High-grade Disease Research Articles

Perioperative systemic therapy, current paradigm and ongoing clinical trials in upper tract urothelial cancer.

To provide of comprehensive overview of existing and future paradigms for perioperative systemic therapy in the treatment of upper tract urothelial carcinoma. Contemporary treatment paradigms for the management of upper tract urothelial carcinoma focus on use of neoadjuvant cisplatin based chemotherapy for high grade disease primarily based on two small single arm phase II clinical trials. More robust evidence from a phase III randomized clinical trial exists for the use of adjuvant platinum based chemotherapy for invasive disease after radical nephroureterectomy, but there are significant concerns about renal function and platinum eligibility after nephroureterectomy. There are currently ongoing clinical trials for nonplatinum based perioperative systemic therapies including checkpoint inhibitors/immunotherapy as well as antibody-drug conjugates, but currently no recommendation can be made for these approaches. Current evidence supports neoadjuvant cisplatin chemotherapy in the setting of high grade disease or concern for significant renal dysfunction after radical nephroureterectomy or platinum based adjuvant chemotherapy in eligible patients with advanced disease after surgery. While there is no established role for nonplatinum based therapies yet, multiple ongoing trials exploring use of immunotherapies and antibody-drug conjugates as monotherapy or combination may provide new therapeutic options in this population.

Post-marketing study design to evaluate the effectiveness of the 9-valent and 4-valent HPV vaccines on serious HPV-related cervical disease in China.

The 4-valent (4 v) and 9-valent (9 v) human papillomavirus (HPV) vaccines are approved in China for females aged 9-45 years. However, the real-world impact of 4vHPV or 9vHPV vaccination for the prevention of high-grade cervical disease in Chinese women is lacking. Two post-marketing surveillance studies will be conducted to measure the occurrence of high-grade cervical lesions in Chinese women who had received ≥1 dose of the 4vHPV (aged 20-45 years) or 9vHPV (aged 16-26 years) vaccine in Ningbo, China. Vaccination data will be extracted from the Ningbo Regional Health Information Platform (NRHIP) from the date of the first 4vHPV (January 9, 2018) or the first 9vHPV (January 25, 2019) vaccination to March 31, 2021. The primary 4vHPV and 9vHPV vaccinated cohorts will include women vaccinated per protocol. The 4vHPV/9vHPV vaccinated test-negative (cervical HPV negative; ThinPrep cytology test negative) and corresponding matched unvaccinated HPV test-negative sub-cohorts will also be assessed. Outcomes will be the occurrence of new-onset cervical intraepithelial neoplasia grade 2/3, adenocarcinoma in situ, and invasive cervical cancer. This study aims to demonstrate that such a methodological approach is feasible and can be used to assess the impact of HPV vaccination in other regions across China.

Characterizing the genomic landscape through the lens of FOLR1 status in low and high grade serous ovarian carcinoma

ObjectiveTargeted therapy in folate receptor alpha (FOLR1)-positive high grade serous ovarian carcinoma (HGSOC) is now a mainstay for platinum-resistant disease. However, the rate of FOLR1-positivity in low grade serous ovarian carcinoma (LGSOC) is not well documented. Less common than HGSOC, LGSOC tends to respond poorly to traditional platinum-based chemotherapeutic regimens, particularly in recurrence. Thus, there is an urgent need to identify molecular targets that may assist in identifying more efficacious treatments for LGSOC. In this work, we assessed the genomic and transcriptomic landscapes in FOLR1-positive/negative LGSOC compared to its high-grade counterpart. MethodsUsing a large precision oncology database, next-generation sequencing and immunohistochemistry was performed on a cohort of 281 LGSOC and 5086 HGSOC. Associated MAPK activation was calculated based on NGS results and patient survival analysis was completed stratified by molecular alteration. ResultsCompared with LGSOC (24.6 %), HGSOC tumors have significantly higher prevalence of FOLR1+ status (43.5 %) and significantly higher PD-L1+ status. Conversely, LGSOC had higher prevalence of KRAS and NRAS mutations, with a near exclusivity for BRAF mutation compared to HGSOC. FOLR1- LGSOC and HGSOC had similar prevalences of T cell-inflamed tumors, though FOLR1+ LGSOC had a significantly lower prevalence of T-Cell inflamed tumors than FOLR1+ HGSOC. MAPK activation, quantified via MAPK activation score (MPAS), was significantly higher in low-grade tumors compared to HGSOC, yet no difference between FOLR1+ vs FOLR1- LGSOC was observed. ConclusionsThough less than in high-grade disease, a notable portion of low-grade tumors were FOLR1+, suggesting FOLR1 expression in LGSOC could be a viable target for this rare histology, particularly in the recurrent setting.

