Safety and Efficacy of Tofacitinib in Combination With Biologic Therapy for Refractory Crohn’s Disease

Background The majority of patients with Crohn’s disease (CD) will not achieve endoscopic remission on current therapy. Addition of tofacitinib to biologics may improve remission rates. Methods We retrospectively assessed safety and clinical and endoscopic effectiveness of off-label tofacitinib and biologics for CD. Results We identified 19 patients treated with tofacitinib and a biologic for refractory CD between 2017 and 2019. Tofacitinib was added for luminal disease on colonoscopy (n = 13), luminal disease on capsule (n = 3), and pyoderma gangrenosum (n = 3). The mean age was 41.2 years (28–62), mean disease was duration 16.9 years (6–36), and prior exposure to biologics was a median of 4 (1–6). Mean treatment duration was 9.6 months (SD, 3.3). Adverse events (AEs) were reported in 36.8% of patients, most commonly minor infection or CD flare, and no patients had a serious AE; 80.0% (n = 8) achieved clinical response, and 60.0% (n = 6) achieved clinical remission based on Harvey-Bradshaw Index. Endoscopic improvement occurred in 54.5% (n = 6), endoscopic remission in 18.2% (n = 2), and endoscopic healing in 18.2% (n = 2) of patients. Mean Simple Endoscopic Score in CD significantly improved from 13.6 ± 5.2 to 6.5 ± 4.0 after treatment (P < .01). Conclusions In patients treated with tofacitinib in combination with a biologic, no new safety signals were observed. Combination tofacitinib and a biologic was effective in achieving clinical and endoscopic improvement in some patients with severe, refractory CD, although a larger sample size is needed to further assess the efficacy and long-term safety of this treatment strategy.

Efficacy of scroto-inguinal microsurgical varicocelectomy in treating male infertility

BackgroundVaricocele presents as the most frequent cause of infertility in men. Most reports showed that varicocelectomy has a significant impact on male fertility and reproductive outcome. This study aims to evaluate the safety and effectiveness of scrotal–inguinal microsurgical varicocelectomy in treating male infertility.MethodsWe prospectively studied preoperatively and postoperatively (at 3 and 6 months) 86 consecutive patients diagnosed with varicocele, abnormal semen parameters, and infertility, undergoing scrotal–inguinal microsurgical varicocelectomy. Semen test was performed before surgery and at 3 months and 6 months after surgery. The reproductive events were short-term followed up.ResultsThe median age of the patient was 32.9 ± 5.1 (20–43). Two cases (2.7%) had a minor infection of the scrotum incision, who were well treated by appropriate antibiotics. After operation, total sperm count and the percentage of motile sperms at 3 months and 6 months were significantly higher than those pre-varicocelectomy, respectively. In total, 26.7% (23/86) of all couples achieved a spontaneous pregnancy. Late complications such as testicular atrophy, hydroceles, and recurrent varicocele have not occurred.ConclusionsScrotal–inguinal microsurgical varicocelectomy is an acceptable method in treating male infertility due to high rate of reproductive outcomes and very low rate of complications.

Pathogenesis of urinary tract infection

The realization of the harms resulting from indiscriminate use of antibiotics for minor infection has added impetus to the need to understand better the interaction between urogenital tract epithelium and invading bacteria during the initial stages of urinary tract infection (UTI). It is thought that uropathogenic Escherichia coli clones develop in the gut and migrate across the perineum to the urethra and up into the bladder. The response of the epithelium to bacterial adherence and the evolution of the invading bacteria will then govern the clinical consequences. These can vary between rapid invasion and further migration to produce systemic sepsis to tolerance of the bacteria in a planktonic state in asymptomatic bacteriuria. The key to these differences is the activation of epithelial pathogen-associated molecular pattern receptors by expressed proteins on the bacterial cell wall. Increased understanding of these interactions will lead to non-antibiotic-based strategies for clinical management of urinary infection.

