Updates on Management of Biochemical Recurrent Prostate Cancer.

OPINION STATEMENT: Patients with biochemical recurrent prostate cancer (BCR) are a heterogeneous group, whereby a personalized approach to management is critical. Patients with high-risk features such as PSA doubling time (PSADT) ≤ 9-12 months warrant earlier imaging for metastasis detection and consideration for intensified therapy (beyond intermittent androgen deprivation alone) during this phase of BCR-only disease. The BCR phase represents a unique opportunity to impact disease survival and delay metastasis progression. There is compelling evidence from the EMBARK trial that ADT monotherapy is no longer the optimal consideration for high-risk BCR patients.

Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer.

Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced-stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that combined transcriptional and genetic profiling with digital spatial profiling. We identify five distinctive genetic and transcriptomic programs and validate these in an independent neoadjuvant CPI trial to identify the features of response or resistance to CPI. By modeling the regulatory network, we identify the histone demethylase KDM5B as a repressor of tumor immune signaling pathways in one resistant subtype (S1, Luminal-excluded) and demonstrate that inhibition of KDM5B enhances immunogenicity in FGFR3-mutated BCa cells. Our study identifies signatures associated with response to CPI that can be used to molecularly stratify patients and suggests therapeutic alternatives for subtypes with poor response to neoadjuvant immunotherapy.

Hormonal Intensification Should Start at the Low-risk Stage in Metastatic Prostate Cancer.

The treatment landscape for metastatic hormone-sensitive prostate cancer (mHSPC) has dramatically evolved. Monotherapy androgen deprivation therapy (ADT) with testosterone suppression alone is no longer the standard of care as multiple global phase 3 trials of different combinatorial strategies have been clinically and statistically successful and the combinations have been incorporated into guidelines on advanced prostate cancer. For appropriate patients, clinicians should consider combining ADT with docetaxel or an androgen receptor pathway inhibitor, or possibly with both. Shared patient-physician decision-making mandates a review of the level 1 evidence supporting the optimization and intensification of combination therapy for patients with mHSPC. Here we discuss the evidence underscoring intensification strategies as the standard of care for low-volume, low-risk mHSPC. Patient summary: We discuss treatment strategies for men with metastatic prostate cancer. Combinations of androgen deprivation therapy (ADT) and drugs that inhibit the androgen receptor pathway are superior to ADT alone and prolong survival in patients with metastatic hormone-sensitive prostate cancer.

First-in-human Intravesical Delivery of Pembrolizumab Identifies Immune Activation in Bladder Cancer Unresponsive to Bacillus Calmette-Guérin.

BACKGROUND: Intravenous immune checkpoint inhibition is an effective anticancer strategy for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) but may be associated with greater systemic toxicity compared with localized therapies. OBJECTIVE: We assessed the safety and antitumor activity of intravesical pembrolizumab combined with BCG. DESIGN, SETTING, AND PARTICIPANTS: A 3 + 3 phase 1 trial of pembrolizumab + BCG was conducted in patients with BCG-unresponsive NMIBC (NCT02808143). INTERVENTION: Pembrolizumab was given intravesically (1-5 mg/kg for 2 h) beginning 2 weeks prior to BCG induction until recurrence. Urine profiling during treatment and spatial transcriptomic profiling of pre- and post-treatment tumors were conducted to identify biomarkers that correlated with response. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Safety and tolerability of immune checkpoint inhibition were assessed, and Kaplan-Meier survival analysis was performed. RESULTS AND LIMITATIONS: Nine patients completed therapy. Median follow-up was 35 months for five patients still alive at the end of the trial. The trial was closed due to the COVID-19 pandemic. Grade 1-2 urinary symptoms were common. The maximum tolerated dose was not reached; however, one dose-limiting toxicity was reported (grade 2 diarrhea) in the only patient who reached 52 weeks without recurrence. One death occurred from myasthenia gravis that was deemed potentially related to treatment. The 6-mo and 1-yr recurrence-free rates were 67% (95% confidence interval [CI]: 42-100%) and 22% (95% CI: 6.5-75%), respectively. Pembrolizumab was detected in the urine and not in blood. CD4+ T cells were significantly increased in the urine after treatment, and a transcriptomic analysis identified decreased expression of T-cell exhaustion markers in late recurrences. CONCLUSIONS: We demonstrate that intravesical pembrolizumab is safe, feasible, and capable of eliciting strong immune responses in a clinical setting and should be investigated further. PATIENT SUMMARY: Direct application of pembrolizumab to the bladder is a promising alternative for non-muscle-invasive bladder cancer unresponsive to Bacillus Calmette-Guérin and should be investigated further.

