Translation and psychometric assessment of the mastectomy module of the BREAST-Q questionnaire for use in Nigeria.

BACKGROUND: The majority of non-metastatic breast cancer patients in sub-Saharan Africa are recommended to have mastectomy. The impact of mastectomy on a predominantly young African patient population requires evaluation. The BREAST-Q is a validated patient-reported outcome measure of quality-of-life following breast surgery that has been translated into 30 languages-none in Africa. This study aimed to translate and assess the psychometric properties of the mastectomy module of the BREAST-Q for use in Nigeria. METHODS: The BREAST-Q mastectomy module was translated from English to Yoruba and its psychometric properties assessed using best practice guidelines. Translation was performed in 4 steps: forward translation (x2), back translation, back translation review, and cognitive interviews with post-mastectomy patients. The translated BREAST-Q instrument was administered to post-mastectomy patients (n = 21) alongside the EORTC-QLQ BR23 to evaluate construct validity. Test-retest reliability was evaluated using intraclass correlation coefficients (ICC); surveys were re-administered 4 weeks apart. RESULTS: The translation process identified English phrases not amenable to direct translation, including "emotionally healthy" and descriptions of pain ("nagging," "throbbing," "sharp"). Translations were amended to reflect local context and question intent. During cognitive interviews, patients provided suggestions to simplify complex phrases, e.g. "discomfort in your breast area.". Internal consistency within scales was over 0.70 for psychosocial wellbeing (α = 0.84-0.87), sexual wellbeing (α = 0.98-0.99), physical wellbeing in chest (α = 0.84-0.86), and satisfaction with care (α = 0.89-0.93). ICC for test-retest reliability was moderate (0.46-0.63). CONCLUSIONS: The Yoruba version of the BREAST-Q mastectomy module presents a unique opportunity to adequately capture the experiences of Nigerian women post mastectomy. This instrument is being used in a pilot study of Nigerian patients to identify targets for intervention to improve the patient experience and compliance with breast cancer surgery.

Genomic Predictors of Recurrence Patterns After Complete Resection of Colorectal Liver Metastases and Adjuvant Hepatic Artery Infusion Chemotherapy.

BACKGROUND: Despite curative hepatectomy, most colorectal liver metastasis (CRLM) patients relapse locally within 2 years. Genomic predictors for hepatic recurrence are poorly understood. This study was designed to identify genomic signatures for recurrence in resected CRLM patients treated with adjuvant hepatic artery infusion (HAI) and/or systemic (SYS) chemotherapy. METHODS: Patients undergoing curative hepatectomy and adjuvant HAI+SYS or SYS between January 2000 and October 2017 with next-generation sequencing data were catalogued. Gene and signaling-level alterations were checked for association with time to any (AR), liver (LR), and extrahepatic recurrence (ER) by using Kaplan-Meier analysis. RESULTS: Of 172 receiving HAI+SYS, 100 patients recurred, with 69 LR and 83 ER. Five- and ten-year LR-free rates were 57% (95% confidence interval [CI] 48-65%) and 51% (95% CI 41-60%), respectively. Five- and 10-year ER-free, rates were 51% (95% CI 43-58%) and 45% (95% CI 36-54%), respectively. More ER was observed with tumors harboring altered KRAS (38% [95% CI 25-50%] vs. 63% [95% CI 53-71%], p-adj = 0.003) and RAS/RAF (36% [95% CI 25-48%] vs. 66% [95% CI 56-74%], p-adj < 0.001) than wild-type. Co-altered RAS/RAF-TP53 was associated with worse AR (26% [95% CI 14-40%] vs. 48% [95% CI 39-57%], p-unadj < 0.001), ER (30% [95% CI 17-45%] vs. 62% [95% CI 53-70%], p-unadj < 0.001), and LR rate (40% [95% CI 24-57%] vs. 70% [95% CI 60-77%], p-unadj = 0.002). On multivariable analysis, controlling for clinical risk score, ablation, margin status, and primary T-stage, co-altered RAS/RAF-TP53 was associated with increased risk for AR (HR = 2.14, 95% CI 1.38-3.31, p-unadj < 0.001), LR (HR = 1.79, 95% CI 1.06-3.02, p-unadj = 0.029), and ER (HR = 2.81, 95% CI 1.78-4.44, p-unadj < 0.001). CONCLUSIONS: Altered KRAS, RAS/RAF, and RAS/RAF-TP53 associated with earlier local and distant recurrence in resected CRLM patients receiving adjuvant HAI+SYS. Co-altered RAS/RAF-TP53 was a novel predictor of LR warranting investigation of whether genomic cooperativity is associated with this relapsing phenotype. Systemic therapies tailored to high-risk tumor biology are needed to reduce distant relapse after hepatectomy.