Development and Evaluation of Diploid and Polyploid Hibiscus moscheutos

Hibiscus moscheutos L. is an herbaceous hibiscus native to eastern North America that has been a popular landscape and container plant exhibiting large and colorful flowers in the summer. However, unsightly fruit develop and remain on the stalks at the end of the blooming season, which greatly decreases the ornamental value. Thus, breeding for sterility was attempted through ploidy level manipulation to reduce formation and growth of seed stalks, and to improve blooming vigor and longevity. Colchicine and oryzalin were used as mitotic inhibitors to induce tetraploid breeding lines that could be used to develop sterile triploids. Germinated seedlings of ‘Luna Red’ were soaked in three concentrations of each doubling agent for three different durations. Exposure to a low concentration of colchicine solution for a long time or to a low concentration of oryzalin for a short period was found to be effective in yielding a high number of tetraploids with a low rate of mortality. Triploids were obtained from the traditional method of crossing tetraploids with diploids. Triploid and tetraploid plants showed a decrease in height with a more compact form. Leaves of tetraploid plants were more ruffled, with an increase in overall leaf thickness, but were not different from leaves of diploids and triploids in regard to leaf mass per area (LMA). Triploid plants bloomed longer but had smaller flowers than diploid plants. Although the whole planting was infected by aerial phytophthora, diploid, tetraploid, and triploid plants were significantly different in their tolerances: all diploid branches were infected, but only a minor infection occurred on one triploid branch, and the transmission remained slow. Flowers of tetraploid plants failed to produce pollen, whereas flowers of triploid plants produced only nonviable pollen grains and fruits aborted after pollination, which led to infertility of induced triploids.

High Risk of Infections in Chronic Lymphocytic Leukemia Patients Treated with B-Cell Receptor Inhibitors

Introduction: Infection is a major source of morbidity and mortality in CLL. Improved treatment efficacy and decreased immune toxicity of treatment could have altered the spectrum and consequences of infections in patients with CLL. A better understanding of infections complicating the course of non-selected patients with CLL could be useful in improving medical management. Methods: Demographic and clinical information was retrospectively extracted from medical records for clinic visits between May 1st, 2000 and May 1st, 2016 for all patients enrolled in the Wilmot Cancer Institute (WCI) CLL database. Data collected on incident infections included site, etiology, treatment, and setting of care. Major infections were defined as requiring either an inpatient stay or IV antimicrobial treatment. Minor infections were defined as any infectious episode requiring oral antimicrobials and outpatient treatment. Incidence rate ratios (IRR) were generated using Poisson regression to compare infection rates across treatment categories. Results: Two hundred and seventy-five CLL patients contributed 937.7 person-years (p-yrs) of follow up from their first clinic visit at WCI (median follow up 2.1 yrs). Median age at diagnosis was 61.6 and only 8.2% of patients had advanced stage CLL. Most patients were CD38 negative (64.7%), ZAP70 negative (54.6%), and IGHV mutated (51.2%, n=89) and 75.1% had either 13q14 deletion as the only defect or no abnormality on FISH analysis. Sixty percent of patients needed treatment for progressive CLL; among those treated, 50.9% were ever treated with either a purine analog or alemtuzumab, 30.4% were treated with other chemotherapies, and 18.6% had non-chemotherapy treatment. B-cell receptor inhibitor (BCR) therapy was used in sixty-seven patients (63 ibrutinib, 4 idelalisib) and was the only therapy in 18 of them (BCR only). Thirty percent of patients experienced at least one major infection (incidence rate 20.4 per 100 p-yrs) and 62.9% experienced at least one minor infection (69.3 per 100 p-yrs). The most common sites of major infections were the lower respiratory tract (7.8 per 100 p-yrs), skin (2.6 per 100 p-yrs), and urogenital tract (2.0 per 100 p-yrs). Minor infections most commonly affected the upper respiratory tract (26.8 per 100 p-yrs), skin (11.0 per 100 p-yrs, including shingles: incidence rate of 2.8 per 100 p-yrs), and bronchi (9.3 per 100 p-yrs). Patients treated for CLL had a higher risk of major infections (IRR 4.15, 95%CI 2.53, 6.80) and minor infections (IRR 1.48, 95%CI 1.23, 1.79) compared to those never treated. The age and gender adjusted risk of both major and minor infections were significantly increased by treatment with a purine analog or alemtuzumab (Table 1). The risk of major infection in the BCR only group was significantly higher than treatment-naive patients (IRR 3.31 95%CI 1.13, 9.80) and was 43% lower compared to patients treated with other modalities (IRR 0.57, 95%CI 0.21,1.55). The BCR group had a significantly higher risk of a minor infection compared to untreated patients (IRR 1.86 95% 1.14, 3.04), but had a slightly lower risk compared to those treated with other modalities (IRR 0.93 95%CI 0.57, 1.48). The BCR only group had a longer infection free survival compared to those on BCR inhibitor salvage therapy (Figure 1). An intra-patient comparison of infection risk for patients receiving BCR inhibitor salvage therapy compared to their previous chemoimmunotherapy showed an 33% increase in the risk of a major infection (IRR 1.33 95%CI 0.96, 1.86) and a 185% increased risk of a minor infection (IRR 2.85 95%CI 1.57, 5.18). Conclusion: CLL is complicated by a large number of infections, especially in patients with progressive disease who require treatment. Minor infections contribute to considerable disease burden and can have serious sequelae (e.g. post herpetic neuralgia). Given their decreased immune toxicity profile, BCR inhibitors may decrease the risk of infections; however, this has not yet been confirmed. Our sample of CLL patients treated solely with BCR inhibitors experienced higher rates of infection compared to untreated patients. Additionally, patients treated with BCR inhibitors as salvage therapy still experienced higher rates of infection compared to their time on chemoimmunotherapy. Therefore, patients treated with BCR inhibitors should be carefully monitored for infections that can cause significant morbidity or mortality. Disclosures Barr: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy.