Predictors of Failed Same-Day Catheter Removal After Holmium Laser Enucleation of the Prostate.

OBJECTIVE: To determine factors associated with failure of same-day trial of void (SDTOV) following holmium laser enucleation of the prostate (HoLEP). BACKGROUND: HoLEP is increasingly utilized for patients with benign prostatic hyperplasia. Advancements in technology have improved operative efficiency and hemostasis making same-day, catheter-free discharge possible. METHODS: We conducted a retrospective review on 190 patients undergoing HoLEP from July, 2021 to January, 2022 by a single center. We assessed pre- and intra-operative variables associated with our primary outcome: failure of same-day catheter removal. Post-operative complications and outcomes at a ≤7 days and 3-month follow up were examined. Continuous and categorical variables were analyzed using unpaired t-tests (Mann Whitney) and chi-square, respectively. Univariate and multivariable logistic regression models were fitted to examine the associations of failed SDTOV. RESULTS: Of 190 candidates for a SDTOV, 90% (171/190) were successful. We found no difference between SDTOV success and failures with regards to age, comorbidities, presence of pre-operative urinary retention, anesthesia factors, operative time, volume resected, enucleation time, and morcellation time (all P>0.05). Pre-operatively, 26.3% (50/190) were on antiplatelet and 6.3% (12/190) were on anticoagulation. While pre-operative antiplatelet therapy was not associated with SDTOV failure (P=0.78), pre-operative anticoagulation use was (4.7% vs. 21.1%, P=0.021). Patients who continued anticoagulation through surgery had the highest rate of SDTOV failure (2.3% (4/171) vs. 15.8% (3/19), P=0.023). For those with successful SDTOV, 4.1% (7/171) required catheterization following discharge. At 3 months, no patient required catheterization. CONCLUSION: On the day of surgery, patients eligible for SDTOV successfully voided 90% of the time. History of preop anticoagulation, whether continued or held, increased SDTOV failure.

Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

The Northwestern University Novel Urology Residency Curriculum: Updated Outcomes from a 13-Year Experience with Flexible Residency Training and Electives.

INTRODUCTION: We evaluated educational outcomes and satisfaction following institution of a novel, flexible and urology-driven resident curriculum. METHODS: A new urology resident curriculum was instituted at Northwestern University in 2006. Rotation schedules and resident electives were recorded annually. Operative case logs and American Urological Association In-Service Examination scores were collected prospectively. Residents and faculty rated satisfaction with the residency program on a 5-point Likert scale from "poor" to "outstanding." Differences in cases logged, In-Service Examination scores and satisfaction ratings under the new and prior curricula were compared. RESULTS: Curriculum changes included full 5-year urology oversight of the residency curriculum by the program director, 8 months of urology rotations in the first postgraduate year and 2 months of general surgery during the second postgraduate year. General surgery rotations were modified annually based on educational rationale and feedback. Cases logged per resident and In-Service Examination scores were comparable between old and new curricula groups. All residents matriculating under the new curriculum took and passed their written boards. The percentage of faculty and residents describing the program as "outstanding" increased from 50% in 2004‒2005 to 82% in 2017‒2018. Program satisfaction increased significantly when comparing the first and last 6 years (percent rating "outstanding": 56.1±2.1% vs 71.6±10.0%, p=0.028). CONCLUSIONS: After 13 years with the novel curriculum, resident case numbers and In-Service Examination scores remained similar while faculty/resident satisfaction increased. Direct control of general surgery rotations enabled adjustments based on educational rationale. These results demonstrate that a urology-directed and flexible residency program can be instituted without compromising learner outcomes.

