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Arsenite-resistance protein 2, also known as serrate RNA effector molecule (ARS2/SRRT), is known to be involved in cellular proliferation and tumorigenicity. However, its role in prostate cancer (PCa) has not yet been established. We investigated the potential role of SRRT in 496 prostate samples including benign, incidental, advanced, and castrate-resistant patients treated by androgen deprivation therapy (ADT). We also explored the association of SRRT with common genetic aberrations in lethal PCa using immunohistochemistry (IHC) and performed a detailed analysis of SRRT expression using The Cancer Genome Atlas (TCGA PRAD) by utilizing RNA-seq, clinical information (pathological T category and pathological Gleason score). Our findings indicated that high SRRT expression was significantly associated with poor overall survival (OS) and cause-specific survival (CSS). SRRT expression was also significantly associated with common genomic aberrations in lethal PCa such as PTEN loss, ERG gain, mutant TP53, or ATM. Furthermore, TCGA PRAD data revealed that high SRRT mRNA expression was significantly associated with higher Gleason scores, PSA levels, and T pathological categories. Gene set enrichment analysis (GSEA) of RNAseq data from the TCGA PRAD cohort indicated that SRRT may play a potential role in regulating the expression of genes involved in prostate cancer aggressiveness. Conclusion: The current data identify the SRRTs potential role as a prognostic for lethal PCa, and further research is required to investigate its potential as a therapeutic target.

Background: Minimal literature exists on outcomes for Canadian patients with gastroesophageal adenocarcinoma (GEA). The objective of our study was to establish a prospective clinical database to evaluate demographic characteristics, presentation and outcomes of patients with GEA. Methods: Patients diagnosed with GEA were recruited from Jan. 30, 2017, to Aug. 30, 2020. Data collected included demographic characteristics, presentation, treatment and survival. A multivariable model for overall survival in patients treated with curative intent was created using sex, lymph node status, resection margin status, age and tumour location as variables. Results: A total of 122 patients with adenocarcinoma of the stomach or gastroesophageal junction were included. Median age was 65 years (interquartile range [IQR] 59-74), 70% of patients were male and 26% were born outside of Canada. Median follow-up time was 14.5 (IQR 8.0-31.0) months. Following staging computed tomography scanning, 88% of patients were deemed to have potentially resectable disease. Eighty-one (76%) received staging laparoscopy and 74 (61%) were treated with curativeintent surgery. Forty-six (62%) patients had nodal metastases. The median number of nodes harvested was 22 (IQR 18-30). The R0 resection margin rate was 82%. The 3-year overall survival for patients who received curative-intent treatment was 63% and 38% for all patients. On multivariable analysis, female sex (hazard ratio [HR] 3.88, p = 0.01), positive nodal status (HR 3.58, p = 0.02), positive margins (HR 3.11, p = 0.03) and tumour location (HR 3.00, p = 0.03) were associated with decreased overall survival. Conclusion: Many of the patients with GEA in this study presented with advanced disease, and only 61% were offered curative-intent surgery. A prospective multicentre national GEA database is now being established. Contexte : Presque rien n'a été publié sur les issues des patients canadiens atteints d'un adénocarcinome gastro-oesophagien. Notre étude avait pour objectif d'établir une base de données prospectives cliniques pour évaluer les caractéristiques démographiques, la présentation et les issues associées à cette population de patients. Méthodes : Le recrutement de patients ayant reçu un diagnostic d'adénocarcinome gastro-oesophagien s'est fait du 30 janvier 2017 au 30 août 2020. Les données recueillies portaient sur les caractéristiques sociodémographiques, la présentation, le traitement et la survie. Nous avons ensuite créé un modèle multivarié de la survie globale des patients ayant reçu un traitement à visée curative, qui inclut