Genomic Determinants Associated with Modes of Progression and Patterns of Failure in Metachronous Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND AND OBJECTIVE: Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better outcomes in comparison to those with higher disease burden. Despite the generally more indolent nature, there is still much heterogeneity, with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Our aim was to investigate correlation of tumor genomics with the mode of progression (MOP) and pattern of failure (POF) following first treatment (metastasis-directed and/or systemic therapy) for omCSPC. METHODS: We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC who underwent tumor next-generation sequencing with at least 1 yr of follow-up after their first treatment. Descriptive MOP and POF results are reported with respect to the presence of genomic alterations in pathways of interest. MOP was defined as class I, long-term control (LTC; no radiographic progression at last follow-up), class II, oligoprogression (1-3 lesions), or class III, polyprogression (≥4 lesions). POF included the location of lesions at first failure. Genomic pathways of interest included TP53, ATM, RB1, BRCA1/2, SPOP, and WNT (APC, CTNNB1, RNF43). Genomic associations with MOP/POF were compared using χ2 tests. Exploratory analyses revealed that the COSMIC mutational signature and differential gene expression were also correlated with MOP/POF. Overall survival (OS) was calculated via the Kaplan-Meier method from the time of first failure. KEY FINDINGS AND CLINICAL IMPLICATIONS: We included 267 patients in our analysis; the majority had either one (47%) or two (30%) metastatic lesions at oligometastasis. The 3-yr OS rate was significantly associated with MOP (71% for polyprogression vs 91% for oligoprogression; p = 0.005). TP53 mutation was associated with a significantly lower LTC rate (27.6% vs 42.3%; p = 0.04) and RB1 mutation was associated with a high rate of polyprogression (50% vs 19.9%; p = 0.022). Regarding POF, bone failure was significantly more common with tumors harboring TP53 mutations (44.8% vs25.9%; p = 0.005) and less common with SPOP mutations (7.1% vs 31.4%; p = 0.007). Visceral failure was more common with tumors harboring either WNT pathway mutations (17.2% vs 6.8%, p = 0.05) or SPOP mutations (17.9% vs 6.3%; p = 0.04). Finally, visceral and bone failures were associated with distinct gene-expression profiles. CONCLUSIONS AND CLINICAL IMPLICATIONS: Tumor genomics provides novel insight into MOP and POF following treatment for metachronous omCSPC. Patients with TP53 and RB1 mutations have a higher likelihood of progression, and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism. PATIENT SUMMARY: We evaluated cancer progression after a first treatment for metastatic prostate cancer with up to five metastases. We found that mutations in certain genes were associated with the location and extent of further metastasis in these patients.

Adjuvant treatment decisions among adults aged 65 years and older with early-stage hormone receptor positive breast cancer seen in a simple multidisciplinary clinic versus standard consultation.