Mutation signatures to Pan-Cancer Atlas: Investigation of the genomic landscape of muscle-invasive bladder cancer.

The Cancer Genome Atlas (TCGA) for bladder cancer was published in 2014 with updated annotation of over 400 patients with muscle-invasive bladder cancer (MIBC) in 2017. This tremendous work established the foundation of the genomic landscape of MIBC. The next steps to utilize information from The Cancer Genome Atlas is to (1) identify the causes of mutation, (2) determine the significant differences and sources of heterogeneity, and (3) apply these tools toward patient care. In this review, we discuss the full spectrum of the genomic landscape of MIBC toward the goal of therapeutic application.

Revisiting One-Stage Urethroplasties for Distal Urethral Strictures.

BACKGROUND: Reconstructive approaches for distal urethral strictures range from simple meatotomy to utilizing grafts or flaps depending on the etiology, length and location. We describe a contemporary cohort of distal urethral strictures and report a surgical technique termed distal one-stage urethroplasty developed to address the majority of distal urethral strictures encountered. METHODS: Thirty-four patients were included. The mean age was 56.7 years (range 15.7-84.9 years), the mean stricture length was 1.1 cm (0.5-1.5) and the mean follow-up was 42.5 months (28-61.3). RESULTS: The vast majority of distal strictures (27/34 (79.4%)) were treated with our hybrid one-stage approach combining a distal urethral reconstruction with excision of the scar tissue without the need to use grafts or flaps. The average stricture length was 0.68 cm and average operative time was 24.43 min. Post-operative spraying was reported in a minority of patients (4/27 (14.8%)). The length of stricture and surgery were significantly longer in those 7/34 (20.6%) patients in whom grafts or flaps were used (2.88 cm and 154.8 min, respectively, p < 0.001 for both when compared to the hybrid one-stage approach). We noted 6/34 (17.6%) recurrences of distal urethral strictures, all of which were treated successfully with graft and flap repairs. CONCLUSIONS: The vast majority of distal urethral strictures are amenable to a distal one-stage urethroplasty, avoiding the use of grafts and/or flaps while achieving reasonable outcomes. This limited approach, at least initially, is associated with shorter operative time and time of catheter placement and avoids morbidity associated with graft or flap harvesting. Spraying of urine is seldomly encountered and comparable to other approaches addressing distal urethral strictures.

Factors Associated with Time to Conversion from Active Surveillance to Treatment for Prostate Cancer in a Multi-Institutional Cohort.

PURPOSE: We examined the demographic and clinicopathological parameters associated with the time to convert from active surveillance to treatment among men with prostate cancer. MATERIALS AND METHODS: A multi-institutional cohort of 7,279 patients managed with active surveillance had data and biospecimens collected for germline genetic analyses. RESULTS: Of 6,775 men included in the analysis, 2,260 (33.4%) converted to treatment at a median followup of 6.7 years. Earlier conversion was associated with higher Gleason grade groups (GG2 vs GG1 adjusted hazard ratio [aHR] 1.57, 95% CI 1.36-1.82; ≥GG3 vs GG1 aHR 1.77, 95% CI 1.29-2.43), serum prostate specific antigen concentrations (aHR per 5 ng/ml increment 1.18, 95% CI 1.11-1.25), tumor stages (cT2 vs cT1 aHR 1.58, 95% CI 1.41-1.77; ≥cT3 vs cT1 aHR 4.36, 95% CI 3.19-5.96) and number of cancerous biopsy cores (3 vs 1-2 cores aHR 1.59, 95% CI 1.37-1.84; ≥4 vs 1-2 cores aHR 3.29, 95% CI 2.94-3.69), and younger age (age continuous per 5-year increase aHR 0.96, 95% CI 0.93-0.99). Patients with high-volume GG1 tumors had a shorter interval to conversion than those with low-volume GG1 tumors and behaved like the higher-risk patients. We found no significant association between the time to conversion and self-reported race or genetic ancestry. CONCLUSIONS: A shorter time to conversion from active surveillance to treatment was associated with higher-risk clinicopathological tumor features. Furthermore, patients with high-volume GG1 tumors behaved similarly to those with intermediate and high-risk tumors. An exploratory analysis of self-reported race and genetic ancestry revealed no association with the time to conversion.