comme variables le sexe, l'atteinte des noeuds lymphatiques, le statut des marges de la résection, l'âge et la position de la tumeur. Résultats : Au total, 122 patients atteints d'un adénocarcinome de l'estomac ou de la jonction gastro-oesophagienne ont été retenus. L'âge médian était de 65 ans (écart interquartile [ÉI] 59-74 ans), 70% étaient de sexe masculin, et 26% étaient nés à l'extérieur du Canada. La durée médiane de suivi était de 14,5 mois (ÉI 8,0-31,0 mo). Après la stadification par tomodensitométrie, il a été conclu que les tumeurs de 88% des patients étaient potentiellement résécables. Parmi ces patients, 81 (76%) ont subi une chirurgie de stadification par laparoscopie, et 74 (61%) ont subi une opération à visée curative. Quarante-six patients (62%) avaient des métastases nodales. Le nombre médian de noeuds excisés était de 22 (ÉI 18-30). Le taux de résection R0 était de 82%. Le taux de survie globale à 3 ans des patients ayant subi un traitement à visée curative était de 63%, et de 38% pour tous les patients. Selon l'analyse multivariée, le sexe féminin (rapport de risque [RR] 3,88, p = 0,01), la présence d'une atteinte nodale (RR 3,58, p = 0,02), les marges positives (RR 3,11, p = 0,03) et la position de la tumeur (RR 3,00, p = 0,03) étaient associés à une baisse de la survie globale. Conclusion : Beaucoup des patients atteints d'un adénocarcinome gastro-oesophagien ayant participé à l'étude avaient une maladie avancée, et seuls 61% d'entre eux se sont fait proposer une opération à visée curative. Une base de données prospectives nationale multicentrique sur ce type de cancer est en cours de création., Gastroesophageal adenocarcinoma (GEA) is a common cancer worldwide and a major cause of cancer-related deaths. (1) Previous literature clearly demonstrates differences in the presentations and disease pathology seen across Asian [...]

BackgroundAtaxia Telangiectasia Mutated (ATM) serine/threonine protein kinase is a known tumor suppressor, involved in DNA damage repair. It has prognostic and predictive therapeutic implications and is associated with aggressive prostate cancer (PCa).ObjectiveTo investigate the prognostic value of ATM protein expression in PCa patients and assessed the combined value of ATM, ERG, and PTEN status.Design setting and participantsThis study consisted of 303 patients with incidental, locally advanced, and castrate-resistant PCa by transurethral resection of the prostate (TURP).Outcome measurements and statistical analysisTURP samples from 303 PCa patients were assessed by immunohistochemistry (IHC for ATM, ERG, and PTEN. Individual and combined marker status were correlated with International Society of Urological Pathology Gleason grade group, overall survival (OS), and PCa-specific mortality (PCSM).Results and limitationsDecreased ATM expression (negative/weak intensity) occurred in 164/303 (54.1%) patients, and was associated with shorter OS and higher PCSM (p = 0.015 and p = 0.001, respectively). Negative/weak ATM expression was significantly associated with PCSM with a hazard ratio of 2.09 (95% confidence interval 1.34-3.27, p = 0.001). Assessment of Combined ATM/PTEN expression showed improved prognostic power to predict OS and PCSM, independent of Gleason grade groups.ConclusionsDecreased ATM protein expression is associated with poor outcomes in advanced PCa patients. Patients with combined low ATM/PTEN negative expression are at the highest risk for reduced OS and PCSM. Assessing the combined status of ATM/PTEN by IHC in PCa patients may aid in risk stratification relative to OS and PCSM. Moreover, since ATM plays an integral role in DNA damage response pathways, future studies will enhance our understanding of how outcomes of patients with altered ATM and PTEN expression can be improved further with poly-ADP ribose polymerase inhibitors (PARPi), combinations of PARPi and androgen receptor-targeted therapies, as well as platinum-based chemotherapies.Patient summaryLower ATM intensity is associated with increased cancer-specific mortality in prostate cancer patients. Patients with lower ATM and PTEN negative expression showed decreased overall survival and increased cancer mortality compared with controls.