INTRODUCTION: Randomized studies support de-escalation of adjuvant therapy for a target population of older adults ≥65 years with stage I, estrogen-receptor (ER) positive breast cancer after breast conserving surgery. We sought to evaluate the impact of a simplified multidisciplinary clinic (s-MDC) in this population by comparing treatment patterns and patient perceptions of adjuvant radiation therapy (RT) and hormone therapy (HT) between patients seen in s-MDC vs. standard consultations. MATERIALS AND METHODS: Medical records were retrospectively reviewed for patients in the above target population who underwent surgery between August 2020 and May 2022 at our institution. Two cohorts were included: (1) patients seen in s-MDC, and (2) patients seen in standard clinic separately by medical and radiation oncology (non-s-MDC cohort). The non-s-MDC patients declined, could not attend, and/or were not referred to the s-MDC. Patients in the s-MDC cohort were prospectively administered validated questionnaires to evaluate patient reported data including the Decision Autonomy Preference Scale (DAPS), e-Prognosis, and Medical Maximizing-Minimizing Scale (MMS). Chi square, t-tests, and non-parametric equivalents compared demographics, and logistic regression evaluated RT and HT use and survey score outcomes between cohorts. RESULTS: A total of 127 patients met inclusion criteria, with 33 s-MDC and 94 non-s-MDC patients. There was no difference between the cohorts in age, margin status, histology, grade, or focality. In the s-MDC cohort there were significantly more patients without sentinel lymph node biopsy (71.3% vs 42.4%, p = 0.003) and mean tumor size was smaller (0.69 vs. 0.96 cm, p < 0.003), and Charlson comborbidity index (CCI) was higher (5.21 vs 4.96, p = 0.038). There was no significant difference in receipt of RT (65% s-MDC vs 77% standard; odds ratio [OR] = 0.55, p = 0.189), HT (78% ss-MDC vs 72% standard; OR = 1.36, p = 0.513), or both (50% s-MDC vs 59% standard; OR = 0.7, p = 0.429). The s-MDC cohort was significantly more likely to undergo accelerated (vs. standard hypofractionated) RT (70% vs 39%; OR = 3.59, p = 0.020). In s-MDC patients with completed questionnaires (n = 33), all whose selected "mostly patient (n=6)" based decision making by DAPS chose RT while all "mostly doctor (n=1)" chose no RT. Based on e-Prognosis, there were lower odds of RT for increasing Schonberg score/ higher 10 yr mortality risk (OR 0.600, p = 0.048). MMS score ≥ 40 ("maximizer") was strongly linked with the use of RT (OR 18.57, p = 0.011). DISCUSSION: For adults ≥65 years with early stage, ER positive breast cancer, s-MDC participation was not significantly associated with lower use of adjuvant RT or HT versus standard consultation but was significantly associated with shorter RT courses. DAPS and MMS results indicate that patient treatment preference may be predictable, highlighting an opportunity to tailor consultation discussions and recommendations based on intrinsic patient preferences and individual goals.

Clinical and Genomic Differences Between Advanced Molecular Imaging-detected and Conventional Imaging-detected Metachronous Oligometastatic Castration-sensitive Prostate Cancer.

In metastatic castration-sensitive prostate cancer (mCSPC), disease volume plays an integral role in guiding treatment recommendations, including selection of docetaxel therapy, metastasis-directed therapy, and radiation to the prostate. Although there are multiple definitions of disease volume, they have commonly been studied in the context of metastases detected via conventional imaging (CIM). One such numeric definition of disease volume, termed oligometastasis, is heavily dependent on the sensitivity of the imaging modality. We performed an international multi-institutional retrospective review of men with metachronous oligometastatic CSPC (omCSPC), detected via either advanced molecular imaging alone (AMIM) or CIM. Patients were compared with respect to clinical and genomic features using the Mann-Whitney U test, Pearson's χ2 test, and Kaplan-Meier overall survival (OS) analyses with a log-rank test. A total of 295 patients were included for analysis. Patients with CIM-omCSPC had significantly higher Gleason grade group (p = 0.032), higher prostate-specific antigen at omCSPC diagnosis (8.0 vs 1.7 ng/ml; p < 0.001), more frequent pathogenic TP53 mutations (28% vs 17%; p = 0.030), and worse 10-yr OS (85% vs 100%; p < 0.001). This is the first report of clinical and biological differences between AMIM-detected and CIM-detected omCSPC. Our findings are particularly important for ongoing and planned clinical trials in omCSPC. PATIENT SUMMARY: Metastatic prostate cancer with just a few metastases only detected via newer scanning methods (called molecular imaging) is associated with fewer high-risk DNA mutations and better survival in comparison to metastatic cancer detected via conventional scan methods.

Medical Student Personality Traits and Clinical Grades in the Internal Medicine Clerkship.

