Excess weight, weight gain, and prostate cancer risk and prognosis: the PROCA-life study.

BACKGROUND: Studies of excess weight and weight changes throughout adult life for prostate cancer (PCa) risk and prognosis have shown inconsistent results. METHODS: In a population-based cohort, the Prostate Cancer Study throughout life (PROCA-life), 16,960 healthy men from the prospective cohort Tromsø Study (1994-2016) were included. Body mass index (BMI) and weight were measured at all four attendings, and weight change was calculated as the difference between the first and last of either Tromsø4, Tromsø5 or Tromsø6. Overall, 904 men developed PCa during 16 years of follow-up, and Poisson regression with fractional polynomials was used to investigate trends in incidence. Cox proportional hazard and logistic regression models were used to study associations between measurements of BMI and weight change and PCa risk, severity, and mortality. RESULTS: At study entry, 46% of the participants (median age 44 years) were overweight, and 14% were obese (BMI > 30 kg/m2). We observed a 127% increase in overall age adjusted PCa incidence in the cohort during 1995 through 2019. No overall associations between BMI or weight change and PCa risk were observed. However, in sub-group analysis, weight gain among obese men was associated with a three-fold higher PCa risk (HR 3.03, 95% CI 1.39-6.58) compared with obese men with stable weight. Overweight was associated with lower risk of metastatic cancer (OR 0.48, 95% CI 0.30-0.75) at diagnosis. Men with obesity had higher risk of PCa-specific death (HR 1.72, 95% CI 1.03-2.88), while nonsmoking obese PCa cases had two times higher PCa-specific mortality compared with normal weighted PCa cases (HR 2.10, 95% CI 1.11-3.70). INTERPRETATION: In our cohort, weight gain among obese men was associated with higher risk of PCa, and obesity was associated with higher PCa-specific mortality, especially among nonsmokers. The relationship between weight and risk for PCa remains complicated, and future studies are needed to determine clinical implications.

Patient-reported outcomes after curative treatment for prostate cancer with prostatectomy, primary radiotherapy or salvage radiotherapy.

BACKGROUND: Trials reporting adverse health outcomes (AHOs) in terms of patient-reported outcome measures (PROMs) after contemporary curative treatment of prostate cancer (PC) are hampered by study heterogeneity and lack of new treatment techniques. Particularly, the evidence regarding toxicities after radiotherapy (RT) with the volumetric arc therapy (VMAT) technique is limited, and comparisons between men treated with surgery, primary radiotherapy (PRT) and salvage radiotherapy (SRT) are lacking. The aim of the study was to evaluate change in PROMs 3 months after treatment with robotic-assisted laparoscopic prostatectomy (RALP), PRT and SRT administered with VMAT. MATERIAL AND METHODS: A prospective cohort study of men with PC who received curative treatment at the University Hospital of North Norway between 2012 and 2017 for RALP and between 2016 and 2021 for radiotherapy was conducted. A cohort of 787 men were included; 406 men treated with RALP, 265 received PRT and 116 received SRT. Patients completed the validated PROM instrument EPIC-26 before (pre-treatment) and 3 months after treatment. EPIC-26 domain summary scores (DSSs) were analysed, and changes from pre-treatment to 3 months reported. Changes were deemed clinically relevant if exceeding validated minimally clinically important differences (MCIDs). RESULTS: Men treated with RALP reported clinically relevant declining urinary incontinence DSS (-41.7 (SD 30.7)) and sexual DSS (-46.1 (SD 30.2)). Men who received PRT reported worsened urinary irritative DSS (-5.2 (SD 19.6)), bowel DSS (-8.2 (SD 15.1)) and hormonal DSS (-9.6 (SD 18.2)). Men treated with SRT experienced worsened urinary incontinence DSS (-7.3 (SD 18.2)), urinary irritative DSS (-7.5 (SD 14.0)), bowel DSS (-12.5 (SD 16.1)), sexual DSS (-14.9 (SD 18.9)) and hormonal DSS (-23.8 (SD 20.9)). CONCLUSION: AHOs 3 months after contemporary curative treatment for PC varied according to treatment modality and worsened in all treatment groups, although most in SRT.

