To test the hypothesis that a genomic classifier (GC) would predict biochemical failure (BF) and distant metastasis (DM) in men receiving radiation therapy (RT) after radical prostatectomy (RP).
...Among patients who underwent post-RP RT, 139 were identified for pT3 or positive margin, who did not receive neoadjuvant hormones and had paraffin-embedded specimens. Ribonucleic acid was extracted from the highest Gleason grade focus and applied to a high-density-oligonucleotide microarray. Receiver operating characteristic, calibration, cumulative incidence, and Cox regression analyses were performed to assess GC performance for predicting BF and DM after post-RP RT in comparison with clinical nomograms.
The area under the receiver operating characteristic curve of the Stephenson model was 0.70 for both BF and DM, with addition of GC significantly improving area under the receiver operating characteristic curve to 0.78 and 0.80, respectively. Stratified by GC risk groups, 8-year cumulative incidence was 21%, 48%, and 81% for BF (P<.0001) and for DM was 0, 12%, and 17% (P=.032) for low, intermediate, and high GC, respectively. In multivariable analysis, patients with high GC had a hazard ratio of 8.1 and 14.3 for BF and DM. In patients with intermediate or high GC, those irradiated with undetectable prostate-specific antigen (PSA ≤0.2 ng/mL) had median BF survival of >8 years, compared with <4 years for patients with detectable PSA (>0.2 ng/mL) before initiation of RT. At 8 years, the DM cumulative incidence for patients with high GC and RT with undetectable PSA was 3%, compared with 23% with detectable PSA (P=.03). No outcome differences were observed for low GC between the treatment groups.
The GC predicted BF and metastasis after post-RP irradiation. Patients with lower GC risk may benefit from delayed RT, as opposed to those with higher GC; however, this needs prospective validation. Genomic-based models may be useful for improved decision-making for treatment of high-risk prostate cancer.
Abstract Background Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25–50% of patients expected to achieve a ...pathologic response. Validated biomarkers predictive of response are currently lacking. Objective To discover and validate biomarkers predictive of response to NAC for MIBC. Design, setting, and participants Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments–certified laboratory. Outcome measurements and statistical analysis The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. Results and limitations Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery ( p = 0.024) and validation ( p = 0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM , RB1 , and FANCC predicted pathologic response ( p < 0.001; 87% sensitivity, 100% specificity) and better overall survival ( p = 0.007). This test remained predictive for pathologic response in the validation set ( p = 0.033), with a trend towards better overall survival ( p = 0.055). These results require further validation in additional sample sets. Conclusions Genomic alterations in the DNA repair-associated genes ATM , RB1 , and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. Patient summary Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.
To improve the outcomes of patients with castration-resistant prostate cancer (CRPC), there is an urgent need for more effective therapies and approaches that individualize specific treatments for ...patients with CRPC. These studies compared the novel taxane cabazitaxel with the previous generation docetaxel, and aimed to determine which tumors are most likely to respond.
Cabazitaxel and docetaxel were compared via in vitro modeling to determine the molecular mechanism, biochemical and cell biologic impact, and cell proliferation, which was further assessed ex vivo in human tumor explants. Isogenic pairs of RB knockdown and control cells were interrogated in vitro and in xenograft tumors for cabazitaxel response.
The data herein show that (i) cabazitaxel exerts stronger cytostatic and cytotoxic response compared with docetaxel, especially in CRPC; (ii) cabazitaxel induces aberrant mitosis, leading to pyknotic and multinucleated cells; (iii) taxanes do not act through the androgen receptor (AR); (iv) gene-expression profiling reveals distinct molecular actions for cabazitaxel; and (v) tumors that have progressed to castration resistance via loss of RB show enhanced sensitivity to cabazitaxel.
Cabazitaxel not only induces improved cytostatic and cytotoxic effects, but also affects distinct molecular pathways, compared with docetaxel, which could underlie its efficacy after docetaxel treatment has failed in patients with CRPC. Finally, RB is identified as the first potential biomarker that could define the therapeutic response to taxanes in metastatic CRPC. This would suggest that loss of RB function induces sensitization to taxanes, which could benefit up to 50% of CRPC cases.