BACKGROUND: Third year clerkship grades include subjective evaluations. The purpose of this study is to identify if personality traits and self-esteem predispose students to better clerkship performance. METHODS: Third-year medical students completed the OCEAN Five Factor Model Personality Test and Rosenberg Self-Esteem Scale. Clerkship grades were matched to survey results. Chi-squared and linear regression analyses assessed the correlation between students' clerkship grades, personality traits, and self-esteem. RESULTS: There was no association between OCEAN personality domains and any component of clerkship grade. In secondary post hoc analysis, students who are "deep thinking" (OR 2.97, 95% CI 1.26-7.01, p = 0.01), "sophisticated" (OR 2.70, 95% CI 1.12-6.50, p = 0.03), and "outgoing" (OR 2.45, 95% CI 1.02-5.89, p = 0.04) were significantly more likely to get an overall clerkship grade of Honors. "Deep thinking" (OR 3.44, 95% CI 1.47-8.04, p = 0.004) and "efficient" (OR 2.87, 95% CI 1.12-7.36, p = 0.03) students scored better on shelf exams, while "shy" students scored worse (OR 0.30, 95% CI 0.13-0.69, p = 0.004); "aloof" students received worse clinical scores (OR 0.57, 95% CI 0.37-0.89, p = 0.03), and "rude" (OR 5.08, 95% CI 1.03-24.94, p = 0.03) and "sophisticated" (OR 2.47, 95% CI 1.02-6.00, p = 0.04) students received higher preceptor scores. There was no correlation between self-esteem and clerkship grades. CONCLUSION: Students with certain personality traits may be predisposed to success during clerkships. Medical educators should be cognizant of biases favoring certain personalities and help students maximize success by recognizing their strengths and identifying gaps.

Association of Addition of Ablative Therapy Following Transarterial Chemoembolization With Survival Rates in Patients With Hepatocellular Carcinoma.

Importance: Hepatocellular carcinoma (HCC) is a heterogeneous disease with many available treatment modalities. Transarterial chemoembolization (TACE) is a valuable treatment modality for HCC lesions. This article seeks to evaluate the utility of additional ablative therapy in the management of patients with HCC who received an initial TACE procedure. Objective: To compare the overall survival (OS) and freedom from local progression (FFLP) outcomes after TACE alone with TACE that is followed by an ablative treatment regimen using stereotactic body radiation therapy, radiofrequency ablation, or microwave ablation for patients with HCC. Design, Setting, and Participants: This cohort study of 289 adults at a single urban medical center examined survival outcomes for patients with nonmetastatic, unresectable HCC who received ablative therapies following TACE or TACE alone from January 2010 through December 2018. The Lee, Wei, Amato common baseline hazard model was applied for within-patient correlation with robust variance and Cox regression analysis was used to assess the association between treatment group (TACE vs TACE and ablative therapy) and failure time events (FFLP per individual lesion and OS per patient), respectively. In both analyses, the treatment indication was modeled as a time-varying covariate. Landmark analysis was used as a further sensitivity test for bias by treatment indication. Exposures: TACE alone vs TACE followed by ablative therapy. Main Outcomes and Measures: Freedom from local progression and overall survival. Hypotheses were generated before data collection. Results: Of the 289 patients identified, 176 (60.9%) received TACE only and 113 (39.1%) received TACE plus ablative therapy. Ablative therapy included 45 patients receiving stereotactic body radiation therapy, 39 receiving microwave ablation, 20 receiving radiofrequency ablation, and 9 receiving a combination of these following TACE. With a median (interquartile range) follow-up of 17.4 (9.5-29.5) months, 242 of 512 (47.3%) lesions progressed, 211 in the group with TACE alone and 31 in the group with TACE plus ablative therapy (P < .001). Over 3 years, FFLP was 28.1% for TACE alone vs 67.4% for TACE with ablative therapy (P < .001). The 1-year and 3-year OS was 87.5% and 47.1% for patients with lesions treated with TACE alone vs 98.7% and 85.3% for patients where any lesion received TACE plus ablative therapy, respectively (P = .01), and this benefit remained robust on landmark analyses at 6 and 12 months. The addition of ablative therapy was independently associated with OS on multivariable analysis for all patients (hazard ratio, 0.26; 95% CI, 0.13-0.49; P < .001) and for patients with Barcelona clinic liver cancer stage B or C disease (hazard ratio, 0.31; 95% CI, 0.14-0.69; P = .004). Conclusions and Relevance: Adding ablative therapy following TACE improved FFLP and OS among patients with hepatocellular carcinoma. This study aims to guide the treatment paradigm for HCC patients until results from randomized clinical trials become available.