Proteomic analyses identify major vault protein as a prognostic biomarker for fatal prostate cancer.

The demographic shift toward an older population will increase the number of prostate cancer cases. A challenge in the treatment of prostate cancer is to avoid undertreatment of patients at high risk of progression following curative treatment. These men can benefit from early salvage treatment. An explorative cohort consisting of tissue from 16 patients who underwent radical prostatectomy, and were either alive or had died from prostate cancer within 10 years postsurgery, was analyzed by mass spectrometry analysis. Following proteomic and bioinformatic analyses, major vault protein (MVP) was identified as a putative prognostic biomarker. A publicly available tissue proteomics dataset and a retrospective cohort of 368 prostate cancer patients were used for validation. The prognostic value of the MVP was verified by scoring immunohistochemical staining of a tissue microarray. High level of MVP was associated with more than 4-fold higher risk for death from prostate cancer (hazard ratio = 4.41, 95% confidence interval: 1.45-13.38; P = 0.009) in a Cox proportional hazard models, adjusted for Cancer of the Prostate Risk Assessments Post-surgical (CAPRA-S) score and perineural invasion. Decision curve analyses suggested an improved standardized net benefit, ranging from 0.06 to 0.18, of adding MVP onto CAPRA-S score. This observation was confirmed by receiver operator characteristics curve analyses for the CAPRA-S score versus CAPRA-S and MVP score (area under the curve: 0.58 versus 0.73). From these analyses, one can infer that MVP levels in combination with CAPRA-S score might add onto established risk parameters to identify patients with lethal prostate cancer.

Tertiary lymphoid structure score: a promising approach to refine the TNM staging in resected non-small cell lung cancer.

BACKGROUND: We previously proposed an immune cell score (tumour node metastasis (TNM)-Immune cell score) classifier as an add-on to the existing TNM staging system for non-small cell lung cancer (NSCLC). Herein, we examined how to reliably assess a tertiary lymphoid structure (TLS) score to refine the TNM staging system. METHODS: Using immunohistochemistry (CD8/cytokeratin), we quantified TLS in resected NSCLC whole-tumour tissue sections with three different scoring models on two independent collections (total of 553 patients). In a pilot setting, NanoString gene expression signatures were analysed for associations with TLS. RESULTS: The number of TLSs significantly decreased in stage III patients as compared to stage II. The TLS score was an independent positive prognostic factor, regardless of the type of (semi)-quantification strategy used (four-scale semi-quantitative; absolute count of total TLS; subpopulation of mature TLS) or the endpoint (disease-specific survival; overall survival; time to recurrence). Subgroup analyses revealed a significant prognostic impact of TLS score within each pathological stage, patient cohort and main histological subtype. Targeted gene expression analysis showed that high TLS levels were associated with the expression of B cell and adaptive immunity genes/metagenes including tumour inflammation signature. CONCLUSIONS: The TLS score increases the prognostic power in each pathological stage and hence has the potential to refine TNM staging in resected NSCLC.

Inflammatory serum markers and risk and severity of prostate cancer: The PROCA-life study.

Whether chronic inflammation mirrored by high levels of systemic inflammatory markers such as high sensitive-CRP (hs-CRP) and white blood cell count (WBC) are associated with prostate cancer development remains unclear. In the Prostate Cancer Study throughout Life (PROCA-life), a prospective population-based cohort study, 7,356 men were included. Prediagnostic WBC and hs-CRP were assessed from blood collected at study entry; 2,210 participants also had a second CRP measure during follow-up. During a mean 11.8 years follow-up, 509 men developed prostate cancer (mean age at diagnosis 71.7 years). Multivariable Cox proportional hazard regression models were used to study whether individual biomarkers (WBC, hs-CRP), a combined score based on analyte tertiles (score range 2-6), or change in CRP were associated with risk and severity of prostate cancer. We observed a positive dose-response relationship between hs-CRP and prostate cancer risk with a Hazard Ratio (HR) per mg/l of 1.3, 95% CI 1.00-1.07. Men with an increase in hs-CRP between two measurements (Δhs-CRP) of ≥1.00 mg/l had a 36% increased risk of prostate cancer (HR 1.36, 95% CI 1.02-1.82), compared to men with no change or decrease in hs-CRP. Men with a systemic inflammatory score of 5 or 6 had a 68% higher risk of being diagnosed with metastatic disease (HR 1.68, 95% CI, 1.04-2.73) compared to men with lower scores. Our study supports that hs-CRP including repeated measurements alone or in combination with WBC may be a useful inflammation-related biomarker for prostate cancer risk and prognosis.