Narrative review of penile distal urethroplasties and suggestions for optimizing outcomes.

Distal urethral strictures can be a challenging entity for urologists. Endoscopic maneuvers such as optical internal urethrotomies or dilations are even less successful than in other urethral locations and the repeated trauma will increase the scarring which advocates for a urethroplasty as primary option for patient management. Success rates of distal urethroplasties have been lower than those for other urethral strictures due to the anatomy of the distal urethra with a very thin corpus spongiosum associated with decreased mucosal blood supply. Also, the high prevalence of lichen sclerosus in this population with circumferential scarring is often a complicating factor. However, in the past two decades several surgical techniques have been described and further developed which has led to significant improvement in stricture recurrence rates. Meatoplasties are indicated for strictures limited to the meatus and involve opening of the stenotic meatus with subsequent reconstruction of it to minimize spraying of urine. Often, however, distal urethral strictures involve the fossa navicularis and may even extend further proximally. These strictures can be addressed with dorsal or ventral inlay procedures using buccal mucosa graft. In addition or alternatively, skin flaps can be mobilized to increase the urethral diameter. Lastly, multi-stage urethroplasty with buccal mucosa are a very successful approach yet given the high success rates of above mentioned procedures are usually reserved for revision surgery or most severe distal urethral strictures. In the following report, we are describing a variety of surgical techniques and their indication which should allow the practicing urologist to successfully address all encountered distal urethral strictures.

Algorithms to Enhance Empiric Antimicrobial Choice for Outpatients With Afebrile Complicated Cystitis Reflects Importance of Status of the Urinary Tract and Patient Place of Residence.

OBJECTIVE: To determine predictive factors for antimicrobial resistance patterns and to develop an antimicrobial treatment algorithm for afebrile outpatients presenting with complicated cystitis. MATERIALS AND METHODS: We performed a retrospective, single-center, cross-sectional study of 2,891 outpatients with a diagnosed afebrile complicated cystitis from 2012 to 2018. For patients with confirmed urinary tract infection and antimicrobial sensitivities, univariate analyses and multivariable regression models were used to determine odds ratios for predicting resistance to trimethoprim-sulfamethoxazole, ciprofloxacin, nitrofurantoin, first-generation cephalosporin, and third-generation cephalosporin for the 2012-2016 data. Antimicrobial choice algorithms were created using 2012-2016 results and tested on 2017-2018 data. RESULTS: For afebrile outpatients presenting with complicated cystitis, overall prevalence of resistance for trimethoprim-sulfamethoxazole, ciprofloxacin, nitrofurantoin, first-generation cephalosporin, and third-generation cephalosporin was 25.6%, 19.5%, 19.1%, 15.0%, and 6.9%, respectively. Consistent predictive factors influencing resistance to all 5 antimicrobials were patient place of residence (ZIP code), status of host urinary tract (complicated vs uncomplicated), and prior resistance to the antimicrobial. Resulting treatment algorithm for complicated cystitis (whether or not prior microbiologic data was available) outperformed real-life provider choice and our previously published algorithm for uncomplicated cystitis. CONCLUSION: Treatment algorithms for urinary tract infections are dependent on patient place of residence (ZIP code), status of the host urinary tract (complicated or uncomplicated), and prior urine culture resistance data. When using our complicated cystitis treatment algorithm regardless of uropathogen, our results outperformed real-life scenario provider choice and our prior published algorithm for uncomplicated cystitis, which can help guide empiric antimicrobial choice.

Anti-TNF agents and potential effects on male fertility: are men being counseled?