The evolutionary history of metastatic pancreatic neuroendocrine tumours reveals a therapy driven route to high-grade transformation.

Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular may progress from a low/intermediate to a high-grade disease. The aim of this work was to understand the molecular mechanisms underlying metastatic progression as well as PanNET transformation from a low/intermediate to a high-grade disease. We performed multi-omics analysis (genome/exome sequencing, total RNA-sequencing and methylation array) of 32 longitudinal samples from six patients with metastatic low/intermediate grade PanNET. The clonal composition of tumour lesions and underlying phylogeny of each patient were determined with bioinformatics analyses. Findings were validated in post-alkylating chemotherapy samples from 24 patients with PanNET using targeted next generation sequencing. We validate the current PanNET evolutionary model with MEN1 inactivation that occurs very early in tumourigenesis. This was followed by pronounced genetic diversity on both spatial and temporal levels, with parallel and convergent tumour evolution involving the ATRX/DAXX and mechanistic target of the rapamycin (mTOR) pathways. Following alkylating chemotherapy treatment, some PanNETs developed mismatch repair deficiency and acquired a hypermutational phenotype. This was validated among 16 patients with PanNET who had high-grade progression after alkylating chemotherapy, of whom eight had a tumour mutational burden >50 (50%). In comparison, among the eight patients who did not show high-grade progression, 0 had a tumour mutational burden >50 (0%; odds ratio 'infinite', 95% confidence interval 1.8 to 'infinite', p = 0.02). Our findings contribute to broaden the understanding of metastatic/high-grade PanNETs and suggests that therapy driven disease evolution is an important hallmark of this disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

When is prostate cancer really cancer?

Prostate cancer (PC) is a major cause of cancer-related deaths worldwide, with far more diagnoses than deaths annually. Recent discussions have challenged whether Grade Group 1 (GG1) PC should be labeled "cancer" due to its indolent nature. To address this question, an international symposium convened stakeholders from various fields. We summarize key discussion points: autopsy studies reveal GG1 is so common in aging males as to be perhaps a normal aspect of aging. Pure GG1 has no capacity to metastasize. Modern diagnostic pathways focus on detecting higher-grade disease, explicitly omitting biopsy if GG 2 or higher is not suspected, so GG1 has effectively become an "incidentaloma." Recent spatial transcriptomics of prostate sections identifies a continuum of genomic changes-including alterations characteristic of malignancy in histologically normal regions, so the designation of cancer based entirely on conventional pathology findings increasingly seems arbitrary at least to an extent. Pathologists discussed heterogeneity and diagnostic challenges, suggesting "acinar neoplasm" as one possible alternative label. GG1 should not be considered "normal," and absolutely requires ongoing active surveillance; whether patients would adhere to surveillance absent a cancer diagnosis is unknown. Patient perspectives highlighted the adverse effects of overtreatment and the burden of a cancer diagnosis. The anticipated impact on screening and treatment varies across health-care systems, but many believe public health would on balance greatly improve if GG1-along with lesions in other organs with no capacity to cause symptoms or threaten life-were labeled something other than "cancer." Ultimately, our goal is to reduce PC mortality while minimizing harms associated with both overdiagnosis and overtreatment.