Simultaneous Detection of Zinc and Its Pathway Metabolites Using MALDI MS Imaging of Prostate Tissue.

Levels of zinc, along with its mechanistically related metabolites citrate and aspartate, are widely reported as reduced in prostate cancer compared to healthy tissue and are therefore pointed out as potential cancer biomarkers. Previously, it has only been possible to analyze zinc and metabolites by separate detection methods. Through matrix-assisted laser desorption/ionization mass spectrometry imaging (MSI), we were for the first time able to demonstrate, in two different sample sets (n = 45 and n = 4), the simultaneous spatial detection of zinc, in the form of ZnCl3-, together with citrate, aspartate, and N-acetylaspartate on human prostate cancer tissues. The reliability of the ZnCl3- detection was validated by total zinc determination using laser ablation inductively coupled plasma MSI on adjacent serial tissue sections. Zinc, citrate, and aspartate were correlated with each other (range r = 0.46 to 0.74) and showed a significant reduction in cancer compared to non-cancer epithelium (p < 0.05, log2 fold change range: -0.423 to -0.987), while no significant difference between cancer and stroma tissue was found. Simultaneous spatial detection of zinc and its metabolites is not only a valuable tool for analyzing the role of zinc in prostate metabolism but might also provide a fast and simple method to detect zinc, citrate, and aspartate levels as a biomarker signature for prostate cancer diagnostics and prognostics.

CTLA-4 expression in the non-small cell lung cancer patient tumor microenvironment: diverging prognostic impact in primary tumors and lymph node metastases.

The immune checkpoint receptor CTLA-4 plays a crucial part in negatively regulating T cell activation and maintaining self-tolerance. It is frequently overexpressed in a variety of malignancies, yet its prognostic impact in non-small cell lung cancer (NSCLC) remains unclear. We constructed tissue microarrays from tumor tissue samples and evaluated the immunohistochemical expression of CTLA-4 in 536 patients with primary resected stage I-IIIA NSCLC. Expression of CTLA-4 was analyzed in tumor and stromal primary tumor tissue and in locoregional metastatic lymph nodes. CTLA-4 expression in neither tumor epithelial cells (T-CTLA-4) nor stromal cells (S-CTLA-4) of primary tumors was significantly associated with disease-specific survival (DSS) in all patients. However, high S-CTLA-4 expression independently predicted significantly improved DSS in the squamous cell carcinoma subgroup (HR 0.62, 95% CI 0.41-0.93, P = 0.021). In contrast, there was an independent negative prognostic impact of T-CTLA-4 expression in metastatic lymph nodes (HR 1.65, 95% CI 1.03-2.65, P = 0.039). Our results indicate that the expression of CTLA-4 has diverging prognostic impacts in metastatic NSCLC lymph nodes versus primary tumors. The presented results highlight important differences in the tumor microenvironments of primary and metastatic NSCLC tissues, and have potential to guide treatment and clinical sampling strategies.

The prognostic significance of CXCL16 and its receptor C-X-C chemokine receptor 6 in prostate cancer.

