Association of Genomic Prostate Score at positive margin with recurrence after radical prostatectomy.

OBJECTIVES: To evaluate the utility of the 17-gene Genomic Prostate Score® (GPS; MDxHealth, Irvine, CA, USA) performed on prostate cancer at the positive margin of the radical prostatectomy (RP) for its association with risk of subsequent biochemical recurrence (BCR). PATIENTS AND METHODS: We designed a case-cohort for the outcome of BCR, selecting 223 from a cohort of 813 RP patients treated at Johns Hopkins from 2008 to 2017 with positive margins and available clinical data; of these, 213 had available tissue and clinical data. RNA was isolated from formalin-fixed paraffin-embedded tumour tissue adjacent to the positive surgical margin and the GPS was evaluable in 203 of these patients with a score ranging from 0 to 100, with higher scores indicating higher risk. All patients underwent RP with or without adjuvant radiation therapy (ART). The statistical analysis employed Cox proportional hazards regression models for outcome of BCR weighted for case-cohort design. RESULTS: In univariable analysis, every 20-unit increase in the GPS was associated with a nearly threefold increase in risk of BCR (hazard ratio [HR] per 20 units 2.82, P < 0.001). In a multivariable Cox model adjusted for age, race, Cancer of the Prostate Risk Assessment Postsurgical score, Grade Group at the positive margin, and ART, the GPS was significantly associated with BCR (HR 1.56 per 20 units; 95% confidence interval 1.11-2.19; P = 0.011). The study is limited by its retrospective and single institution design. CONCLUSIONS: The GPS at the positive surgical margin could help stratify prognosis and inform clinical decision-making regarding adjuvant therapy after RP.

PTEN Loss Is Associated with Adverse Outcomes in the Setting of Salvage Radiation Therapy.

BACKGROUND: Salvage radiation therapy (SRT) is a mainstay of treatment for biochemical relapse following radical prostatectomy; however, few studies have examined genomic biomarkers in this context. OBJECTIVE: We characterized the prognostic impact of previously identified deleterious molecular phenotypes-loss of PTEN, ERG expression, and TP53 mutation-for patients undergoing SRT. DESIGN, SETTING, AND PARTICIPANTS: We leveraged an institutional database of 320 SRT patients with available tissue and follow-up. Tissue microarrays were used for genetically validated immunohistochemistry assays. INTERVENTION: All men underwent SRT with or without androgen deprivation therapy OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable and multivariable Cox-proportional hazard models assessed the association of molecular phenotypes with biochemical recurrence-free (bRFS) and metastasis-free (MFS) survival after SRT. RESULTS AND LIMITATIONS: Loss of PTEN (n = 123, 43%) and ERG expression (n = 118, 39%) were common in this cohort, while p53 overexpression (signifying TP53 missense mutation) was infrequent (n = 21, 7%). In univariable analyses, any loss of PTEN portended worse bRFS (hazard ratio [HR] 1.86; 95% confidence interval 1.36-2.57) and MFS (HR 1.89; 1.21-2.94), with homogeneous PTEN loss being associated with the highest risk of MFS (HR 2.47; 1.54-3.95). Similarly, p53 overexpression predicted worse bRFS (HR 1.95; 1.14-3.32) and MFS (HR 2.79; 1.50-5.19). ERG expression was associated with worse MFS only (HR 1.6; 1.03-2.48). On the multivariable analysis adjusting for known prognostic features, homogeneous PTEN loss remained predictive of adverse bRFS (HR 1.82; 1.12-2.96) and MFS (HR 2.08; 1.06-4.86). The study is limited by its retrospective and single-institution design. CONCLUSIONS: PTEN loss by immunohistochemistry is an independent adverse prognostic factor for bRFS and MFS in prostate cancer patients treated with SRT. Future trials will determine the optimal approach to treating SRT patients with adverse molecular prognostic features. PATIENT SUMMARY: Loss of the PTEN tumor suppressor protein is associated with worse outcomes after salvage radiotherapy, independent of other clinical or pathologic patient characteristics.

MLH1 Loss in Primary Prostate Cancer.

