Pathogenic Germline Variants in 10,389 Adult Cancers.

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

Integrated transcriptomic-genomic tool Texomer profiles cancer tissues.

Profiling of both the genome and the transcriptome promises a comprehensive, functional readout of a tissue sample, yet analytical approaches are required to translate the increased data dimensionality, heterogeneity and complexity into patient benefits. We developed a statistical approach called Texomer ( https://github.com/KChen-lab/Texomer ) that performs allele-specific, tumor-deconvoluted transcriptome-exome integration of autologous bulk whole-exome and transcriptome sequencing data. Texomer results in substantially improved accuracy in sample categorization and functional variant prioritization.

Hybrid oncocytic/chromophobe renal tumors are molecularly distinct from oncocytoma and chromophobe renal cell carcinoma.

Hybrid oncocytic/chromophobe tumor (HOCT) of the kidney represents a poorly understood clinicopathologic entity with pathologic features that overlap between benign renal oncocytoma (RO) and malignant chromophobe renal cell carcinoma (ChRCC). Consequently, characterization of HOCT and its separation from the foregoing entities are clinically important. The aim of this study was to describe the pathologic and molecular features of HOCT and to compare them with those of RO and ChRCC. We retrospectively identified a cohort of 73 cases with renal oncocytic tumors (19 RO, 27 HOCT, and 27 ChRCC) for whom clinical follow-up data were available by 2 tertiary care hospitals. All cases were sporadic except for 2 HOCTs that were associated with Birt-Hogg-Dubé syndrome. Lesional tissues were retrieved for molecular analysis. We performed targeted gene sequencing of all exons of 261 cancer related genes on a subset of HOCT samples (n = 16). Gene expression profiling of a customized codeset was conducted on 19 RO, 24 HOCT, and 27 ChRCC samples. Clinicopathologic characteristics as well as DNA copy number alterations, mutational and transcriptional features of HOCT derived from sequencing and expression profiling data are described and compared to those in RO and ChRCC. HOCTs were more frequently multifocal and did not exhibit mutations in genes that are recurrently mutated in RO or ChRCC but showed copy number alterations primarily involving losses in chromosomes 1 and X/Y. The mRNA transcript data show that HOCT can be separated from RO and ChRCC. Hence, HOCT appears to represent a distinct renal tumor entity with genomic features that are intermediate between those of RO and ChRCC.

Dutasteride, who is it more effective for? Second to fourth digit ratio and the relationship with prostate volume reduction by dutasteride treatment.

UNLABELLED: Study Type--Prognosis (cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? The second to fourth digit ratio (hereafter the digit ratio) of the right hand is related to the activity of the androgen receptor. Five α-reductase inhibitor (5ARI) reduces the prostate volume of patients with BPH. In terms of prostate volume reduction, large-scale placebo-controlled studies show that patients with BPH do not always respond well to 5ARI treatment. Patients with a higher digit ratio respond well to dutasteride treatment compared to those with a lower digit ratio. These results suggest that the digit ratio might be a predictor of the response to dutasteride treatment. OBJECTIVE: • To investigate the relationship between second to fourth digit ratio (hereafter the digit ratio) and prostate volume reduction by dutasteride treatment. PATIENTS AND METHODS: • A total of 142 men aged ≥ 40 years with a clinical diagnosis of benign prostatic hyperplasia and an enlarged prostate (prostate volume ≥ 30 mL) were prospectively enrolled. • Before prostate-specific antigen (PSA) level determination and transrectal ultrasonography (TRUS), the lengths of the second and fourth digits of the right hand were measured by an investigator using a digital vernier calliper. • Using TRUS, pre- and post-treatment prostate volume (PV1 and PV2) were measured by an uroradiologist who was unaware of finger lengths. We investigated the change in prostate volume and PSA level at least 6 months after the initiation of dutasteride therapy. RESULTS: • When the patients were divided into two groups according to digit ratio (A: digit ratio <0.95, n = 71; B: digit ratio ≥ 0.95, n = 71), there was a greater reduction in prostate volume in group B compared to group A (PV2-PV1: -9.4 mL vs -13.2 mL, P = 0.042; [PV2-PV1]/PV1: -17.5% vs -24.5%, P = 0.027; [PV2-PV1]/duration: -1.1 mL/month vs -1.6 mL/month, P = 0.041; [PV2-PV1]/PV1/duration: -2.0%/month vs -3.0%/month, P= 0.016). • Significant negative correlations were found between the digit ratio and reduction rate ([PV2-PV1]/duration: r = -0.165, P = 0.049; [PV2-PV1]/PV1/duration: r = -0.191, P = 0.023). CONCLUSIONS: • Patients with higher digit ratios respond well to dutasteride treatment. • The results obtained in the present study suggest that the digit ratio is a predictor of the response to dutasteride treatment.