The chemokine CXCL16 and its receptor, C-X-C chemokine receptor (CXCR6), affect tumor progression through different pathways, including leukocyte recruitment and function, cellular senescence, tumor cell proliferation, survival, invasion, and metastasis. We examined how the expression of CXCL16/CXCR6 in prostate cancer (PC) was related to clinicopathological features and activation of inflammatory cells. Tissue microarrays from 535 patients were constructed from tumor epithelial and tumor stromal areas of primary PC. Immunohistochemistry was used to evaluate the expression of CXCL16/CXCR6, CD3(+) T cells (CD4(+), CD8(+)), and CD20(+) B cells. Survival analyses were used to evaluate their prognostic impact. Expression of CXCL16 in PC cell lines (DU145 and PC3) and the effect on proliferation and migration were examined. High expression levels of CXCL16 [hazard ratio (HR), 2.52; 95% CI, 1.12-5.68; P = 0.026] and CXCR6 (HR, 2.29; 95% CI, 1.10-4.82; P = 0.028) were each independent predictors for clinical failure. High co-expression of CXCL16 and CXCR6 (HR, 5.1; 95% CI, 1-15.9; P = 0.05) was associated with negative prognostic factors, such as Gleason grade 4 + 3, Gleason score ≥7, vascular infiltration, and positive surgical margins. As a conclusion, high protein expression of CXCL16 and high protein co-expression of CXCL16/CXCR6 in PC were independent predictors for a worse clinical outcome.

Keratin 34betaE12/keratin7 expression is a prognostic factor of cancer-specific and overall survival in patients with early stage non-small cell lung cancer.

BACKGROUND: Carcinomas and their metastases often retain the keratin patterns of their epithelial origin, and are therefore useful as lineage-specific markers in diagnostic pathology. Recently, it has become clear that intermediate filaments composed by keratins play a role in modulation of cell proliferation, migration, and possibly cancer invasion, factors impacting prognosis in early stage non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Tumor tissue from a retrospective Danish cohort of 177 patients with completely resected NSCLC, stage I-IIIA tumors, were analyzed for keratin 7 (K7) and keratin 34ßE12 expression by immunohistochemistry and validated in a comparable independent Norwegian cohort of 276 stage I-IIIA NSCLC patients. RESULTS: Based on keratin 34ßE12/K7 expression, three subgroups with significantly different median cancer-specific survival rates were identified (34ßE12+/K7+, 168 months vs. 34ßE12+/K7+, 73 months vs. 34ßE12-/K7+, 30 months; p = 0.0004). In multivariate analysis, stage II-IIIA (HR 2.9), 34ßE12+/K7+ (HR 1.90) and 34ßE12-/K7+ (HR 3.7), were prognostic factors of poor cancer-specific survival (CSS) (p < 0.001). Validation in the Norwegian cohort confirmed that stage II-IIIA (HR 2.3), 34ßE12+/K7+ (HR 1.6), and 34ßE12-/K7+ (HR 2.0) were prognostic factors of poor CSS (p < 0.05). Multivariate Cox proportional-hazard analysis demonstrated that 34ßE12+/K7 + and 34ßE12+/K7 + status was significantly associated with poor overall survival (p < 0.05). CONCLUSION: Keratin 34ßE12/K7 expression is a prognostic parameter in resected early stage NSCLC that allows identification of high-risk NSCLC patients with poor cancer-specific and overall survival.

Stromal expression of VEGF-A and VEGFR-2 in prostate tissue is associated with biochemical and clinical recurrence after radical prostatectomy.

BACKGROUND: There is probably significant overtreatment of patients with prostate cancer due to a lack of sufficient diagnostic tools to predict aggressive disease. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are potent mediators of angiogenesis and tumor proliferation, but have been examined to a limited extent in large prostate cancer studies. Meanwhile, recent promising results on VEGFR-2 inhibition have highlighted their importance, leading to the need for further investigations regarding their expression and prognostic impact. DESIGN: Using tissue microarray and immunohistochemistry, the expression of VEGFs (VEGF-A and VEGF-C) and their receptors (VEGFR-2 and VEGFR-3) were measured in neoplastic tissue and corresponding stroma from radical prostatectomy specimens in 535 Norwegian patients. Their expression was evaluated semiquantatively and associations with event-free survival were calculated. RESULTS: High expression of VEGFR-2 in either stroma or epithelium was independently associated with a higher incidence of prostate cancer relapse (HR = 4.56, P = 0.038). A high combined expression of either VEGF-A, VEGFR-2 or both in stroma was independently associated with a higher incidence of biochemical failure (HR = 1.77, P = 0.011). CONCLUSIONS: This large study highlights the prognostic importance of VEGF-A and VEGFR-2 stromal expression. Analyses of these biomarkers may help distinguish which patients will benefit from radical treatment. Together with previous studies showing efficiency of targeting VEGFR-2 in prostate cancer, this study highlights its potential as a target for therapy, and may aid in future selection of prostate cancer patients for novel anti-angiogenic treatment.

