase III trial for breast cancer patients.

Impact of prepregnancy body mass index on adverse pregnancy outcomes: analysis from the Longitudinal Indian Family hEalth cohort study.

BACKGROUND: Both high and low maternal prepregnancy body mass index can lead to suboptimal fetal growth and risk of pregnancy complications. In developed countries, nearly half of all women of childbearing age are either overweight or obese, and most data linking maternal body mass index and adverse pregnancy complications are limited to these populations. OBJECTIVE: This study aimed to prospectively evaluate the relationships between prepregnancy body mass index and adverse pregnancy outcomes using the Longitudinal Indian Family hEalth (LIFE) study. STUDY DESIGN: We modeled the relationships between prepregnancy body mass index and adverse pregnancy outcomes such as low birthweight, preterm birth, cesarean delivery, intrauterine growth restriction, miscarriage, and fetal death among 675 women aged 15 to 35 years with singleton pregnancies in the Longitudinal Indian Family hEalth study, a population-based prospective pregnancy cohort study conducted in Telangana, India. Prepregnancy body mass index was calculated as weight in kilograms divided by height in meters squared and was classified into 4 categories using the World Health Organization recommendations for Asian adults. Prepregnancy body mass index was assessed at a mean of 12.3 months before pregnancy. Odds ratios and 95% confidence intervals of adverse pregnancy outcomes were modeled and adjusted for confounders. RESULTS: Obese women had a 3-fold increased risk of cesarean delivery (odds ratio, 3.13; 95% confidence interval, 1.56-6.29) compared with normal-weight women. Those who were overweight also had a marginally increased risk of cesarean delivery, albeit not statistically significant (odds ratio, 1.17; 95% confidence interval, 0.61-2.24). Underweight women had a modestly increased risk of low birthweight, compared with normal-weight women (odds ratio, 1.12; 95% confidence interval, 0.71-1.77), although results were not significant. Conversely, obese (odds ratio, 0.71; 95% confidence interval, 0.28-1.77) and overweight (odds ratio, 0.61; 95% confidence interval, 0.24-1.51) women had a marginally decreased risk of low birthweight. CONCLUSION: Our data suggest that women with elevated prepregnancy body mass index may have a higher risk of adverse pregnancy outcomes, especially cesarean delivery. Although this study has limited generalizability, our findings are generalizable to rural to periurban regions of India. Further studies exploring the translatability of these findings to other populations are needed. In addition, targeted prepregnancy intervention studies and programs that include counseling on optimization of preconception health and lifestyle modification for improvement of subsequent pregnancy outcomes among overweight and obese women are needed.

Autoimmunity May Explain Diabetes in a Subset of Patients With Recurrent Acute and Chronic Pancreatitis: A Pilot Study.

Pancreatogenic diabetes mellitus, also termed type 3c diabetes (T3cD), or glucose intolerance develops in 25%-75% of adults with chronic pancreatitis (CP). The primary pathophysiologic defect in T3cD is insulin deficiency, thought to result largely from "bystander" injury to the islets from fibrotic changes in the exocrine pancreas and cytokine-induced beta cell dysfunction from intrapancreatic inflammation.1.

Pancreatic Enzyme Replacement Therapy in Patients with Non-pancreatic Digestive Conditions: A Nationwide Claims Analysis.

BACKGROUND AND AIMS: Pancreatic enzyme replacement therapy (PERT) is most commonly used to treat exocrine insufficiency related to pancreatic diseases, but can be used for non-pancreatic digestive conditions (NPDC). We aimed to determine the prevalence of PERT use and describe prescription patterns in individuals with NPDC. METHODS: A nationally representative claims database of 48.6 million enrollees was used to identify individuals who received PERT prescription(s) in the absence of any pancreas-related diagnosis. Data on demographics, enrolment, comorbidities, exocrine function testing, treatment and potential indications for PERT were retrieved, and compared with individuals who received PERT for primary diagnosis of chronic pancreatitis (CP). RESULTS: A total of 29,234 individuals (64.1% female, mean age 52.4 ± 16.5 years) received PERT for NPDC. The overall estimated US population prevalence rate for PERT use for NDPC was 60.2/100,000 persons. Rates increased significantly with age and were higher in women in all age groups except 1-20 years old. When compared with CP, individuals with NPDC receiving PERT were more likely to be older (52.4 vs. 50.1 years), female (64.1% vs. 51.0%), have lower prevalence of alcoholism (3.6% vs. 25.0%), tobacco abuse (8.4% vs. 30.1%), and received PERT for shorter mean duration (5.3 vs. 8.2 months) (all p < 0.001). Median dose of PERT in individuals with NPDC was 2880 lipase units/day. CONCLUSIONS: Although proportionally low, a sizable population receives PERT for NPDC. PERT for NPDC is usually prescribed at a low dose and for shorter duration, suggesting it is used mostly as a trial for or until resolution of symptoms.