Second to fourth digit ratio: its relationship with core cancer volume and Gleason score in prostate biopsy.

OBJECTIVE: To investigate the relationships between 2nd to 4th digit ratio (digit ratio) and prostate cancer detection rate and biopsy findings, including Gleason score. MATERIALS AND METHODS: In 770 consecutive men aged 40 years or older that presented with lower urinary tract symptoms (LUTS), right hand 2nd and 4th digit lengths were measured prior to PSA determinations, DRE and transrectal ultrasonography (TRUS). Among these, 166 men with a prostate specific antigen (PSA) level ≥ 3 ng/mL or abnormal digit rectal examination (DRE) prospectively underwent prostate biopsies. The relationship between digit ratio and prostate cancer detection rate and biopsy findings was investigated. RESULTS: The study subjects were allocated to two groups by digit ratio (group A: digit ratio < 0.95; n = 420; group B: digit ratio ≥ 0.95; n = 350). Despite similar biopsy rates (22.4% vs. 20.6%, p = 0.544), group A had higher cancer detection rate (46.8% (44/94) vs. 23.6% (17/72), p = 0.002; OR = 2.847, 95% CI = 1.445-5.610). When we analyzed 408 positive biopsy cores (group A: digit ratio < 0.95, n = 282; group B: digit ratio ≥ 0.95, n = 126), group A had higher percentage of core cancer volume (46.7% vs. 37.1%, p = 0.005) and more biopsy cores with high Gleason score (sum of Gleason score ≥ 9: 18/282 (6.4%) vs. 1/126 (0.8%), p = 0.010; primary Gleason score = 5: 12/282 (4.3%) vs. 0/126 (0.0%), p = 0.021). CONCLUSIONS: A lower digit ratio is related to an increased detection rate of prostate cancer, a high percentage of core cancer volume and a high Gleason score.

Impact of birth season on second-to-fourth digit ratio, prostate volume, and prostate cancer.

PURPOSE: The second-to-fourth digit ratio (digit ratio), which is determined in utero, is associated with exposure to visible sunlight during early pregnancy and the season of birth. The digit ratio is also associated with benign prostatic hyperplasia (BPH) and prostate cancer. This suggests that BPH and prostate cancer may be related to the birth season. Therefore, this study aimed to determine whether prostate volume and prostate cancer were related to the birth season. MATERIALS AND METHODS: A total of 858 male patients with lower urinary tract symptoms were enrolled. The right digit ratio was measured, and the month of birth was surveyed. Serum prostate-specific antigen (PSA) levels were measured, and prostate volumes were measured by transrectal ultrasonography. Patients with suspected prostate cancer underwent prostate biopsy. RESULTS: The mean age, digit ratio, prostate volume, and serum PSA level of 858 patients were 61.6 years, 0.947, 36.2 mL, and 4.24 ng/mL, respectively. Age, serum PSA levels, prostate biopsy rates, and cancer detection rates did not differ significantly according to the birth season. However, compared with the summer birth group, the winter birth group had lower digit ratios (0.951±0.040 vs. 0.941±0.040; p=0.014), larger prostate volumes (33.4±14.9 mL vs. 38.2±20.7 mL; p=0.008), and more prostate cancer (5.3% vs. 11.3%; p=0.031). Multivariate analysis showed that birth season independently predicted prostate cancer. CONCLUSIONS: The relationships of birth season with prostate volume and prostate cancer may be due to differences in the amount of light exposure during early pregnancy.