Prognostic impact of CXCL16 and CXCR6 in non-small cell lung cancer: combined high CXCL16 expression in tumor stroma and cancer cells yields improved survival.

BACKGROUND: The chemokine CXCL16 and its receptor CXCR6 are expressed by a variety of immune cells and have been shown to influence angiogenesis. The expression of CXCR6 and CXCL16 has been examined in numerous human cancers; however no studies have yet investigated their influence on prognosis in non-small cell lung cancer (NSCLC). We aimed to explore their prognostic significance in NSCLC, in addition to examining associations with previously investigated markers. METHODS: Resected tumor tissue from 335 consecutive unselected stage I-IIIA NSCLC patients (1990-2005) were collected. Immunohistochemistry was used to evaluate the expression of CXCR6 and CXCL16 on tissue microarrays. In vitro, NSCLC cells (NCI-H460, A549 cells) were transfected with CXCL16 siRNA to examine effects on proliferation. RESULTS: In univariate analysis, ↑ stromal cell CXCL16 expression was a significant positive prognostic factor (P = 0.016). CXCR6 was expressed in cancer cells, but did not show any prognostic impact. In the multivariate analysis, combined ↑cancer, and ↑stromal cell CXCL16 expression was an independent positive prognostic factor when compared to ↓stromal and ↓cancer cell expression (HR: 0.42; 95 % CI: 0.20-0.88; P = 0.022). Knockdown of CXCL16 by siRNA resulted in accelerated proliferation of NSCLC cell lines. CONCLUSION: We have shown that combined ↑cancer and ↑stromal cell CXCL16 expression is an independent positive prognostic factor in NSCLC. Further studies are warranted to elucidate the biological mechanism underlying this finding.

Infiltration of CD8+ lymphocytes is an independent prognostic factor of biochemical failure-free survival in prostate cancer.

BACKGROUNDS: The adaptive immune system can potentially have dual roles in cancer development and progression by contributing to or suppressing tumor progression and metastasis. The aim of this study was to evaluate the prognostic impact of adaptive immune cells residing in different tumor compartments in prostate cancer. METHODS: Tissue microarrays from 535 patients were constructed from viable and representative tumor epithelial and stromal areas of primary PC tumors, as well as from normal epithelial and stromal areas. Immunohistochemistry was used to evaluate the density of CD3+, CD4+, CD8+, and CD20+ lymphocytes in both tumor epithelial and tumor stromal areas. RESULTS: In univariate analysis, a high density of CD3+ (P = 0.037) and CD8+ lymphocytes (P = 0.010) in tumor epithelial areas was associated with significantly shorter biochemical failure-free survival. When analyzing both tumor epithelial and stromal tissue compartments as one entity, similar relationships were observed for CD3+ (P = 0.046), CD4+ (P = 0.026), and CD8+ (P = 0.003) lymphocytes. In multivariate analysis, high densities of CD8+ lymphocytes limited to tumor epithelial areas (HR = 1.45, P = 0.032), as well as in the total tumor tissue (HR = 1.57, P = 0.007), were independent negative prognostic factors for biochemical failure-free survival. CONCLUSIONS: A high density of CD8+ lymphocytes, especially in tumor epithelial areas, is an independent negative prognostic factor for biochemical failure-free survival.

Disease-specific outcomes of radical prostatectomies in Northern Norway; a case for the impact of perineural infiltration and postoperative PSA-doubling time.