Recurrence of Hepatocellular Carcinoma After Complete Radiologic Response to Trans-Arterial Embolization: A Retrospective Study on Patterns, Treatments, and Prognoses.

BACKGROUND: There is limited information about the long-term outcomes and patterns of progression in patients who have unresectable, liver-confined hepatocellular carcinoma (HCC) with complete response (CR) to transarterial embolization and do not undergo resection or transplantation (LT). METHODS: A retrospective review analyzed participants in a randomized trial comparing hepatic artery embolization (HAE) and drug-eluting bead transarterial chemoembolization (DEB-TACE) with doxorubicin who had CR according to modified response evaluation criteria in solid tumors (mRECIST). The overall survival (OS), incidence and patterns of progression, and factors associated with progression were assessed. RESULTS: Of the 101 patients in the trial, 37 with CR were included in this study. This cohort had 17 patients treated with HAE (46 %), and 20 patients managed with DEB-TACE (54 %). The median age was 67 years (range, 42-82 years). Most of the cohort were male (86.5 %) and Caucasian (78 %). The median pre-treatment Model for End-Stage Liver Disease (MELD) score was 10, and 70 % of the cohort had Barcelona Clinic Liver Cancer (BCLC) stage B or C. The median follow-up period was 49 months (95 % confidence interval [CI], 9-108 months), and the median OS was 25 months (95 % CI, 18.9-30.9 months). The 3- and 5-year survival rates were respectively 31 % (95 % CI, 16.7-45.9 %) and 18 % (95 % CI, 6.8-32.1 %). The 1- and 2-year cumulative incidences of progression were respectively 76 % (95 % CI, 57.7-86.8 %) and 92 % (95 % CI, 74.5-97.6 %). The most common first site of progression was the previously treated hepatic site or local site (32 %, 12/37). The 3-year cumulative incidence of progression was 65 % (95 % CI, 46.4-78.4 %) for the local site. CONCLUSION: Patients with advanced-stage HCC and CR to embolization do not have durable responses and experience inevitable disease progression. Most patients with progression have liver-confined disease and should be evaluated for additional consolidative treatments.

An Anatomic Analysis of Fibula Flap Mandible Reconstructions: Implications for Endosseous Implant Placement.

BACKGROUND: Precise planning and evaluation of the fibula bone are necessary if immediate endosseous implant placement is considered. Limited information is available on the anatomical dimensions or density of fibula used in mandibular reconstructions. This study aimed to describe the morphology and dimensions of the fibula used to reconstruct segmental mandibular defects and contrast the findings with the native mandible. METHODS: A retrospective analysis was performed of patients who underwent segmental mandibulectomy reconstructed with osteocutaneous fibula flaps and had at least one postoperative computed tomography scan. Fibula cross sectional dimensions and densities were evaluated with three-dimensional software. Radiographic measurements were obtained from the contralateral mandible medial to the first molar for comparison. RESULTS: Four hundred seventy-seven fibula cross sections from 159 segments were evaluated. Cross-sectional oval, quadrilateral, triangular, and pentagonal shapes differed significantly in proportion (p < 0.001). Thirty-eight percent of segments (95 percent CI, 30 to 46 percent) had differences in cross-section height greater than 1 mm (p < 0.001). Between segments within the same patient, the median height difference was 1.58 mm (range, 0.14 to 6 mm). The superior cortex density was significantly higher for the fibula than the native mandible; however, the medullary space density was significantly lower (p < 0.001). CONCLUSIONS: The current study comprises the most comprehensive description of fibula morphology in mandibular reconstructions and highlights the significant variability that exists. The findings provide justification for the added time and cost of computer-aided design and computer-aided manufacturing in centers interested in performing immediate dental implant placement, as the technology provides the necessary precision and accuracy.