The prognostic significance of androgen receptor expression in gliomas

Androgen receptor (AR) overexpression has been identified in gliomas and its stem cells, suggesting that AR plays an important role in tumor carcinogenesis. The prognostic significance of AR overexpression in gliomas remains unknown. AR mRNA expression in gliomas and relevant clinical data were obtained from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. AR expression levels were compared across gliomas of different histopathologic grades and molecular subtypes. Kaplan–Meier analyses in patients with different AR expression levels were investigated for the potential prognostic values of AR. Compared with normal brain tissue, gliomas show significantly higher AR mRNA expression (p < 0.01). AR mRNA expression was more prominent in higher grade disease and in worse prognostic molecular subtypes (p < 0.01). AR protein is more abundant in glioblastoma than in lower grade gliomas (LGG) (grade 2/3) (p < 0.0001). This is corroborated by a linear association between AR mRNA and protein expression (r = 0.65). In LGG, both higher AR mRNA and protein expression was associated with significantly worse overall survival (OS). Five-year OS for LGG patients with high versus low AR expression were 59.1% and 73.3%, respectively (p < 0.0001). AR expression is not prognostic for OS within glioblastoma patients. Gender was not associated with AR expression or prognosis. Higher AR expression levels are associated with higher grade disease and histopathologic features predicting poorer prognosis in lower grade gliomas. Higher gene expression in LGG patients is correlated with poor prognosis but not in the glioblastoma cohort suggesting saturated expression/functions of AR in glioblastoma.

Does insulin resistance predict prostate cancer? Results from the Reduction by Dutasteride of Prostate Cancer (REDUCE) Trial.

Prior studies testing the association between insulin resistance (IR) and prostate cancer (PC) risk are inconsistent. We examined the association between Homeostatic Assessment of Insulin Resistance (HOMA-IR; calculated from fasting baseline insulin and glucose) and PC in REDUCE, a 4-year randomized trial of dutasteride vs. placebo for PC prevention. All patients had prestudy negative biopsies and underwent study mandated biopsies at 2 and 4 years regardless of prostate-specific antigen. Multivariable logistic regression models were used to investigate the associations between log-transformed or categorized HOMA-IR scores and PC risk. Multinominal regression was used to assess associations between HOMA-IR scores and tumor grade (low grade [grade group 1]; high-grade [grade groups 2-5]). Among 5430 REDUCE participants (1212 with PC; 856 low- and 356 high-grade), higher HOMA-IR was associated with lower PC risk (log-HOMA-IR: OR,0.89; 95% CI,0.80-0.99; p=.03; categorized HOMA-IR: p-trend=.04). When stratified by grade, HOMA-IR was significantly associated with reduced low-grade PC risk (log-HOMA-IR: OR,0.84; 95% CI,0.74-0.94; p=.003; categorized HOMA-IR: p-trend=.002) but was unrelated to high-grade PC (log-HOMA-IR: OR,1.02; 95% CI,0.86-1.21; p=.81; categorized HOMA-IR: p-trend=.26). Results were similar in placebo and treatment arms. In summary, higher HOMA-IR was associated with a reduced risk of low-grade PC but was not associated with high-grade disease. The mechanisms to explain these findings are unclear.

Upgrading of Grade Group 1 Prostate Cancer at Prostatectomy: Germline Risk Factors in a Prospective Cohort.

Localized prostate tumors show significant spatial heterogeneity, with regions of high-grade disease adjacent to lower-grade disease. Consequently, prostate cancer biopsies are prone to sampling bias, potentially leading to underestimation of tumor grade. To study the clinical, epidemiologic and molecular hallmarks of this phenomenon, we conducted a prospective study of grade upgrading: differences in detected prostate cancer grade between biopsy and surgery. We established a prospective, multi-institutional cohort of men with Grade Group 1 (GG1) prostate cancer on biopsy who underwent radical prostatectomy. Upgrading was defined as detection of GG2+ in the resected tumor. Germline DNA from 192 subjects was subjected to whole-genome sequencing to quantify ancestry, pathogenic variants in DNA damage response genes and polygenic risk. Of 285 men, 67% upgraded at surgery. PSA density and percent of cancer in pre-prostatectomy positive biopsy cores were significantly associated with upgrading. No assessed genetic risk factor was predictive of upgrading, including polygenic risk scores for prostate cancer diagnosis. In a cohort of low-grade prostate cancer patients, a majority upgraded at radical prostatectomy. PSA density and percent of cancer in pre-prostatectomy positive biopsy cores portended the presence of higher-grade disease, while germline genetics was not informative in this setting. Patients with low-risk prostate cancer, but elevated PSA density or percent cancer in positive biopsy cores, may benefit from repeat biopsy, additional imaging or other approaches to complement active surveillance. Further risk stratification of patients with low-risk prostate cancer may provide useful context for active surveillance decision-making.