Background: Despite guidelines recommending diagnostic laparoscopy in patients with gastric cancer, implementation is low. We aimed to explore trends in the use of laparoscopy for staging of gastric cancer in Alberta, Canada, determine the rate of positive findings and identify factors predictive of positive staging laparoscopy (SL) findings in this patient population. Methods: In August 2018, we sent a survey to all general surgeons in Alberta who were members of the Alberta Association of General Surgeons to identify those treating gastric cancer. The survey inquired about type of practice (academic or community), gastric cancer case volume, routine versus selective use of SL and, if selective use of SL, criteria used to select cases. Participants were also asked to provide data from their SL cases from July 2007 to February 2019. We double-checked surgeon records with chart review. The primary outcome was evidence of metastatic disease on SL or cytologic examination or both. We performed logistic regression analysis to identify factors predictive of positive laparoscopy findings. Results: The survey was completed by 41 of 127 surgeons (response rate 32.3%). We reviewed 116 cases from 5 surgeons at 4 centres. Gross metastatic disease or positive findings on cytologic examination or both were identified in 37 patients (31.9%). On univariate analysis, the following were associated with an increased risk of identification of metastatic disease at laparoscopy: visualization of the primary tumour on computed tomography (CT) (odds ratio [OR] 9.8, 95% confidence interval [CI] 1.2-76.5), presence of abdominal lymphadenopathy greater than 1 cm (OR 2.4, 95% CI 1.1-5.4) and presence of ascites (OR 19.1, 95% CI 2.2-161.8). Visualization of the primary tumour on CT (OR 8.4, 95% CI 1.0-68.3) and the presence of ascites (OR 15.9, 95% CI 1.8-137.0) remained statistically significant predictors on multivariate analysis. Conclusion: Metastatic disease was identified at SL in almost one-third of cases, which suggests that SL should still be used routinely in gastric cancer staging in Canadian centres. Our study identified several preoperative imaging findings associated with evidence of metastatic disease on laparoscopy; however, further studies are needed to establish robust predictors of positive findings before advocating for a selective SL approach. Contexte : Bien que les directives recommandent une laparoscopie diagnostique chez les patients atteints d'un cancer de l'estomac, cette intervention est peu utilisee. Nous avons voulu explorer les tendances du recours a la laparoscopie pour la stadification du cancer de l'estomac en Alberta, au Canada, etablir le taux de resultats positifs et cibler les facteurs predictifs de resultats positifs de la laparoscopie de stadification dans cette population de patients. Methodes : En aout 2018, nous avons envoye un sondage a tous les chirurgiens generaux de l'Alberta membres de l'Alberta Association of General Surgeons pour savoir lesquels traitaient le cancer de l'estomac. L'enquete portait sur le type de pratique (universitaire ou communautaire), le volume de cas de cancer de l'estomac, le recours systematique ou selectif de la laparoscopie de stadification et, en cas de recours selectif, les criteres de selection. Les participants ont egalement ete invites a fournir des donnees sur les cas ou la laparoscopie de stadification avait ete utilisee de juillet 2007 a fevrier 2019. Nous avons reverifie les dossiers des medecins. Le principal indicateur etait la presence d'une maladie metastatique lors de la laparoscopie de stadification ou de l'examen cytologique (ou les deux). Nous avons procede a une analyse de regression logistique pour cerner les facteurs predictifs de resultats positifs a la laparoscopie. Resultats : Sur 127 chirurgiens 41 ont repondu au sondage (taux de reponse de 32,3 %). Nous avons examine 116 cas traites par 5 chirurgiens dans 4 centres. Une maladie metastatique brute ou des resultats positifs a l'examen cytologique ou les deux ont ete identifies chez 37 patients (31,9 %). Une analyse univariee a revele que les elements suivants etaient associes a un risque accru d'identification de maladie metastatique lors de la laparoscopie : visualisation de la tumeur primaire a la tomodensito-metrie (TDM) (rapport des cotes [RC] 9,8, intervalle de confiance [IC] de 95 % 1,2-76,5), presence d'une lymphadenopathie abdominale superieure a 1cm (RC 2,4, IC de 95 % 1,1-5,4) et presence d'ascite (RC 19,1, IC de 95 % 2,2-161,8). La visualisation de la tumeur primaire a la TDM (RC 8,4, RC de 95 % 1,0-68,3) et la presence d'ascite (RC 15,9, RC de 95 % 1,8-137,0) sont demeurees des facteurs predictifs statistiquement significatifs dans l'analyse multivariee. Conclusion : Une maladie metastatique a ete identifiee a la laparoscopie de stadification dans pres d'un tiers des cas, ce qui suggere que la laparoscopie de stadification devrait con inuer d'etre utilisee de facon systematique dans la stadification du cancer de l'estomac dans les centres canadiens. Notre etude a montre plusieurs resultats d'imagerie preoperatoire associes a des signes de maladie metastatique a la laparoscopie; cependant, d'autres etudes sont necessaires pour etablir des predicteurs solides de resultats positifs avant de preconiser une approche selective de la laparoscopie de stadification., Gastric cancer remains the fifth most common cancer diagnosed worldwide and the third most common cause of cancer-related death. (1) In Canada, the incidence of gastric adenocarcinoma is estimated to [...]