BACKGROUND: Prostate cancer is the most common male malignancy and a mayor cause of mortality in the western world. The impact of clinicopathological variables on disease related outcomes have mainly been reported from a few large US series, most of them not reporting on perineural infiltration. We therefore wanted to investigate relevant cancer outcomes in patients undergoing radical prostatectomy in two Norwegian health regions with an emphasis on the impact of perineural infiltration (PNI) and prostate specific antigen- doubling time (PSA-DT). METHODS: We conducted a retrospective analysis of 535 prostatectomy patients at three hospitals between 1995 and 2005 estimating biochemical failure- (BFFS), clinical failure- (CFFS) and prostate cancer death-free survival (PCDFS) with the Kaplan-Meier method. We investigated clinicopathological factors influencing risk of events using cox proportional hazard regression. RESULTS: After a median follow-up of 89 months, 170 patients (32%) experienced biochemical failure (BF), 36 (7%) experienced clinical failure and 15 (3%) had died of prostate cancer. pT-Stage (p = 0.001), preoperative PSA (p = 0.047), Gleason Score (p = 0.032), non-apical positive surgical margins (PSM) (p = 0.003) and apical PSM (p = 0.031) were all independently associated to BFFS. Gleason score (p = 0.019), PNI (p = 0.012) and non-apical PSM (p = 0.002) were all independently associated to CFFS while only PNI (P = 0.047) and subgroups of Gleason score were independently associated to PCDFS. After BF, patients with a shorter PSA-DT had independent and significant worse event-free survivals than patients with PSA-DT > 15 months (PSA-DT = 3-9 months, CFFS HR = 6.44, p < 0.001, PCDFS HR = 13.7, p = 0.020; PSA-DT < 3 months, CFFS HR = 11.2, p < 0.001, PCDFS HR = 27.5, p = 0.006). CONCLUSIONS: After prostatectomy, CFFS and PCDFS are variable, but both are strongly associated to Gleason score and PNI. In patients with BF, PSA-DT was most strongly associated to CF and PCD. Our study adds weight to the importance of PSA-DT and re-launches PNI as a strong prognosticator for clinically relevant endpoints.

Post-Conization HPV Vaccination and Its Impact on Viral Status: A Retrospective Cohort Study in Troms and Finnmark, 2022.

Human papillomavirus (HPV) is associated with cellular changes in the cervix leading to cancer, which highlights the importance of vaccination in preventing HPV infections and subsequent cellular changes. Women undergoing the loop electrosurgical excision procedure (LEEP), a treatment for high-grade cervical intraepithelial neoplasia (CIN2+), remain at risk of recurrence. This study assessed the effect of post-conization HPV vaccination on the viral status of women at six months post-conization, aiming to evaluate the vaccine's effectiveness in preventing recurrence of CIN2+. A retrospective cohort study was conducted among women in Troms and Finnmark who underwent conization in 2022. Using the SymPathy database and the national vaccination register (SYSVAK), we analyzed the vaccination statuses and HPV test results of women born before 1991, who had not received the HPV vaccine prior to conization. Out of 419 women undergoing conization, 243 met the inclusion criteria. A significant association was found between post-conization HPV vaccination and a negative HPV test at six months of follow-up (ARR = 12.1%, p = 0.039). Post-conization HPV vaccination significantly reduced the risk of a positive HPV test at the first follow-up, suggesting its potential in preventing the recurrence of high-grade cellular changes. However, the retrospective design and the insufficient control of confounding variables in this study underscore the need for further studies to confirm these findings.

The Longitudinal Course of Prospectively Recorded Patient-reported Outcomes in Prostate Cancer Patients Treated with Surgery and Salvage Radiotherapy.