The optimal timing of postoperative radiotherapy (RT) after radical prostatectomy (RP) is unclear. We hypothesized that a genomic classifier (GC) would provide prognostic and predictive insight into ...the development of clinical metastases in men receiving post-RP RT and inform decision making.
GC scores were calculated from 188 patients with pT3 or margin-positive prostate cancer, who received post-RP RT at Thomas Jefferson University and Mayo Clinic between 1990 and 2009. The primary end point was clinical metastasis. Prognostic accuracy of the models was tested using the concordance index for censored data and decision curve analysis. Cox regression analysis tested the relationship between GC and metastasis.
The cumulative incidence of metastasis at 5 years after RT was 0%, 9%, and 29% for low, average, and high GC scores, respectively (P = .002). In multivariable analysis, GC and pre-RP prostate-specific antigen were independent predictors of metastasis (both P < .01). Within the low GC score (< 0.4), there were no differences in the cumulative incidence of metastasis comparing patients who received adjuvant or salvage RT (P = .79). However, for patients with higher GC scores (≥ 0.4), cumulative incidence of metastasis at 5 years was 6% for patients treated with adjuvant RT compared with 23% for patients treated with salvage RT (P < .01).
In patients treated with post-RP RT, GC is prognostic for the development of clinical metastasis beyond routine clinical and pathologic features. Although preliminary, patients with low GC scores are best treated with salvage RT, whereas those with high GC scores benefit from adjuvant therapy. These findings provide the first rational selection of timing for post-RP RT.
Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare epithelial tumor with a biallelic mutation involving any subunit of the SDH complex. Mostly, it has low-grade morphology ...and a favorable prognosis. We present a case of a 36-year-old woman with weight loss, night sweats, and symptomatic anemia. Her imaging showed a hypo-enhancing heterogeneous right renal mass with invasion of the renal vein and inferior vena cava. Microscopically, the tumor had focal low-grade areas (5%) and extensive areas with high-grade features, including rhabdoid (85%) and sarcomatoid (10%) dedifferentiation. Cytoplasmic inclusions, foci of extracellular mucin, coagulative necrosis, and inflammatory infiltrate were present. The tumor cells, including rhabdoid differentiated, were focally positive for AE1/AE3. Tumor cells showed loss of SDHB immunostaining, consistent with diagnosis. Genetics testing was recommended, but the patient expired due to metastatic carcinoma. Prior studies suggest that sarcomatoid transformation and coagulative necrosis increase the risk of metastasis by up to 70% in SDH-deficient RCC. Follow-up with surveillance for other SDH-deficient neoplasms is recommended in cases of germline mutation. Here, we report the first case of SDH-deficient RCC with concomitant rhabdoid and sarcomatoid features and a detailed review of diagnostic difficulties associated with high-grade tumors.
Objective To report on assessments of face, content, and construct validity for the commercially available da Vinci Skills Simulator (dVSS). Methods A total of 38 subjects participated in this ...prospective study. Participants were classified as novice (0 robotic cases performed), intermediate (1-74 robotic cases), or expert (≥75 robotic cases). Each subject completed 5 exercises. Using the metrics available in the simulator software, the performances of each group were compared to evaluate construct validation. Immediately after completion of the exercises, each subject completed a questionnaire to evaluate face and content validation. Results The novice group consisted of 18 medical students and 1 resident. The intermediate group included 6 residents, 1 fellow, and 2 faculty urologist. The expert group consisted of 2 residents, 1 fellow, and 7 faculty surgeons. The mean number of robotic cases performed by the intermediate and expert groups was 29.2 and 233.4, respectively. An overall significant difference was observed in favor of the more experienced group in 4 skill sets. When intermediates and experts were combined into a single “experienced” group, they significantly outperformed novices in all 5 exercises. Intermediates and experts rated various elements of the simulators realism at an average of 4.1/5 and 4.3/5, respectively. All intermediate and expert participants rated the simulator's value as a training tool as 4/5 or 5/5. Conclusion Our study supports the face, content, and construct validation attributed to the dVSS. These results indicate that the simulator may be most useful to novice surgeons seeking basic robot skills acquisition.
Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC); however, it is infrequently adopted in practice because of concerns regarding toxicity and ...delay to cystectomy. We hypothesized that three cycles of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) would be safe, shorten the time to surgery, and yield similar pathologic complete response (pT0) rates compared with historical controls.