Second to fourth digit ratio: a predictor of prostate-specific antigen level and the presence of prostate cancer.

OBJECTIVE: To investigate the relationships between the 2nd to 4th digit ratio (digit ratio) and prostate volume, prostate-specific antigen (PSA) level, and the presence of prostate cancer. PATIENTS AND METHODS: Of the men that presented with lower urinary tract symptoms (LUTS) at a single tertiary academic center, 366 men aged 40 or older with a PSA level ≤ 40 ng/mL were prospectively enrolled. Right-hand 2nd and 4th digit lengths were measured prior to the PSA determinations and transrectal ultrasonography (TRUS). Prostate volumes were measured by TRUS without information about digit length. Patients with a PSA level ≥ 3 ng/mL underwent prostate biopsy. RESULTS: No relationship was found between prostate volume and digit ratio [correlation coefficient (r) = -0.038, P = 0.466]. But, significant negative correlations were found between digit ratio and PSA (r = -0.140, P = 0.007). When the patients were divided into two groups (Group A: digit ratio < 0.95, n = 184; Group B: digit ratio ≥ 0.95, n = 182), Group A had a higher mean PSA level than Group B (3.26 ± 5.54 ng/mL vs 1.89 ± 2.24 ng/mL, P = 0.002) and had significantly higher risks of prostate biopsy [odds ratio (OR) = 1.75, 95% CI = 1.07-2.84] and prostate cancer (OR = 3.22, 95% CI = 1.33-7.78). CONCLUSIONS: Patients with a lower digit ratio have higher risks of prostate biopsy and prostate cancer.

Clinical and urodynamic effect of methylphenidate for the treatment of giggle incontinence (enuresis risoria).

AIMS: We retrospectively investigated the efficacy of methylphenidate (MPH) in giggle incontinence (GI), and the relationship between GI and urodynamic parameters. METHODS: Nine (n = 9) female GI patients underwent 1 year of treatment with 5 mg MPH. Three questionnaires, voiding diaries, and UDS were conducted before and after treatment. The severity of GI was classified into mild, moderate, and severe. Clinical success was characterized as: full response, response, partial response, and non-response. RESULTS: The mean age of all patients was 16.2 ± 2.3 years. Five patients had mild, one had moderate, and three had severe grade incontinent. All patients reported complete cessation of wetting after MPH treatment. The mean duration of asymptomatic period was 7 ± 3.2 months. There were no statistically significant score changes in all three questionnaires: Urgency Perception Scale (UPS), Overactive Bladder Symptom Score (OABSS) and Primary Overactive Symptom Questionnaire (POSQ), and voiding diaries (P > 0.05). In UDS, there were no statistically significant altered parameters, except maximum urethral closure pressure (MUCP) and maximum urethral pressure (MUP). After treatment, the mean MUCP was increased from 52.2 ± 6.8 to 73.0 ± 5.4 cmH(2) O (P < 0.05), and the mean MUP was increased from 48.6 ± 7.3 to 70.2 ± 5.0 cmH(2) O (P < 0.05). CONCLUSIONS: MPH can be a viable option for the primary treatment of GI, and it may be related to increasing urethral closure pressure. It was not possible to establish if a relationship between GI and detrusor overactivity exists.

Genomic, Transcriptomic, and Proteomic Profiling of Metastatic Breast Cancer.