PURPOSE: Among mismatch repair-deficient (MMRd) prostate cancers, loss of MLH1 is relatively uncommon and few cases have been reported in detail. METHODS: Here, we describe the molecular features of two cases of primary prostate cancer with MLH1 loss detected by immunohistochemistry, and in one case, confirmed via transcriptomic profiling. RESULTS: Both cases were microsatellite stable on standard polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing, but showed evidence of MSI on a newer PCR-based long mononucleotide repeat (LMR) assay and by next-generation sequencing. Germline testing was negative for Lynch syndrome-associated mutations in both cases. Targeted or whole-exome tumor sequencing using multiple commercial/academic platforms (Foundation, Tempus, JHU, and UW-OncoPlex) showed modestly elevated, though variable, tumor mutation burden estimates (2.3-10 mutations/Mb) consistent with MMRd, but without identifiable pathogenic single-nucleotide or indel mutations in MLH1. Copy-number analysis confirmed biallelic MLH1 loss in one case and monoallelic MLH1 loss in the second case, without evidence of MLH1 promoter hypermethylation in either. The second patient was treated with single-agent pembrolizumab and demonstrated a short-lived prostate-specific antigen response. CONCLUSION: These cases highlight the challenges in identifying MLH1-deficient prostate cancers using standard MSI testing and commercial sequencing panels, and support the utility of immunohistochemical assays and LMR- or sequencing-based MSI testing for detection of MMRd prostate cancers.

Revolutionary transformation lowering the mortality of pancreaticoduodenectomy: a historical review.

The History Maker paper focuses on the extraordinary revolution that dramatically improved the surgical results for the Whipple procedure (pancreaticoduodenectomy) in the 1980s and identifies Dr. Cameron as the leader of this revolution, who reported a mortality rate of approximately 1%. The revolutionary reduction of postoperative mortality for the Whipple procedure was achieved by adherence to gentle and precise Halstedian surgical techniques with adequate drainage of pancreatico-jejunal anastomosis with closed-suction silastic drains, along with the development of high-volume surgeons and hospitals. Excellent teamwork in patient care, including but not limited to preoperative evaluation by multidisciplinary teams, intraoperative communication between surgeons and anaesthesiologists, and postoperative management, contributed to a successful Whipple procedure.

Combination of Hydroquinone and Fractional CO2 Laser versus Hydroquinone Monotherapy in Melasma Treatment: A Randomized, Single-blinded, Split-face Clinical Trial.

BACKGROUND: Melasma is a chronic hyperpigmentation skin disorder mainly affecting women in the reproductive age. Available treatments for melasma do not lead to long-term satisfactory results. AIMS: This study aimed to compare the efficacy of fractional CO2 laser in combination with topical therapy to topical therapy alone. MATERIALS AND METHODS: Forty women with bilateral melasma were studied in this randomized single-blinded clinical trial. Each side of the face was randomly allotted to either topical hydroquinone 4% or combination of topical hydroquinone 4% and fractional CO2 laser. Patients received three sessions of laser therapy at 3-week intervals. Hydroquinone 4% application on both sides maintained for 3 months after the last laser session. The clinical improvement (darkness [D] and homogeneity [H] of hyperpigmentation) was measured by a blinded main investigator and an outcome assessor. Furthermore, improvement was assessed by physician's global assessment (PGA) and patient satisfaction (visual analog scale [VAS] score). RESULTS: Significant reduction in D observed 3 weeks after combination therapy (P<0.001) and 6 weeks after monotherapy (P<0.001). Reduction in H became significant after 6 weeks in both groups (P<0.001). However, the two methods were not considerably different in any session (P>0.05). Furthermore, control and experiment sides were not significantly different considering VAS score and PGA (P>0.05). CONCLUSION: Considering the short-term outcome of laser and hydroquinone therapy, we can apply it to obtain earlier positive results. However, because of the lack of significant difference between the two methods and also the high cost of laser therapy, it seems better not to recommend fractional CO2 laser to patients as adjunctive therapy for long-term treatment of melasma.