Universal Genetic Testing for Newly Diagnosed Invasive Breast Cancer

Between 5% and 10% of breast cancer cases are associated with an inherited germline pathogenic or likely pathogenic variant (GPV) in a breast cancer susceptibility gene (BCSG), which could alter local and systemic therapy recommendations. Traditional genetic testing criteria misses a proportion of these cases. To evaluate the prevalence and clinicopathological associations of GPVs in 2 groups of BCSGs among an ethnically diverse cohort of women with newly diagnosed breast cancer. This cross-sectional study, conducted at 3 Montreal hospitals between September 2019 and April 2022, offered universal genetic counseling and testing to all women with a first diagnosis of invasive breast cancer. Women were offered an obligatory primary panel of BRCA1, BRCA2, and PALB2 (B1B2P2) and an optional secondary panel of 14 additional BCSGs. Eligible participants were women 18 years of age or older who received a diagnosis of a first primary invasive breast cancer not more than 6 months before the time of referral to the study. Data were analyzed from November 2023 to June 2024. Of 1017 referred patients, 805 were eligible and offered genetic counseling and testing, and 729 of those 805 (90.6%) consented to be tested. The median age at breast cancer diagnosis was 53 years (range, 23-91 years), and 65.4% were White and of European ancestry. Fifty-four GPVs were identified in 53 patients (7.3%), including 39 patients (5.3%) with B1B2P2 and 15 patients (2.1%) with 6 of the 14 secondary panel BCSGs (ATM, BARD1, BRIP1, CHEK2, RAD51D, and STK11). On multivariable analysis, clinical factors independently associated with B1B2P2-positive status included being younger than 40 years of age at diagnosis (odds ratio [OR], 6.83; 95% CI, 2.22-20.90), triple-negative breast cancer (OR, 3.19; 95% CI, 1.20-8.43), high grade disease (OR, 1.68; 95% CI, 1.05-2.70), and family history of ovarian cancer (OR, 9.75; 95% CI, 2.65-35.85). Of 39 B1B2P2-positive patients, 13 (33.3%) were eligible for poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. In this cross-sectional universal genetic testing study of women with newly diagnosed invasive breast cancer, the prevalence of GPVs was 7.3%, with 5.3% of patients testing positive for B1B2P2. Among B1B2P2-women women, one-third were eligible for PARP inhibitors.

Volumetric Modulated Arc Therapy for High-Risk and Very High-Risk Locoregional Prostate Cancer in the Modern Era: Real-World Experience from an Asian Cohort.

This study retrospectively evaluates the clinical outcomes of definitive volumetric modulated arc therapy (VMAT) for high-risk or very high-risk locoregional prostate cancer patients from an Asian institution. Consecutive patients who received VMAT (76 Gy in 38 fractions) between January 2017 and June 2022 were included. Whole pelvic radiotherapy (WPRT) (46 Gy in 23 fractions) was employed for clinically node-negative disease (cN0) and a Roach estimated risk of ≥15%, as well as simultaneous integrated boost (SIB) of 55-57.5 Gy to node-positive (cN1) disease. The primary endpoint was biochemical relapse-free survival (BRFS). Secondary endpoints included radiographic relapse-free survival (RRFS), metastasis-free survival (MFS) and prostate cancer-specific survival (PCSS). A total of 209 patients were identified. After a median follow-up of 47.5 months, the 4-year actuarial BRFS, RRFS, MFS and PCSS were 85.2%, 96.8%, 96.8% and 100%, respectively. The incidence of late grade ≥ 2 genitourinary (GU) and gastrointestinal (GI) toxicity were 15.8% and 11.0%, respectively. No significant difference in cancer outcomes or toxicity was observed between WPRT and prostate-only radiotherapy for cN0 patients. SIB to the involved nodes did not result in increased toxicity. International Society of Urological Pathology (ISUP) group 5 and cN1 stage were associated with worse RRFS (p < 0.05). PSMA PET-CT compared to conventional imaging staging was associated with better BRFS in patients with ISUP grade group 5 (p = 0.039). Five-year local experience demonstrates excellent clinical outcomes. PSMA PET-CT staging for high-grade disease and tailored pelvic irradiation based on nodal risk should be considered to maximize clinical benefit.