PURPOSE: Metastatic breast cancer (MBC) is not curable and there is a growing interest in personalized therapy options. Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations. EXPERIMENTAL DESIGN: Sixty-two patients with MBC were included. An analysis of DNA, RNA, and functional proteomics was done, and matched primary and metastatic tumors were compared when feasible. RESULTS: Targeted exome sequencing of 41 tumors identified common alterations in TP53 (21; 51%) and PIK3CA (20; 49%), as well as alterations in several emerging biomarkers such as NF1 mutations/deletions (6; 15%), PTEN mutations (4; 10%), and ARID1A mutations/deletions (6; 15%). Among 27 hormone receptor-positive patients, we identified MDM2 amplifications (3; 11%), FGFR1 amplifications (5; 19%), ATM mutations (2; 7%), and ESR1 mutations (4; 15%). In 10 patients with matched primary and metastatic tumors that underwent targeted exome sequencing, discordances in actionable alterations were common, including NF1 loss in 3 patients, loss of PIK3CA mutation in 1 patient, and acquired ESR1 mutations in 3 patients. RNA sequencing in matched samples confirmed loss of NF1 expression with genomic NF1 loss. Among 33 patients with matched primary and metastatic samples that underwent RNA profiling, 14 actionable genes were differentially expressed, including antibody-drug conjugate targets LIV-1 and B7-H3. CONCLUSIONS: Molecular profiling in MBC reveals multiple common as well as less frequent but potentially actionable alterations. Genomic and transcriptional profiling demonstrates intertumoral heterogeneity and potential evolution of actionable targets with tumor progression. Further work is needed to optimize testing and integrated analysis for treatment selection.

Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer.

PURPOSE: On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance. PATIENTS AND METHODS: We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days. RESULTS: A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 (n = 6); therefore, DL1 was reexplored (n = 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics. CONCLUSIONS: The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit.

Intermediate versus low or high prostate-specific antigen density level: comparison of cancer detection rate between 12- and 18-core prostate biopsy.

OBJECTIVE: To compare the diagnostic values of 12- and 18-core biopsies with respect to prostate-specific antigen (PSA) levels, prostate volumes (PV) and prostate-specific antigen density (PSAD). MATERIAL AND METHODS: Transrectal ultrasound-guided prostate biopsies were performed on 233 patients at a single tertiary academic center. Patients were prospectively randomized to the two protocols (12 or 18 core). The cancer detection rates achieved using these two methods were analyzed at different PSA levels, PVs and PSADs. RESULTS: Considering PSA level and PV simultaneously, patients were stratified into four groups (group A: PSA < 7 ng/ml and PV ≥ 45 cm(3); group B: PSA < 7 ng/ml and PV < 45 cm(3); group C: PSA ≥ 7 ng/ml and PV ≥ 45 cm(3); group D: PSA ≥ 7 ng/ml and PV < 45 cm(3)). 18-core biopsy had a higher cancer detection rate than 12-core biopsy only in group C (55.2% vs 24.1%, p = 0.015). The 233 patients were also stratified into three groups according to PSAD level: the low PSAD group (PSAD < 0.15 ng/ml/cm(3)), the intermediate PSAD group (0.15 ng/ml/cm(3) ≤ PSAD < 0.25 ng/ml/cm(3)) and the high PSAD group (PSAD ≥ 0.25 ng/ml/cm(3)). In the intermediate PSAD group, 18-core biopsy had a higher cancer detection rate than 12-core biopsy (54.2% vs 28.9%, p = 0.048). CONCLUSION: An 18-core biopsy is more useful than a 12-core biopsy for detecting prostate cancer in patients with high PSA and large PV, that is, with intermediate PSAD level.

Urodynamic findings of the painful bladder syndrome/interstitial cystitis: a comparison with idiopathic overactive bladder.