Differentiation of mucinous cysts and simple cysts of the liver using preoperative imaging.

PURPOSE: Preoperative radiographic differentiation of mucinous cystic neoplasms (MCN) and simple cysts (SLC) of the liver is challenging. Previous data have demonstrated that the finding of septations arising from the cyst wall without indentation on cross-sectional imaging is associated with MCN. We aim to assess whether this radiographic feature is diagnostic of MCN. METHODS: A prospectively maintained database was queried for patients with a preoperative diagnosis of a cystic liver lesion who subsequently underwent operative intervention. The feature of septations without indentation of the cyst wall was evaluated on cross-sectional imaging obtained within 3 months of operation. Imaging was independently evaluated by three radiologists blinded to pathology and interobserver agreement was compared to assess the diagnostic accuracy of this feature as well as the overall likelihood of the lesion representing a MCN. RESULTS: There were 95 patients who met inclusion criteria; 80 (84%) had SLC on pathology, while 15 (16%) had MCN. Presence of septa without indentation of cyst wall had high sensitivity (range 80-87%), but low specificity (range 48-66%). Interobserver percent agreement (PA) was 51% [κ = 0.35 (95% CI 0.22-0.47)]. Sensitivity among the three radiologists ranged between 20 and 80% and specificity between 71 and 91% for the likelihood of the lesion representing MCN versus SLC, with an area under the curve (AUC) of 0.67-0.79; however, interobserver agreement was fair [κ = 0.40 (95% CI 0.25-0.55), PA = 67%]. CONCLUSION: The presence of septations without indentation of cyst wall demonstrates adequate sensitivity to differentiate MCN and SLC. However, there is variability for detection of this feature and therefore, it alone is of limited clinical value.

Induction FOLFIRINOX for patients with locally unresectable pancreatic ductal adenocarcinoma.

OBJECTIVES: Patients with locally advanced pancreatic adenocarcinoma (PDAC) receive induction chemotherapy with or without radiation, with the goal of R0 resection and improving survival. Herein, we evaluate the outcomes of patients who presented with Stage III PDAC and received induction FOLFIRINOX. METHODS: An institutional database was queried for consecutive patients who received induction FOLFIRINOX for locally unresectable PDAC between 2010 and 2016. Clinical and radiographic parameters were assessed pre- and posttreatment, and clinical outcomes were evaluated. RESULTS: There were 200 patients who met the inclusion criteria. The median number of cycles of FOLFIRINOX was 8, 70% (n = 140) received radiation, and 18% (n = 36) underwent resection. Median overall survival (OS) in resected patients was 36 months (95% confidence interval [CI]: 24-56), and this group had improved OS compared to patients that did not undergo resection (hazard ratio (95% CI): 0.41 (0.26-0.64), p < 0.001). Patients (n = 112) who did not progress on induction therapy but remained unresectable had a median OS of 23.9 months (95% CI: 21.1-25.4). CONCLUSION: Nearly 20% of patients with locally advanced PDAC responded sufficiently to induction FOLFIRINOX to undergo resection, which was associated with improved OS compared to patients that did not undergo resection. Patients with stable disease who remain unresectable represent a group of patients with locally advanced PDAC who may benefit from optimization of additional nonoperative treatment.

Distinct Genomic Profiles are Associated With Conversion to Resection and Survival in Patients With Initially Unresectable Colorectal Liver Metastases Treated With Systemic and Hepatic Artery Chemotherapy.