Background: The ability to accurately predict which patients will achieve a pathologic complete response (pCR) after neoadjuvant chemotherapy could help identify those who could safely be spared the potential morbidity of axillary lymph node dissection. We performed a retrospective analysis of a cohort of clinically node-positive patients managed with neoadjuvant chemotherapy with the goal of identifying predictors of axillary pCR. Methods: Eligible patients were aged 18 years or older, had clinical T1-T4, N1-N3, M0 breast cancer and received neoadjuvant chemotherapy followed by surgical axillary lymph node staging between 2001 and 2017 at Misericordia Hospital, Edmonton, Alberta. Patient data, including tumour characteristics, details of neoadjuvant chemotherapy, imaging results before and after neoadjuvant chemotherapy, and final pathologic analysis, were collected from the appropriate provincial electronic data repositories. We summarized the data using descriptive statistics. We characterized associations between clinical/tumour characteristics and pCR using univariate and multivariate regression analysis. Results: Of the 323 patients included in the study, 130 (40.2%) achieved axillary pCR. Absence of residual disease in the breast was associated with axillary pCR (odds ratio 6.74, 95% confidence interval 2.89-15.67). HER2-positive, triple-negative and ER-positive/PR-negative/HER2-negative tumours were significantly associated with a pCR on univariate analysis; the association trended toward significance on multivariate analysis. Conclusion: Our findings support the routine use of neoadjuvant chemotherapy and sentinel lymph node biopsy in patients with an absence of residual disease in the breast, and potentially in those with HER2-positive or triple-negative subtypes, and highlight the ER-positive/PR-negative biomarker subtype as a potential predictor of nodal response. Contexte : La capacité de prédire avec précision quelles patientes obtiendront une réponse pathologique complète (RpC) après une chimiothérapie néoadjuvante pourrait faciliter l'identification de celles chez qui on pourrait sécuritairement éviter la morbidité potentielle associée à l'exérèse des ganglions lymphatiques axillaires. Nous avons procédé à une analyse rétrospective sur une cohorte de patientes traitées par chimiothérapie néoadjuvante dont les ganglions étaient cliniquement positifs, dans le but de dégager les prédicteurs d'une RpC axillaire. Méthodes : Les patientes admissibles avaient 18 ans ou plus, présentaient un cancer du sein clinique MO T1-T4, N1-N3 et avaient reçu une chimiothérapie néoadjuvante suivie d'une stadification chirurgicale des ganglions lymphatiques axillaires entre 2001 et 2017 à l'Hôpital Misecordia d'Edmonton, en Alberta. Les données sur les patientes, y compris les caractéristiques des tumeurs, les détails de la chimiothérapie néoadjuvante, les résultats de l'imagerie avant et après la chimiothérapie néoadjuvante et l'analyse anatomopathologique finale ont été recueillis à partir des registres de données électroniques provinciaux appropriés. Nous avons résumé les données sous forme de statistiques descriptives. Nous avons dégagé les liens entre les caractéristiques cliniques/tumorales et la RpC à l'aide d'analyses de régression univariées et multivariées. Résultats : Parmi les 323 patientes incluses dans l'étude, 130 (40,2%) avaient obtenu une RpC axillaire. L'absence de maladie résiduelle dans le sein a été associée à une RpC axillaire (rapport des cotes 6,74, intervalle de confiance de 95% 2,89-15,67). Les tumeurs HER2-positives, triples négatives et ER-positives/PR-négatives/HER2-négatives ont été significativement associées à une RpC à l'analyse univariée; à l'analyse multivariée, l'association tendait à être significative. Conclusion : Nos conclusions appuient l'utilisation de routine de la chimiothérapie néoadjuvante et la biopsie des ganglions sentinelles chez les patientes en l'absence de maladie résiduelle dans le sein, et potentiellement chez celles qui présentent les soustypes HER2-positif ou triple négatif, et elles évoquent le sous-type de biomarqueur ER-positif/PR-négatif comme prédicteur potentiel d'une réponse ganglionnaire., Axillary lymph node status is an important determinant of long-term survival in patients with breast cancer and is used to guide local, regional and systemic treatment. (1,2) In patients with [...]

Background: The management of advanced prostate cancer continues to evolve rapidly, particularly with the earlier use of survival-prolonging therapies in metastatic castration-sensitive prostate cancer (mCSPC). Though approved prior to the use of intensification therapy in mCSPC, taxane-based chemotherapies remain a relevant option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is little evidence determining the outcomes of taxane chemotherapies as the first subsequent taxane (FST) in mCRPC pts who received docetaxel intensification (DI) in mCSPC. The purpose of this study is to compare outcomes between the survival-prolonging taxanes, docetaxel and cabazitaxel as FST after DI. Methods: New patient consults seen at the Cross Cancer Institute from 1 July 2014 to 31 December 2020 were retrospectively reviewed. Pts were considered eligible if they received DI for mCSPC and then received either docetaxel or cabazitaxel in mCRPC. Variables of interest were collected from electronic medical records. The primary endpoint was ≥50% PSA response at 12 weeks relative to baseline for FST. Secondary endpoints included OS from mCSPC diagnosis, as well as PFS and OS from the FST start date. PSA responses were compared using the chi-squared test, and time-based endpoints were compared using the Kaplan–Meier method. Results: In total, 34 pts were identified: docetaxel = 22 and cabazitaxel = 12 as FST. 91.2% of pts (docetaxel 95.5% vs. cabazitaxel 83.3%) received FST in 2nd line mCRPC. The median age at diagnosis (63.1 vs. 67.1 yrs, p = 0.236) and the median time to CRPC (18.6 vs. 14.2 mos, p = 0.079) were similar for docetaxel and cabazitaxel, respectively. The median time to FST (24.1 vs. 34.6 mos, p = 0.036) and OS from mCSPC diagnosis (30.9 vs. 52.7 mos, p = 0.002) were significantly shorter for pts receiving cabazitaxel vs. docetaxel. PSA responses occurred in 40.9% of pts treated with docetaxel compared to 25.0% treated with cabazitaxel (p = 0.645). There was no significant difference in median PFS (2.7 vs. 3.5 mos, p = 0.727) or median OS (11.4 vs. 8.1 mos, p = 0.132) from the time of FST for pts treated with docetaxel vs. cabazitaxel, respectively. Conclusions: Both docetaxel and cabazitaxel demonstrated activity as FST after DI in mCSPC. Pts who received cabazitaxel had a shorter time to FST and OS from mCSPC. The reasons for this may reflect clinician preference for cabazitaxel in pts with aggressive or rapidly progressing disease. No difference was found in PSA response, PFS, or OS from FST with docetaxel compared to cabazitaxel. While limited by its retrospective nature and small sample size, this study suggests that docetaxel is active as FST despite treatment with DI in mCSPC. [ABSTRACT FROM AUTHOR]