Interactions Between Coniothyrium minitans and Sclerotinia minor Affect Biocontrol Efficacy of C. minitans

Coniothyrium minitans, marketed as Contans, has become a standard management tool against Sclerotinia sclerotiorum in a variety of crops, including winter lettuce. However, it has been ineffective against lettuce drop caused by S. minor. The interactions between C. minitans and S minor were investigated to determine the most susceptible stage in culture to attack by C. minitans, and to determine its consistency on S minor isolates belonging to four major mycelial compatibility groups (MCGs). Four isolates of S. minor MCG 1 and 5 each from MCGs 2 and 3 and one from MCG 4 were treated in culture at purely mycelial, a few immature sclerotial, and fully mature sclerotial phases with a conidial suspension of C. minitans. Sclerotia from all treatments were harvested after 4 weeks, air dried, weighed, and plated on potato dextrose agar for recovery of C. minitans. S. minor formed the fewest sclerotia in plates that received C. minitans at the mycelial stage; C. minitans was recovered from nearly all sclerotia from this treatment and sclerotial mortality was total. However, the response of MCGs was inconsistent and variable. Field experiments to determine the efficacy of C. minitans relative to the registered fungicide, Endura, on lettuce drop incidence and soil inoculum dynamics were conducted from 2006 to 2009. All Contans treatments had significantly lower numbers of sclerotia than Endura and unsprayed control treatments, and drop incidence was as low as in Endura-treated plots (P > 0.05). Although the lower levels of lettuce drop in Contans treatments were correlated with significantly lower levels of sclerotia, the lower levels of lettuce drop, despite the presence of higher inoculum in the Endura treatment, was attributable to the prevention of infection by S. minor. A useful approach to sustained lettuce drop management is to employ Contans to lower the number of sclerotia in soil and to apply Endura to prevent S. minor infection within a cropping season.