Background: Patient-reported outcome measures (PROMs) after prostate cancer (PC) treatment, including both radical prostatectomy (RP) and salvage radiation therapy (SRT), are under-reported. Objective: To investigate PROMs longitudinally from before SRT until 18 mo after SRT for men treated with contemporary treatment modalities. Design setting and participants: This prospective, longitudinal cohort study included 120 men (whole cohort) treated with SRT administered with volumetric modulated arc radiotherapy from 2016 to 2021 at the University Hospital of North Norway. The whole cohort was followed from before SRT until 18 mo after SRT. A subcohort of 48 men was followed from before RP until 18 mo after SRT. Outcome measurements and statistical analysis: PROMs were collected with the Expanded Prostate Cancer Index-26 (EPIC-26), covering symptoms of urinary incontinence, urinary irritative, bowel, sexual, and hormonal domains. The domain scores were inquired before RP, 3 mo after RP, before SRT, at SRT termination, and 3 and 18 mo after SRT. We used linear mixed models with repeated measurements design to assess changes in PROMs throughout the treatment period. Results and limitations: The median age before SRT was 63 yr. For the whole cohort, all five domains worsened at 3 and 18 mo after SRT compared with those before SRT. The estimated mean changes from before SRT to 18 mo after SRT are as follows: urinary incontinence -13.1, urinary irritative function -10.4, bowel -16.8, sexual function -9.1, and hormonal function -20.2 (at clinically important levels for all domains but sexual). For the subcohort, the mean urinary incontinence, bowel, sexual, and hormonal functions were significantly worsened 3 and 18 mo after SRT compared with those before RP at clinically important levels. Conclusions: Men treated for PC report particular increased severity of urinary, bowel, sexual, and hormonal symptoms after SRT compared with baseline status. Patient summary: For men with prostate cancer, the treatment combination of surgery and salvage radiotherapy worsens urinary incontinence and bowel, sexual, and hormonal functions.

Association of Machine Learning-Based Assessment of Tumor-Infiltrating Lymphocytes on Standard Histologic Images With Outcomes of Immunotherapy in Patients With NSCLC.

Importance: Currently, predictive biomarkers for response to immune checkpoint inhibitor (ICI) therapy in lung cancer are limited. Identifying such biomarkers would be useful to refine patient selection and guide precision therapy. Objective: To develop a machine-learning (ML)-based tumor-infiltrating lymphocytes (TILs) scoring approach, and to evaluate TIL association with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This multicenter retrospective discovery-validation cohort study included 685 ICI-treated patients with NSCLC with median follow-up of 38.1 and 43.3 months for the discovery (n = 446) and validation (n = 239) cohorts, respectively. Patients were treated between February 2014 and September 2021. We developed an ML automated method to count tumor, stroma, and TIL cells in whole-slide hematoxylin-eosin-stained images of NSCLC tumors. Tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) expression were assessed separately, and clinical response to ICI therapy was determined by medical record review. Data analysis was performed from June 2021 to April 2022. Exposures: All patients received anti-PD-(L)1 monotherapy. Main Outcomes and Measures: Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were determined by blinded medical record review. The area under curve (AUC) of TIL levels, TMB, and PD-L1 in predicting ICI response were calculated using ORR. Results: Overall, there were 248 (56%) women in the discovery cohort and 97 (41%) in the validation cohort. In a multivariable analysis, high TIL level (≥250 cells/mm2) was independently associated with ICI response in both the discovery (PFS: HR, 0.71; P = .006; OS: HR, 0.74; P = .03) and validation (PFS: HR = 0.80; P = .01; OS: HR = 0.75; P = .001) cohorts. Survival benefit was seen in both first- and subsequent-line ICI treatments in patients with NSCLC. In the discovery cohort, the combined models of TILs/PD-L1 or TMB/PD-L1 had additional specificity in differentiating ICI responders compared with PD-L1 alone. In the PD-L1 negative (<1%) subgroup, TIL levels had superior classification accuracy for ICI response (AUC = 0.77) compared with TMB (AUC = 0.65). Conclusions and Relevance: In these cohorts, TIL levels were robustly and independently associated with response to ICI treatment. Patient TIL assessment is relatively easily incorporated into the workflow of pathology laboratories at minimal additional cost, and may enhance precision therapy.

Expression of miR-24-1-5p in Tumor Tissue Influences Prostate Cancer Recurrence: The PROCA-life Study.