Urinary Free Glycosaminoglycans Identify Adults at High Risk of Developing Early-stage High-grade Bladder Cancer

Background and objectiveScreening for bladder cancer (BCa) could reduce mortality via early detection of early-stage high-grade (Ta/T1 N0 M0 grade 2–3) disease. Noninvasive biomarkers could aid in screening, but current markers lack the specificity required. The urinary free glycosaminoglycan profile (GAGome) is a promising biomarker for early detection of BCa metabolism. MethodsIn a prospective case-control development study, we included patients with BCa or no evidence of disease (NED) and measured the urinary GAGome. We then developed a score to predict the probability of BCa using GAGome features that correlated with BCa versus NED according to Bayesian regression. Next, in a retrospective, population-based, case-control study, we included adults from the Lifelines Cohort Study who were presumed healthy at baseline. All cases with BCa confirmed in the cancer registry by the 2-yr or 6-yr study visit were matched to randomly selected control subjects. We developed a reference logistic regression model using age and sex to predict BCa at 7 yr after baseline. We then added the GAGome score to the model and assessed model improvement using the likelihood ratio test. We dichotomized outputs for the reference model and saturated model (reference + GAGome score) into high-risk versus low-risk categories using a 99% specificity cutoff and estimated the sensitivity for association with BCa at 7 yr. Key findings and limitationsWe prospectively included 51 individuals with BCa and 38 with NED and observed alterations in three GAGome features compatible with BCa. We developed a score that discriminated BCa with an area under the receiver operating characteristic curve of 0.77 (95% confidence interval [CI] 0.67–0.87). We retrospectively selected a cohort of 1088 presumed healthy adults (median age 48 yr, 56% females), of whom 48 had developed BCa by 7 yr after baseline (median time to diagnosis 1.4 yr). The GAGome score was an independent predictor of BCa at 7 yr when added to the reference model (p < 0.001). The sensitivity for BCa at 7 yr for high-risk subjects was 31% (95% CI 20–43%) using the saturated model and 17% (95% CI 4.7–29%) using the reference model at 99% specificity (95% CI 98–99%). Conclusions and clinical implicationsThe urinary free GAGome is specifically altered in BCa and can be used for noninvasive identification of adults at high risk of developing BCa, independent of age and sex. This information could be useful for the design of risk-stratified targeted screening programs for BCa. Patient summaryWe tested whether measurement of a class of sugars called glycosaminoglycans (GAGs) in urine could be used for early detection of bladder cancer. Our results show that GAG levels in urine can distinguish people at high risk of developing bladder cancer within 7 years, even if they are healthy at the time of the urine sampling.

New therapeutic approaches for non-muscle invasive bladder cancer-is organ preservation also possible after BCG (Bacillus Calmette Guérin)?

Bacillus Calmette-Guérin (BCG) therapy is the standard of care in the treatment of high-risk non-muscle invasive bladder cancer (NMIBC). In the absence of aresponse to BCG and persistent high-grade disease, cystectomy is recommended depending on the clinical risk. Avariety of targeted therapy approaches, which aim at immune- and gene-based molecular targets, such as PD-(L)1 and FGFR, are currently being investigated in randomized studies for BCG-unresponsive NMIBC. Furthermore, novel forms of application for instillation therapy, such as the TAR device, in combination with gemcitabine or erdafitinib are being investigated in clinical trials in order to extend the duration of action of the active substance on the urothelium. Thus, there are now many developments that could make bladder-preserving therapy with comparable survival data possible as an alternative to BCG or in the event of BCG failure. In the future, it will be necessary to clarify how BCG response can be predicted by using molecular markers and how to define risk groups that should primarily be given an alternative therapy to BCG.

Selective Gastrectomy with Knowledge of Gastric Anatomy and Blood Supply are Key to Complete Tumour Removal in Advanced Pseudomyxoma: Single-Centre Experience with 120 Gastrectomies Over 20 Years.