PURPOSE: In this study we identify the characteristics of the urodynamic results in patients with painful bladder syndrome/interstitial cystitis and in those with idiopathic overactive bladder. MATERIALS AND METHODS: The fluoroscopic urodynamic study results were analyzed retrospectively in 40 consecutive female patients with painful bladder syndrome/interstitial cystitis and 78 female patients with idiopathic overactive bladder between October 2005 and August 2007. Before treatment a symptom assessment, questionnaires, 3-day voiding diary and laboratory tests were performed at the initial outpatient clinic visit. All patients had been diagnosed and grouped according to painful bladder syndrome/interstitial cystitis or overactive bladder based on the clinical features before cystoscopy, potassium chloride sensitivity test and urodynamic investigation. RESULTS: Mean (+/-SD) age of patients with painful bladder syndrome/interstitial cystitis and overactive bladder was 57.8 (+/-12.9) and 61.9 (+/-11.9) years, respectively. Maximum flow rate and voided volume based on free uroflowmetry were significantly different between the 2 groups (p <0.05). For the static urethral pressure profile there was a significant difference between the groups in terms of maximal urethral closing pressure and maximal urethral pressure (p <0.05). For filling cystometry the volumes at each interval (first desire, normal desire, strong desire) and the volumes at maximum cystometric capacity were significantly lower (p <0.001) in patients with painful bladder syndrome/interstitial cystitis, as was bladder compliance (p = 0.025). No involuntary detrusor contraction was observed in the painful bladder syndrome/interstitial cystitis group but it was observed in 53 patients (67.9%) with overactive bladder (chi-square p <0.001). There was no significant difference in maximal detrusor pressure on voiding and fluoroscopic results between the 2 groups (p >0.05). Logistic regression analysis after adjusting for age, symptom duration, number of major comorbidities and disease groups showed that all variables in the urethral pressure profile were not significantly different between the painful bladder syndrome/interstitial cystitis and overactive bladder groups. CONCLUSIONS: This study showed that the urodynamic results were significantly different between the painful bladder syndrome/interstitial cystitis and overactive bladder groups. Combined with other clinical findings urodynamic studies might provide additional information to confirm a diagnosis of painful bladder syndrome/interstitial cystitis.

The Efficacy of Early Extracorporeal Shockwave Lithotripsy for the Treatment of Ureteral Stones.

PURPOSE: To determine the efficacy of early extracorporeal shockwave lithotripsy (e-ESWL) in colic patients with ureteral stones and the patient criteria for the most effective e-ESWL. MATERIALS AND METHODS: 335 patients who received ESWL due to ureteral stone, were divide in two groups: e-ESWL and d-ESWL by the critical cut-off point. we performed the sensitivity and specificity cut-off analyses to identified the critical cut off point. To assess the difference in the factors affecting ESWL success, univariate and multivariate logistic analyses were implemented with using variables: ESWL success; age; gender; BMI; comor-bidity; serum creatinine; stone size; stone location; stone laterality; Hounsfield unit (HU); presence of hydrone-phrosis; and presence of tissue rim. The subgroup analysis for the screened variables was conducted. RESULT: Optimal e-ESWL was defined to occur within a 24-hour critical cut-off time. Multivariate regression anal-ysis concluded with screened variables: age, stone size, stone location, and HU, that ESWL success was 1.85-fold higher in the e-ESWL patient group. The subgroup analyses the following conditions: ? 65 years old by 1.784- fold; ?10 mm stone size by 1.866-fold; mid to distal stone location by 2.234-fold; and ? 815 HU by 2.130-fold. When all the conditions were met, the e-ESWL success was 3.22-fold higher. CONCLUSION: In case of colic due to ureteral stones, the patient is recommended to receive a lithotripsy within the first 24 hours. E-ESWL is recommended especially in patients who are ? 65 years, or with a ureteral stone HU ? 815, sized ? 10 mm, or in a mid to distal location.

Use of Targeted Next-Generation Sequencing to Identify Activating Hot Spot Mutations in Cherry Angiomas.