BACKGROUND: Adult men with autoimmune conditions are commonly prescribed anti-tumor necrosis factor (anti-TNF) agents; however, there is a paucity of quality evidence as to their effect on male fertility (e.g. semen parameters and sperm quality). Our objective was to determine if men with autoimmune conditions are being counseled regarding the unknown reproductive effects of anti-TNF agents prior to initiation of therapy. METHODS: A retrospective analysis of 1010 male patients age 18-45 who were prescribed an anti-TNF agent were assessed for (1) receipt of counseling regarding potential reproductive effects; (2) screening for anatomic or laboratory abnormalities associated with infertility; (3) election for sperm cryopreservation. RESULTS: Only 10.3% of men received counseling, and this was not associated with age (p = 0.77). Those who received counseling were significantly more likely to have a genitourinary exam performed, be assessed for presence of a varicocele, be asked about or endorse low libido or erectile dysfunction, have a testosterone, LH, FSH, or prolactin level checked, and have a semen analysis performed (all, p < 0.0001). Rates of sperm cryopreservation were low, but statistically higher in men who received counseling (5.77% (+) counseling, 1.10% (-) counseling) (p = 0.002). CONCLUSIONS: The limited current literature lacks a consensus regarding the short- and long-term male reproductive effects of anti-TNF therapy. Despite this lack of clarity, rates of pre-initiation counseling were low. Rates of sperm cryopreservation, while improved in the counseled group remained low, suggesting prescribing physicians may be unaware of this option for patients.

Association between inflammatory bowel disease and prostate cancer: A large-scale, prospective, population-based study.

Inflammatory bowel disease (IBD) is an established risk factor for colorectal cancer. Recent reports suggesting IBD is also a risk factor for prostate cancer (PC) require further investigation. We studied 218 084 men in the population-based UK Biobank cohort, aged 40 to 69 at study entry between 2006 and 2010, with follow-up through mid-2015. We assessed the association between IBD and subsequent PC using multivariable Cox regression analyses, adjusting for age at assessment, ethnic group, UK region, smoking status, alcohol drinking frequency, body mass index, Townsend Deprivation Index, family history of PC and previous prostate-specific antigen testing. Mean age at study entry was 56 years, 94% of the men were white, and 1.1% (n = 2311) had a diagnosis of IBD. After a median follow-up of 78 months, men with IBD had an increased risk of PC (adjusted hazard ratio [aHR] = 1.31, 95% confidence interval [CI] = 1.03-1.67, P = .029). The association with PC was only among men with the ulcerative colitis (UC; aHR = 1.47, 95% CI = 1.11-1.95, P = .0070), and not Crohn's disease (aHR 1.06, 95% CI = 0.63-1.80, P = .82). Results are limited by lack of data on frequency of health care interactions. In a large-scale, prospective cohort study, we detected an association between IBD, and UC specifically, with incident PC diagnosis.

Genomic and Therapeutic Landscape of Non-muscle-invasive Bladder Cancer.

Non-muscle-invasive bladder cancer (NMIBC) is heterogeneous, but current diagnostic and treatment strategies rely primarily on clinical parameters, lacking individualization to tumor and host genetics and biology. The heterogeneity of NMIBCs is derived from mutations, mutation signatures, chromosomal loss, and disruption of molecular pathways, which ultimately affects tumor progression, recurrence, and responsiveness to intravesical and systemic chemotherapy. Although research is still underway, advances in sequencing technology, insight into differential bacillus Calmette-Guérin responses, and new investigational treatment targets will soon offer clinicians new, precision-based tools to risk stratify and determine treatment regimens for future patients with bladder cancer.

Canine-assisted Therapy as an Adjunct Tool in the Care of the Surgical Patient: A Literature Review and Opportunity for Research.