Late endosomal/lysosomal adaptor, MAPK and mTOR, or LAMTOR, is a scaffold protein complex that senses nutrients and integrates growth factor signaling. The role of LAMTOR4 in tumorigenesis is still unknown. However, there is a considerable possibility that LAMTOR4 is directly involved in tumor cell proliferation and metastasis. In the current study, we investigated the protein expression of LAMTOR4 in a cohort of 314 men who were undergoing transurethral resection of prostate (TURP) consisting of incidental, advanced and castration-resistant cases. We also correlated the data with ERG and PTEN genomic status and clinicopathological features including Gleason score and patients' outcome. Additionally, we performed in vitro experiments utilizing knockdown of LAMTOR4 in prostate cell lines, and we performed mRNA expression assessment using TCGA prostate adenocarcinoma (TCGA-PRAD) to explore the potential differentially expressed genes and pathways associated with LAMTOR4 overexpression in PCa patients. Our data indicate that high LAMTOR4 protein expression was significantly associated with poor overall survival (OS) (HR: 1.44, CI: 1.01–2.05, p = 0.047) and unfavorable cause-specific survival (CSS) (HR: 1.71, CI: 1.06–2.77, p = 0.028). Additionally, when high LAMTOR4 expression was combined with PTEN-negative cases (score 0), we found significantly poorer OS (HR: 2.22, CI: 1.37–3.59, p = 0.001) and CSS (HR: 3.46, CI: 1.86–6.46, p < 0.0001). Furthermore, ERG-positive cases with high LAMTOR4 exhibited lower OS (HR: 1.98, CI: 1.18–3.31, p = 0.01) and CSS (HR: 2.54, CI: 1.32–4.87, p = 0.005). In vitro assessment showed that knockdown of LAMTOR4 decreases PCa cell proliferation, migration, and invasion. Our data further showed that knockdown of LAMTOR4 in the LNCaP cell line significantly dysregulated the β catenin/mTOR pathway and tumorigenesis associated pathways. Inhibiting components of the mTOR pathway, including LAMTOR4, might offer a strategy to inhibit tumor progression and metastasis in prostate cancer. [ABSTRACT FROM AUTHOR]

Immunotherapy-based systemic treatment (ST) is the standard of care for most patients diagnosed with metastatic renal cell carcinoma (mRCC). Cytoreductive nephrectomy (CN) has historically shown benefit for select patients with mRCC, but its role and timing are not well understood in the era of immunotherapy. The primary objective of this study is to assess outcomes in patients who received ST only, CN followed by ST (CN-ST), and ST followed by CN (ST-CN). The Canadian Kidney Cancer information system (CKCis) database was queried to identify patients with de novo mRCC who received immunotherapy-based ST between January 2014 and June 2023. These patients were classified into three categories as described above. Cox proportional hazards models were used to assess the impact of the timing of ST and CN on overall survival (OS) and progression-free survival (PFS), after adjusting for the International Metastatic RCC Database Consortium (IMDC) risk group, age, and comorbidities. Best overall response and complications of ST and CN for these cohorts were collected. A total of 588 patients were included in this study: 331 patients received ST only, 215 patients received CN-ST, and 42 patients received ST-CN. Patient and disease characteristics including age, gender, performance status, IMDC risk category, comorbidity, histology, type of ST, and metastatic sites are reported. OS analysis favored patients who received ST-CN (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.13–0.68) and CN-ST (HR 0.68, CI 0.47–0.97) over patients who received ST only. PFS analysis showed a similar trend for ST-CN (HR 0.45, CI 0.26–0.77) and CN-ST (HR 0.9, CI 0.68–1.17). This study examined baseline features and outcomes associated with the use and timing of CN and ST using real-world data via a large Canadian real-world cohort. Patients selected to receive CN after ST demonstrated improved outcomes. There were no appreciable differences in perioperative complications across groups. Limitations include the small number of patients in the ST-CN group and residual confounding and selection biases that may influence the outcomes in patients undergoing CN. [ABSTRACT FROM AUTHOR]