Patients with cT2-T4a and N0-N1 MIBC were eligible and received three cycles of AMVAC with pegfilgrastim followed by radical cystectomy with lymph node dissection. The primary end point was pT0 rate. Telomere length (TL) and p53 mutation status were correlated with response and toxicity.
Forty-four patients were accrued; 60% had stage III to IV disease; median age was 64 years. Forty patients were evaluable for response, with 15 (38%; 95% CI, 23% to 53%) showing pT0 at cystectomy, meeting the primary end point of the study. Another six patients (14%) were downstaged to non-muscle invasive disease. Most (82%) experienced only grade 1 to 2 treatment-related toxicities. There were no grade 3 or 4 renal toxicities and no treatment-related deaths. One patient developed metastases and thus did not undergo cystectomy; all others (n = 43) proceeded to cystectomy within 8 weeks after last chemotherapy administration. Median time from start of chemotherapy to cystectomy was 9.7 weeks. TL and p53 mutation did not predict response or toxicity.
AMVAC is well tolerated and results in similar pT0 rates with 6 weeks of treatment compared with standard 12-week regimens. Further analysis is ongoing to ascertain whether molecular alterations in tumor samples can predict response to chemotherapy.
To determine whether microwave ablation (MWA) has equivalent outcomes to those of cryoablation (CA) in terms of technical success, adverse events, local tumor recurrence, and survival in adult ...patients with solid enhancing renal masses ≤4 cm.
A retrospective review was performed of 279 small renal masses (≤4 cm) in 257 patients (median age, 71 years; range, 40-92 years) treated with either CA (n = 191) or MWA (n = 88) between January 2008 and December 2020 at a single high-volume institution. Evaluations of adverse events, treatment effectiveness, and therapeutic outcomes were conducted for both MWA and CA. Disease-free, metastatic-free, and cancer-specific survival rates were tabulated. The estimated glomerular filtration rate was employed to examine treatment-related alterations in renal function.
No difference in patient age (P = .99) or sex (P = .06) was observed between the MWA and CA groups. Cryoablated lesions were larger (P < .01) and of greater complexity (P = .03). The technical success rate for MWA was 100%, whereas 1 of 191 cryoablated lesions required retreatment for residual tumor. There was no impact on renal function after CA (P = .76) or MWA (P = .49). Secondary analysis using propensity score matching demonstrated no significant differences in local recurrence rates (P = .39), adverse event rates (P = .20), cancer-free survival (P = .76), or overall survival (P = .19) when comparing matched cohorts of patients who underwent MWA and CA.
High technical success and local disease control were achieved for both MWA and CA. Cancer-specific survival was equivalent. Higher adverse event rates after CA may reflect the tendency to treat larger, more complex lesions with CA.
To analyze potential racial disparities in the diagnosis and management of depression associated with androgen deprivation therapy.
TriNetX health record network was queried for prostate cancer ...patients treated with androgen deprivation therapy from 2003-2023. Differences in rates of depression diagnosis and treatment were compared between White and Black patients. Means, odds ratios, and t tests were calculated in univariate analysis with 95% confidence intervals (CI).
Data were queried from 93 health care organizations to yield 78,313 prostate cancer patients treated with androgen deprivation therapy. Patients on androgen deprivation therapy had 60% greater odds of developing depression vs other patients 9% vs 6%; odds ratio (OR) 1.6; 95% CI (1.5-1.7); P <.0001. Of those with depression secondary to androgen deprivation therapy, only 35% were treated with antidepressants. After starting androgen deprivation therapy, White patients had 30% greater odds of being diagnosed with depression, compared to Black patients 10% vs 8%; OR 1.3; 95% CI (1.2-1.4); P <.001. White patients also had higher odds of being treated with a first line antidepressant than Black patients 56% vs 48%; OR 1.4, 95% CI (1.2-1.6), P <.001.
This analysis confirms a significant association between androgen deprivation therapy and the development of clinical depression, and highlights its medical undertreatment. Importantly, our findings also indicate significant racial disparities in the identification and treatment of depression. Routine screening initiatives that account for social determinants of health may alleviate this disparity. Limitations of this study include retrospective design and lack of data describing severity of depression, which might correlate with need for medication.
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