The use of canine-assisted therapy (CAT) in healthcare is expanding and the purpose of this review is to highlight its potential use in the surgical patient. While CAT literature to date has detailed widespread benefits in blood pressure control and improving pain, anxiety, and stress, little research has been performed specifically in surgical patients who may benefit significantly from CAT interventions. Critical points highlighted herein are as follows: (1) Hypertension is common and significantly increases morbidity and mortality associated with elective surgery. Pet ownership and brief CAT interventions (5-20 min) have demonstrated significant reductions in blood pressure and blood pressure variability in both adult and pediatric populations. (2) Pain management is of utmost importance in hospitalized, surgical patients and unfortunately the growing opioid addiction epidemic has complicated our ability to treat postoperative pain. CAT interventions have been shown to reduce self-reported pain. Therefore, CAT represents a cost-effective, safe, and noninvasive approach to pain management. (3) Patient satisfaction is of growing concern as reimbursement by Medicare, Medicaid, and other insurers is now linked to patient reported satisfaction with their hospital stay. While very limited data is available on this subject, some studies have showed that CAT intervention, specifically, improved patient reported satisfaction in multiple categories of the HCAHPS survey compared with patients who did not receive CAT. Overall, this is a novel narrative review detailing the therapeutic efficacy of CAT, highlighting the specific indications of CAT in the surgical patient, and urging further research of CAT in the surgical patient.

Impaired immunological synapse in sperm associated antigen 6 (SPAG6) deficient mice.

Sperm associated antigen 6 (SPAG6), a component of the central apparatus of the "9 + 2" axoneme, plays a central role in ciliary and flagellar motility; but, its contribution to adaptive immunity and immune system development is completely unknown. While immune cells lack a cilium, the immunological synapse is a surrogate cilium as it utilizes the same machinery as ciliogenesis including the nucleation of microtubules at the centrosome. This prompted our hypothesis that SPAG6 critically regulates the formation and function of immunological synapses. Using bone marrow reconstitution studies of adult WT mice, we demonstrate that SPAG6 is expressed in primary and secondary lymphoid tissues, is associated with the centrosome in lymphocytes, and its deficiency results in synapse disruption due to loss of centrosome polarization and actin clearance at the synaptic cleft. Improper synapse formation in Spag6KO mice was associated with defective CTL functions and impaired humoral immunity as indicated by reduced germinal centers reactions, follicular CD4 T cells, and production of class-switched antibody, together with expansion of B1 B cells. This novel report demonstrates the requirement of SPAG6 for optimal synapse formation and function, its direct role in immune cell function, and provides a novel mechanism for infertility disorders related to SPAG6.

Increased B Cell ADAM10 in Allergic Patients and Th2 Prone Mice.

ADAM10, as the sheddase of the low affinity IgE receptor (CD23), promotes IgE production and thus is a unique target for attenuating allergic disease. Herein, we describe that B cell levels of ADAM10, specifically, are increased in allergic patients and Th2 prone WT mouse strains (Balb/c and A/J). While T cell help augments ADAM10 expression, Balb WT B cells exhibit increased ADAM10 in the naïve state and even more dramatically increased ADAM10 after anti-CD40/IL4 stimulation compared C57 (Th1 prone) WT B cells. Furthermore, ADAM17 and TNF are reduced in allergic patients and Th2 prone mouse strains (Balb/c and A/J) compared to Th1 prone controls. To further understand this regulation, ADAM17 and TNF were studied in C57Bl/6 and Balb/c mice deficient in ADAM10. C57-ADAM10B-/- were more adept at increasing ADAM17 levels and thus TNF cleavage resulting in excess follicular TNF levels and abnormal secondary lymphoid tissue architecture not noted in Balb-ADAM10B-/-. Moreover, the level of B cell ADAM10 as well as Th context is critical for determining IgE production potential. Using a murine house dust mite airway hypersensitivity model, we describe that high B cell ADAM10 level in a Th2 context (Balb/c WT) is optimal for disease induction including bronchoconstriction, goblet cell metaplasia, mucus, inflammatory cellular infiltration, and IgE production. Balb/c mice deficient in B cell ADAM10 have attenuated lung and airway symptoms compared to Balb WT and are actually most similar to C57 WT (Th1 prone). C57-ADAM10B-/- have even further reduced symptomology. Taken together, it is critical to consider both innate B cell levels of ADAM10 and ADAM17 as well as Th context when determining host susceptibility to allergic disease. High B cell ADAM10 and low ADAM17 levels would help diagnostically in predicting Th2 disease susceptibility; and, we provide support for the use ADAM10 inhibitors in treating Th2 disease.