The role of gastrectomy to achieve complete cytoreduction (CCR) for pseudomyxoma peritonei (PMP) is controversial due to uncertain risk/benefit ratio. The outcomes of patients who gastrectomy over a twenty-year period in a high-volume unit are reported. All patients requiring gastrectomy to achieve CCR for appendiceal PMP between 2000 and 2020 were reviewed. Demographics, disease, operative, complication, and survival data were analysed. The first and second decades were compared. A total of 2148 patients underwent CRS and HIPEC, of which 78% had CCR. Gastrectomy was performed in 7.1%. Median age was 55 years, and 52% were female. Among gastrectomy patients, 94.2% had ≥1 elevated tumour marker, and 18% had high-grade disease. Median PCI was 30, and 30% required subtotal colectomy. Clavien-Dindo III-IV complications occurred in 32%, and 90-day mortality was 1.75%. Median survival was 104 months, and 10-year OS was 47%. Comparing the two decades, total CRS cases almost tripled, with a greater proportion achieving CCR (82.2% vs. 67.8%) but fewer requiring gastrectomy (5.3% vs. 13.5%). In those who had gastrectomy, disease was more advanced (higher PCI, more high-grade disease, more colectomies) in the later period. However, on multivariable analysis, there was no difference in survival between decades. High-grade histology was the only predictor of survival. Gastrectomy can achieve good long-term survival with low mortality and acceptable morbidity and should not deter surgeons from achieving CCR. However, increasing experience shows CCR can be achieved, preserving the stomach in the majority of cases through careful consideration of the anatomy and gastric blood supply.

Radiographic predictors of muscle-invasive upper tract urothelial cancer

Introduction: Accurate diagnostic staging of upper tract urothelial cancer (UTUC) is challenging. Endoscopic staging is limited by its ability to provide adequate sampling of deeper layers of the ureter and renal pelvis. Further ability to accurately predict invasive disease would aid in better selecting the appropriate treatment for patients. We aimed to analyze the ability of preoperative cross-sectional radiologic findings to predict pathologic outcomes, including tumor grade, muscle-invasive disease, and presence of lymphovascular invasion (LVI). Methods: All patients diagnosed with localized UTUC (cN0M0) who underwent nephroureterectomy between February 2012 and December 2018 in Manitoba, Canada, were identified. Preoperative radiologic characteristics, including the presence and severity of hydronephrosis, as well as tumor location were recorded. Patients’ and pathologic characteristics were also recorded. Logistic regression analysis was used to assess the association between radiologic variables and pathologic outcomes at radical surgery. Results: A total of 112 pathology reports of patients with UTUC were obtained. The median age was 70 years (range 50–87), and 58.8% of patients were men. On univariate analysis, ureteric location on computed tomography (odds ratio [OR] 2.240, 95% confidence interval [CU] 1.049–4.783, p=0.037) and presence of hydronephrosis (OR 2.455, 95% CI 1.094–5.506, p=0.0029) were each independently associated with locally invasive disease (&gt;pT2). No radiologic variables were found to be a predictor of adverse pathology on multivariable analysis. Only the presence of hydronephrosis was associated with high-grade disease on univariate analysis (OR 2.533, 95% CI 1.083–5.931, p=0.032). Conclusions: Our findings suggest a limited role for cross-sectional imaging in predicting the presence of high-grade disease, LVI, or locally advanced disease in UTUC.

Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants.

Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10-4) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.

Risk of cervical high-grade squamous intraepithelial neoplasia in cytologic negative and persistently high-risk human papillomavirus positive patients according to genotypes: a retrospective single center analysis