Urodynamics less likely to change diagnosis and management in uncomplicated overactive bladder.

INTRODUCTION: Given the invasive nature of urodynamics and its unclear impact on altering patient management, we aimed to determine whether performing a urodynamic study (UDS) resulted in a change in either patient diagnosis or treatment offered in women with uncomplicated urinary incontinence. MATERIALS AND METHODS: A retrospective review was performed of all female patients who underwent UDS for urinary incontinence at our practice between January 2014 and 2017. Patients with neurogenic lower urinary tract dysfunction, incomplete emptying, urinary retention, or prior anti-incontinence surgery were excluded. We compared the ICD-10 diagnosis and primary treatment offered in the absence of UDS to their post-UDS diagnosis and recommended therapy. Descriptive statistics, chi-squared, and multivariable analyses were performed. RESULTS: A total of 141 patient charts were analyzed. The indications for UDS were mixed urinary incontinence (MUI) (45.3%), stress urinary incontinence (SUI) (29.1%), and overactive bladder (OAB) (25.5%). A change in diagnosis following UDS was seen in 40.4% of the entire cohort including 53.1% of patients with MUI and 48.8% of those with SUI compared to 8.3% of those with OAB. A change in treatment was seen in 32.6% of patients including 54.9% with MUI, 41.7% with SUI, and 10% with OAB. When compared to patients with SUI on adjusted multivariate logistic regression, those with OAB were less likely to have a change in either diagnosis (OR 0.06 (0.01-0.31)) or management (OR 0.15 (0.04-0.62)). CONCLUSIONS: Diagnosis and management are unlikely to change after UDS in patients presenting with uncomplicated OAB. Conversely, UDS provided important diagnostic information that often changed management in those presenting with MUI and SUI. Our results suggest that UDS may be omitted in patients with uncomplicated refractory OAB in favor of earlier initiation of third line therapies.

Racial and Ethnic Differences in Urodynamic Parameters in Women With Overactive Bladder Symptoms.

OBJECTIVES: This study aimed to identify differences in severity of overactive bladder (OAB) symptoms in women of different races and ethnicities using urodynamic study (UDS) parameters. METHODS: We performed a 5-year retrospective chart review from January 2014 to January 2019 of women 18 years and older who endorsed OAB symptoms and underwent UDS at a racially and ethnically diverse academic urban medical center. Logistic and linear regressions were used to examine the associations of various UDS parameters between racial/ethnic groups, after adjusting for age, diabetes, and parity. RESULTS: A total of 161 women with an average age of 59 years were included in the study. The racial/ethnic composition of the group was Hispanic (62%), black (24%), and white (11%). Symptoms on presentation included urgency and/or frequency (11.8%), urge incontinence (23.0%), or mixed urinary symptoms (65.2%). Black and Hispanic women presented with differing symptoms (urgency/frequency vs mixed urinary symptoms). Half of the patients (n = 82) had detrusor overactivity. Compared with whites, blacks were 3.4-fold more likely to have detrusor overactivity (95% confidence interval, 0.99-11.40) and had lower volumes at time of "strong desire" (-102.6 mL, P = 0.003). Hispanics had on average 75.88 mL less volume at sensation of "strong desire" (P = 0.016) than did whites. CONCLUSIONS: Our study suggests that minority race and ethnicity may be associated with worse performance on certain UDS parameters. Future studies should aim to understand if these differences are due to genetic, disease-related, behavioral, and/or socioeconomic factors and whether these differences are associated with worse subjective OAB.