Importance: Shared gene variants in benign-malignant process pairs, such as BRAF mutations common to benign nevi and melanoma, are associated with differing phenotypic manifestations. Study of gene mechanisms underlying cherry angioma may uncover previously unknown disease relationships. Objective: To identify somatic mutations present in cherry angioma specimens by using targeted next-generation sequencing. Design, Setting, and Participants: In a single-center case series, 10 formalin-fixed, paraffin-embedded cherry angioma specimens from biopsies performed at Massachusetts General Hospital in Boston from July 10, 2016, to January 23, 2018, were obtained and underwent sequencing across a panel of 323 genes most relevant to cancer. Somatic mutations were curated by excluding variants that were presumed to be germline or of low mapping quality. Main Outcomes and Measures: Identification of somatic mutations associated with cherry angiomas. Results: In 10 cherry angioma tissue samples originating from 6 female and 4 male patients with a median (range) age of 54 (26-79) years, 5 samples (50%) revealed somatic missense mutations in GNAQ (Q209H, Q209R, and R183G) and GNA11 (Q209H). Individually, these mutational hot spots are known to be involved in entities that include congenital and anastomosing hemangiomas, hepatic small-vessel neoplasms (Q209), port-wine stains, and Sturge-Weber syndrome (R183). Both hot spots are associated with blue nevi, melanoma associated with blue nevus, and uveal melanoma. Conclusions and Relevance: In this case series study, the high prevalence of 5 known genetic drivers within the benign cherry angioma entity appears to support the context-dependent role of gene alterations in both benign and malignant proliferations from various cellular origins.

Sonographic findings of mass-forming extramammary Paget's disease in the scrotum.

Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy involving the scrotum and may be confused with other scrotal malignancy. We describe the sonographic findings of an extremely rare case of mass-forming EMPD of the scrotal wall. Ultrasonography, which shows mild heterogeneous hyperechoic masses with a stalk connected to the dermis, can help predict the depth of vertical invasion of the lesion. The lesion extent should be precisely evaluated because the presence of dermal invasion of EMPD is the risk factor in distant metastasis and is known to result in a worse prognosis. Ultrasonography is a primary imaging modality to evaluate the extent and vertical invasion of EMPD. Surgical local wide excision is the treatment of choice for EMPD and histopathology confirmed the diagnosis.

Adaptive responses in a PARP inhibitor window of opportunity trial illustrate limited functional interlesional heterogeneity and potential combination therapy options.

Poly (ADP-ribose) polymerase inhibitor (PARPi)-based combination therapies are demonstrating efficacy in patients, however, identifying the right combination for the right patient remains a critical challenge. Thus, it is urgent to develop approaches able to identify patients likely to benefit from specific combination therapies. Several groups, including ours, have demonstrated that targeting adaptive responses induced by PARPi increases depth and duration of response. In this study, we instituted a talazoparib (PARPi) monotherapy window of opportunity trial to identify informative adaptive responses in high grade serous ovarian cancer patients (HGSOC). Patients were treated for 7 to 14 days with PARPi monotherapy prior to surgery with tissue samples from multiple sites being collected pre- and post-treatment in each patient. Analysis of these samples demonstrated that individual patients displayed different adaptive responses with limited interlesional heterogeneity. Ability of combination therapies designed to interdict adaptive responses to decrease viability was validated using model systems. Thus, assessment of adaptive responses to PARPi provides an opportunity for patient-specific selection of combination therapies designed to interdict patient-specific adaptive responses to maximize patient benefit.

A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries.

Mouse models of gastroesophageal junction (GEJ) cancer strive to recapitulate the intratumoral heterogeneity and cellular crosstalk within patient tumors to improve clinical translation. GEJ cancers remain a therapeutic challenge due to the lack of a reliable mouse model for preclinical drug testing. In this study, a novel patient-derived orthotopic xenograft (PDOX) was established from GEJ cancer via transabdominal surgical implantation. Patient tumor was compared to subcutaneously implanted patient-derived tumor xenograft (PDX) and PDOX by Hematoxylin and Eosin staining, immunohistochemistry and next-generation sequencing. Treatment efficacy studies of radiotherapy were performed. We observed that mechanical abrasion of mouse GEJ prior to surgical implantation of a patient-derived tumor in situ promotes tumor engraftment (100%, n=6). Complete PDOX engraftment was observed with rapid intra- and extraluminal tumor growth, as evidenced by magnetic resonance imaging. PDOXs contain fibroblasts, tumor-associated macrophages, immune and inflammatory cells, vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJ cancers are recapitulated in a GEJ PDOX mouse model. PDOXs demonstrate tumor invasion into vasculature and perineural space. Next-generation sequencing revealed loss of heterozygosity with very high allelic frequency in NOTCH3, TGFB1, EZH2 and KMT2C in the patient tumor, the subcutaneous PDX and the PDOX. Immunohistochemical analysis of Her2/neu (also known as ERBB2), p53 (also known as TP53) and p16 (also known as CDKN2A) in PDX and PDOX revealed maintenance of expression of proteins found in patient tumors, but membranous EGFR overexpression in patient tumor cells was absent in both xenografts. Targeted radiotherapy in this model suggested a decrease in size by 61% according to Response Evaluation Criteria in Solid Tumors (RECIST), indicating a partial response to radiation therapy. Our GEJ PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture, providing a novel tool for translating findings from studies on human GEJ cancer. This model can be applied to study metastatic progression and to develop novel therapeutic approaches for the treatment of GEJ cancer.This article has an associated First Person interview with the first author of the paper.

Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy.

We demonstrate that concurrent administration of poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors is effective in inhibiting tumor growth but poorly tolerated. Concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage, and abrogates the G2 DNA damage checkpoint in both normal and malignant cells. Following cessation of monotherapy with PARP or WEE1 inhibitors, effects of these inhibitors persist suggesting that sequential administration of PARP and WEE1 inhibitors could maintain efficacy while ameliorating toxicity. Strikingly, while sequential administration mirrored concurrent therapy in cancer cells that have high basal replication stress, low basal replication stress in normal cells protected them from DNA damage and toxicity, thus improving tolerability while preserving efficacy in ovarian cancer xenograft and patient-derived xenograft models.

Urology as rehabilitation medicine: a literature review.

As a urologist, we usually encounter with two representative functional behaviors, namely, voiding and sexual function. These are not only important but also complex and synchronized so if these functions are impaired, patients need active functional rehabilitation to recover. These functional impairments should be recognized and corrected early because they could not only cause direct damage to the affected functions but also have harmful consecutive consequences such as kidney damage due to voiding abnormality and self-esteem damage due to decreased sexual function. Numerous rehabilitative methods are currently available, which help minimize the negative effects of these functional impairments. In terms of voiding function, pelvic floor muscle exercise, biofeedback, functional magnetic stimulation, neuromodulation, and clean intermittent self-catheterization are representative rehabilitation modalities. In case of children, extra-attention should be paid because this might affect their entire life. In impairment of sexual function, early intervention to maintain male erection is the main target of rehabilitation to prevent corporal fibrosis and penile deformity and increase recovery chance in patients who underwent radical prostatectomy or major surgery. In this review, we will elucidate various rehabilitation methods in urology to further increase our understanding of the rehabilitative characteristics of urology and widen our view of rehabilitation medicine.

Intralymphatic Immunotherapy With Autologous Semen in a Korean Man With Post-Orgasmic Illness Syndrome.

Post-orgasmic illness syndrome (POIS) is a very rare disease characterized by local allergic symptoms and transient flu-like illness that nearly always occur after masturbation, coitus, or spontaneous ejaculation and last for 2 to 7 days. In a previous case report, 2 patients with POIS received hyposensitization therapy composed of multiple subcutaneous injections of autologous semen that resulted in a gradual decrease of symptoms. However, this procedure requires patients to endure pain and discomfort during frequent subcutaneous injections and preceding masturbations to obtain the autologous semen used for therapy. Recent studies have suggested that intralymphatic immunotherapy is a promising new method of allergen-specific immunotherapy against allergic diseases, showing a faster onset and longer duration of therapeutic effects after only several intralymphatic injections. We report on a case of a Korean man with POIS who received intralymphatic immunotherapy that alleviated POIS-related symptoms and in whom the existence of semen-specific immunoglobulin E was confirmed using immunoglobulin E immunoblotting and enzyme-linked immunosorbent assay. Kim TB, Shim YS, Lee, SM, et al. Intralymphatic Immunotherapy With Autologous Semen in a Korean Man With Post-Orgasmic Illness Syndrome. Sex Med 2018;6:174-179.