In January 2020, a different cervical cancer screening program started in Germany. Women above the age of 35 are recommended to have a combined HPV and cytology swab every three years. Showing persistent high-risk human papillomavirus (hrHPV), cytologic negative cervical samples at baseline and after 12 months, patients are referred to colposcopy. Entailing considerable additional workload due to the required colposcopies, we analyzed the risk of high-grade cervical intraepithelial neoplasia (CIN 3) in cytologic negative and persistent hrHPV women according to their hrHPV genotypes.Methods In this single center retrospective study, patients with persistent hrHPV, cytology negative cervical samples from our certified Colposcopy Unit in 2020 and 2021 were analyzed. Patient demographics, hrHPV types, biopsy rates and histological reports were collected.Results During the study, 69 patients were enrolled. Most frequent hrHPV genotypes were: hrHPV other 72.5%; HPV 16, 20.3% and HPV 18, 7.2%. Colposcopy showed no or minor changes in 92.7% and major changes in 7.2%. CIN 3 was found in 7 patients (10.1%). Prevalence of CIN 3 by hrHPV genotypes was 27.3% for HPV16, 20.0% for HPV18 and 7.1% for HPVO. A statistically significant dependency between hrHPV and cervical intraepithelial neoplasia was demonstrated (p = 0.048).Conclusion Within this single center study of persistent hrHPV, cytologic negative samples, patients with HPV 16 were more likely to have high-grade disease compared to other hrHPV subtypes. Larger prospective randomized trials are needed to substantiate our results and obtain adjusted cervical cancer screening time intervals according to the hrHPV genotypes.

Augmentation of tumor expression of HLA-DR, CXCL9, and CXCL10 may improve olfactory neuroblastoma immunotherapeutic responses

BackgroundOlfactory neuroblastoma is a rare malignancy of the anterior skull base typically treated with surgery and adjuvant radiation. Although outcomes are fair for low-grade disease, patients with high-grade, recurrent, or metastatic disease oftentimes respond poorly to standard treatment methods. We hypothesized that an in-depth evaluation of the olfactory neuroblastoma tumor immune microenvironment would identify mechanisms of immune evasion in high-grade olfactory neuroblastoma as well as rational targetable mechanisms for future translational immunotherapeutic approaches.MethodsMultispectral immunofluorescence and RNAScope evaluation of the tumor immune microenvironment was performed on forty-seven clinically annotated olfactory neuroblastoma samples. A retrospective chart review was performed and clinical correlations assessed.ResultsA significant T cell infiltration was noted in olfactory neuroblastoma samples with a stromal predilection, presence of myeloid-derived suppressor cells, and sparse natural killer cells. A striking decrease was observed in MHC-I expression in high-grade olfactory neuroblastoma compared to low-grade disease, representing a mechanism of immune evasion in high-grade disease. Mechanistically, the immune effector stromal predilection appears driven by low tumor cell MHC class II (HLA-DR), CXCL9, and CXCL10 expression as those tumors with increased tumor cell expression of each of these mediators correlated with significant increases in T cell infiltration.ConclusionThese data suggest that immunotherapeutic strategies that augment tumor cell expression of MHC class II, CXCL9, and CXCL10 may improve parenchymal trafficking of immune effector cells in olfactory neuroblastoma and augment immunotherapeutic responses.

Current Treatment Options: Uterine Sarcoma.

The cornerstone of treatment for uterine sarcoma, regardless of histologic type, remains en bloc surgical resection with total hysterectomy. In the case of incidental diagnosis during another procedure, such as myomectomy, where a hysterectomy was not performed initially, completion hysterectomy or cervical remnant removal is recommended. The completion of additional surgical procedures, including bilateral salpingo-oophorectomy and lymphadenectomy, remains nuanced. Bilateral salpingo-oophorectomy remains controversial in the setting of most subtypes of uterine sarcoma, except in the case of hormone-receptor positivity, such as in low grade endometrial stromal sarcoma, where it is indicated as part of definitive surgical treatment. In the absence of apparent nodal involvement, we do not recommend performing universal lymphadenectomy for patients with sarcoma. We recommend systemic therapy for patients with extra-uterine or advanced stage disease, high-grade histology, and recurrence. The most active chemotherapy regimens for advanced, high-grade disease remain doxorubicin or gemcitabine and docetaxol combination therapy. A notable exception is low grade endometrial stromal sarcoma, where we recommend anti-hormonal therapy in the front-line setting. Radiation therapy is reserved for selected cases where it can aid in palliating symptoms.

Morphologic patterns observed in prostate biopsy cases with discrepant grade group and molecular risk classification.