Comparing outcomes following total neoadjuvant therapy and following neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer.

BACKGROUND: There is recent interest in treating locally advanced rectal cancer (LARC) patients with total neoadjuvant therapy (TNT). However, whether TNT is associated with improved overall survival (OS) remains unknown. This study compares outcomes following TNT and following neoadjuvant chemoradiation therapy (nCRT) in patients with LARC, clinically defined cT3/4 or node positive disease, using the National Cancer Database. METHODS: LARC patients diagnosed between 2004-2015 were included. TNT was defined as multi-agent chemotherapy given at least 2 months before RT followed by pre-operative chemoradiation therapy and definitive surgery without adjuvant chemotherapy. nCRT was defined as pre-operative RT and chemotherapy started within 2 weeks from each other followed by definitive surgery with or without adjuvant chemotherapy. Kaplan-Meier curve with logrank test and multivariable Cox proportional hazards regression modelling were used to analyse the primary endpoint of overall survival (OS). Multivariable logistic regression modelling was used for secondary outcomes to determine if TNT is associated with pathological complete response (pCR), defined as ypT0N0, and negative circumferential resection margin (CRM). FINDINGS: Data from 372 TNT patients and 707 nCRT patients were analysed after a 2:1 propensity matching with replacement. Kaplan-Meier curve showed that OS with TNT was comparable to that with nCRT (p = 0•16). The 5-year OS rates for TNT and nCRT were 73•6% vs. 78•5% (p = 0•20). Multivariable Cox proportional hazards regression modelling confirmed no difference in OS between TNT and nCRT (HR = 1•21, p = 0•25). With TNT, 16•9% patients achieved pCR, whereas 13•1% patients achieved pCR with nCRT (p = 0•12). TNT was not found to be significantly associated with pCR (OR = 1•36, p = 0•13) or negative CRM (OR = 1•77, p = 0•19) in multivariable logistic regression modelling. INTERPRETATION: With results from current clinical trials pending, our data suggested that TNT and nCRT resulted in similar survival, while TNT led to higher pCR and CRM negative rate, albeit not statistically significant.

Axillobifemoral bypass: a brief surgical and historical review.

Peripheral artery disease (PAD) occurs when plaque accumulates in the arterial system and obstructs blood flow. Narrowing of the abdominal aorta and the common iliac arteries due to atherosclerotic plaques restricts blood supply to the lower limbs. Clinically, the lower limb symptoms of PAD are intermittent claudication, discoloration of the toes, and skin ulcers, all due to arterial insufficiency. Surgical revascularization is the primary mode of treatment for patients with severe limb ischemia. The objective of the surgical procedure is to bypass a blockage in an occluded major vessel by constructing an alternate route for blood flow using an artificial graft. This article presents information on aortoiliac reconstruction, with an emphasis on axillobifemoral bypass grafting.

Axillobifemoral Bypass Graft: A Student Dissection Experience.

As first-year medical students, we were excited, but nervous, to start the anatomy course. We were prepared to dedicate ourselves to the physical demands of dissection, and the hours of memorizing names and relations of countless anatomic features. We expected to leave the anatomy course with a comprehensive understanding of the human body that we would apply to our future studies and careers. We were not prepared, however, for the experience we had with our cadaver, Lucy.* Lucy was a small woman, but as we learned, she had endured a lot, physically and medically, in her 83 years of life. She had a pacemaker. She had coronary artery disease and a triple bypass procedure. She also had severe peripheral artery disease and had undergone at least one extraordinary surgical graft procedure to maintain blood flow into her lower extremities. The surprise of discovering a small piece of an axillobifemoral bypass graft and then continuing to uncover it, region by region, throughout the anatomy course, brought our dissection experience and our connection to Lucy to a more profound level than we could ever have anticipated. *The name Lucy was chosen as a pseudonym to protect the identity of the cadaver.