The role of miR-24-1-5p and its prognostic implications associated with prostate cancer are mainly unknown. In a population-based cohort, the Prostate Cancer Study throughout life (PROCA-life), all men had a general health examination at study entry and were followed between 1994 and 2016. Patients with available tissue samples after a prostatectomy with curative intent were identified (n = 189). The tissue expression of miR-24-1-5p in prostate cancer was examined by in situ hybridization (ISH) in tissue microarray (TMA) blocks by semi-quantitative scoring by two independent investigators. Multivariable Cox regression models were used to study the associations between miR-24-1-5p expression and prostate cancer recurrence. The prostate cancer patients had a median age of 65.0 years (range 47−75 years). The Cancer of the Prostate Risk Assessment Postsurgical Score, International Society of Urological Pathology grade group, and European Association of Urology Risk group were all significant prognostic factors for five-year recurrence-free survival (p < 0.001). Prostate cancer patients with a high miR-24-1-5p expression (≥1.57) in the tissue had a doubled risk of recurrence compared to patients with low expression (HR 1.99, 95% CI 1.13−3.51). Our study suggests that a high expression of miR-24-1-5p is associated with an increased risk of recurrence of prostate cancer after radical prostatectomy, which points to the potential diagnostic and therapeutic value of detecting miR-24-1-5p in prostate cancer cases.

Systolic and diastolic blood pressure, prostate cancer risk, treatment, and survival. The PROCA-life study.

BACKGROUND: Inflammation has been linked to prostate cancer and hypertension, but it remains equivocal whether elevated blood pressure (BP) influence prostate cancer risk and survival. METHOD: Using Cox regression models, we examined the association between prediagnostic BP and prostate cancer risk among 12,271 men participating in the Prostate Cancer throughout life (PROCA-life) study. Systolic and diastolic BP were measured. A total of 811 men developed prostate cancer, and followed for additional 7.1 years, and we studied the association between prediagnostic BP and overall mortality among patients with prostate cancer. RESULTS: Men (>45 years) with a systolic BP >150 mmHg had a 35% increased risk of prostate cancer compared with men with a normal systolic BP (<130 mmHg) (HR 1.35, 95% CI 1.08-1.69). Among patients with prostate cancer, men with systolic BP >150 mmHg had a 49% increased overall mortality compared with men with a normal systolic BP (HR 1.49, 1.06-2.01). Among patients with prostate cancer treated with curative intent, those with a high diastolic BP (>90 mmHg) had a threefold increase in overall mortality risk (HR 3.01, 95% CI 1.40-6.46) compared with patients with a normal diastolic BP (<80 mmHg). CONCLUSION: Our results support that systolic and diastolic BP are important factors when balancing disease management in patients with prostate cancer.

Prognostic value of absolute quantification of mutated KRAS in circulating tumour DNA in lung adenocarcinoma patients prior to therapy.

Droplet digital polymerase chain reaction (ddPCR) is a highly sensitive and accurate method for quantification of nucleic acid sequences. We used absolute quantification of mutated v-Ki-ras2 Kirsten rat sarcoma viral oncogene homology gene (KRAS) by ddPCR to investigate the prognostic role of mutated KRAS in patients with KRAS-mutated lung adenocarcinomas. Pre-treatment plasma samples from 60 patients with stages I-IV KRAS-mutated lung adenocarcinomas were analysed for KRAS mutations. The associations between survival, detectable KRAS mutations in plasma, and the plasma concentration of mutated KRAS were assessed. Overall, 23 of 60 (38%) patients had detectable KRAS mutation in plasma. The percentage of patients with detectable mutation was 8% in stage I, 30% in stage II, 71% in stage III, and 73% in stage IV. Estimated overall median progression-free survival (PFS) and overall survival (OS) were 26.2 months [95% confidence interval (CI) 12.5-39.9] and 50.8 months (95% CI 0-107.3), respectively. Patients with detectable mutations in plasma had significantly worse median PFS compared to patients with undetectable mutation (13.1 versus 70.1 months) and shorter median OS (20.7 versus not reached). High circulating tumour DNA (ctDNA) concentrations of mutated KRAS were significantly associated with shorter PFS [hazard ratio (HR) 1.008, 95% CI 1.004-1.012] and OS (HR 1.007, 95% CI 1.003-1.011). All associations remained statistically significant in multivariable analyses. In conclusion, ddPCR is an accurate and easily feasible technique for quantification of KRAS mutations in ctDNA. The presence of detectable KRAS mutation in plasma at baseline was associated with worse PFS and OS. High concentration of mutated KRAS in ctDNA was an independent negative prognostic factor for both PFS and OS.