Molecular-based risk classifier tests are increasingly being utilized by urologists and radiation oncologists to guide clinical decision making. The Decipher prostate biopsy test is a 22-gene RNA biomarker assay designed to predict likelihood of high-grade disease at radical prostatectomy and risk of metastasis and mortality. The test provides a risk category of low, intermediate, or high. We investigated histologic features of biopsies in which the Grade Group (GG) and Decipher risk category (molecular risk) were discrepant. Our institutional urologic outcomes database was searched for men who underwent prostate biopsies with subsequent Decipher testing from 2016 to 2020. We defined discrepant GG and molecular risk as either GG1-2 with high Decipher risk category or GG ≥ 3 with low Decipher risk category. The biopsy slide on which Decipher testing was performed was re-reviewed for GG and various histologic features, including % Gleason pattern 4, types of Gleason pattern 4 and 5, other "high risk" features (e.g., complex papillary, ductal carcinoma, intraductal carcinoma [IDC]), and other unusual and often "difficult to grade" patterns (e.g., atrophic carcinoma, mucin rupture, pseudohyperplastic carcinoma, collagenous fibroplasia, foamy gland carcinoma, carcinoma with basal cell marker expression, carcinoma with prominent vacuoles, and stromal reaction). Follow-up data was also obtained from the electronic medical record. Of 178 men who underwent prostate biopsies and had Decipher testing performed, 41 (23%) had discrepant GG and molecular risk. Slides were available for review for 33/41 (80%). Of these 33 patients, 23 (70%) had GG1-2 (GG1 n = 5, GG2 n = 18) with high Decipher risk, and 10 (30%) had GG ≥ 3 with low Decipher risk. Of the 5 GG1 cases, one case was considered GG2 on re-review; no other high risk features were identified but each case showed at least one of the following "difficult to grade" patterns: 3 atrophic carcinoma, 1 collagenous fibroplasia, 1 carcinoma with mucin rupture, and 1 carcinoma with basal cell marker expression. Of the 18 GG2 high Decipher risk cases, 2 showed GG3 on re-review, 5 showed large cribriform and/or other high risk features, and 10 showed a "difficult to grade" pattern. Of the 10 GG ≥ 3 low Decipher risk cases, 5 had known high risk features including 2 with large cribriform, 1 with IDC, and 1 with Gleason pattern 5. In GG1-2 high Decipher risk cases, difficult to grade patterns were frequently seen in the absence of other known high risk morphologic features; whether these constitute true high risk cases requires further study. In the GG ≥ 3 low Decipher risk cases, aggressive histologic patterns such as large cribriform and IDC were observed in half (50%) of cases; therefore, the molecular classifier may not capture all high risk histologic patterns.

A cross-sectional study of ERG expression and the relationship with clinicopathological features of Prostate cancer in Southwestern Uganda

BackgroundProstate cancer is the leading cause of cancer-related death and the second most commonly diagnosed cancer among men in Uganda and most countries in Sub-Saharan Africa (SSA). The TMPRSS2-ERG fusion gene is the most common genetic alteration seen among prostate cancer patients. There are several contradicting reports about the association of ERG protein with poor prognosis, high PSA, and Gleason score. This study determined the prevalence of ERG expression and the relationship with PSA, Gleason score, and Age of prostate cancer patients in Southwestern Uganda.MethodsWe reviewed 130 archived prostate biopsy (needle and TURP) specimens from patients of age ≥ 50 years who had a histological diagnosis of prostate cancer. We obtained their biodata, and preoperative PSA, from the archived records. We did Immunohistochemistry (IHC) to determine the prevalence of ERG expression.ResultsThe mean patient age in our study was 74.64 ± 10.19 years. Pre-operative PSA levels had been done for 79.2% of the participants. Most cancers (58.46%) were of high grade (grade group 3–5). ERG expression prevalence was 75.4% and its expression was independent of age, re-operative PSA, and Gleason score.ConclusionThere is a significantly higher prevalence of ERG expression in our study compared to what is reported in other African-based studies. The expression of the ERG is independent of age, Gleason score, and serum PSA levels. A high proportion of our prostate cancer has high-grade disease at the time of diagnosis.