OBJECTIVE: To examine genomic correlates of conversion to resection (CTR and overall survival (OS) in patients with initially unresectable colorectal liver metastasis (IU-CRLM) treated with combination systemic and hepatic artery infusion (HAI) chemotherapy. BACKGROUND: In patients presenting with IU-CRLM, combination systemic and HAI chemotherapy enables CTR with associated long-term OS in a subset of patients. Genomic correlates of CTR and OS in IU-CRLM have not been previously explored. METHODS: Specimens from IU-CRLM patients receiving systemic/HAI chemotherapy (2003-2017) were submitted for next-generation sequencing. Fisher Exact test assessed associations with CTR, and Kaplan-Meier/Cox methods assessed associations with OS from HAI initiation. RESULTS: Of 128 IU-CRLM patients, 51 (40%) underwent CTR at median 6 months (range: 3-35) from HAI initiation. CTR and persistently unresectable cohorts differed significantly in preoperative systemic chemotherapy exposure, node-positive primary status, and size of largest liver metastasis. Median and 5-year OS was 66 months and 51%. CTR was associated with prolonged survival (time-dependent HR 0.23,95% CI: 0.12-0.46, P < 0.001). The most frequently altered genes were APC (81%), TP53 (77%), and KRAS (37%). Oncogenic mutations in SOX9 and BRAF were associated with CTR. BRAF mutations, any RAS pathway alterations, and co-altered RAS/RAF-TP53 mutations wereassociated with worse survival. Classification and regression tree analysis defined prognostically relevant clusters of genomic risk to reveal co-altered RAS/RAF-TP53 as the highest risk subgroup. Co-altered RAS/RAF-TP53 remained independently associated with worse survival (HR 2.52, 95% CI: 1.37-4.64, P = 0.003) after controlling for CTR, number of liver metastases, and preoperative extrahepatic disease. CONCLUSIONS: Distinct genomic profiles are associated with CTR and survival in patients with IU-CRLM treated with HAI/systemic chemotherapy. Presence of SOX9, BRAF , and co-altered RAS/RAF- TP53 mutations are promising biomarkers that, when validated in larger datasets, may impact treatment of IU-CRLM patients.

Adaptive Dosing of Nivolumab + Ipilimumab Immunotherapy Based Upon Early, Interim Radiographic Assessment in Advanced Melanoma (The ADAPT-IT Study).

PURPOSE: Nivolumab + ipilimumab (nivo + ipi) is highly efficacious but has high toxicity. Standard treatment in advanced melanoma is four doses of nivo + ipi followed by nivo alone. Whether four doses of nivo + ipi are needed is unclear. METHODS: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT) study (NCT03122522) is a multicenter, single-arm phase II clinical trial. Patients received two doses of nivo (1 mg/kg) + ipi (3 mg/kg) followed by a computed tomography scan at week 6. Patients without new lesions or index lesion tumor growth of > 4% had protocol-defined early favorable antitumor effect (FATE) and ceased nivo + ipi, transitioning to nivo monotherapy. Patients without FATE at week 6 received the standard third and fourth doses of nivo + ipi followed by nivo monotherapy. The primary end point was response rate by RECIST 1.1 at week 12. Secondary end points included additional efficacy assessments and safety. RESULTS: Sixty patients were enrolled; 41 patients (68%) had FATE at week 6 and met criteria for stopping nivo + ipi. Best overall response rates by RECIST at week 12 or any time afterward were 48% (95% CI, 35 to 62) and 58% (95% CI, 45 to 71), respectively. With a median follow-up of 25 months, the estimated 18-month progression-free survival and overall survival are 52% and 80%, respectively. Fifty seven percent of patients had grade 3-5 treatment-related toxicity. CONCLUSION: The efficacy and toxicity of standard four dose nivo + ipi induction therapy in melanoma is likely driven by the first two doses. An interim computed tomography scan after two doses guided cessation of combination dosing and identified almost all responders. Longer follow-up and further study are needed to fully understand the implications of a shortened induction course of nivo + ipi.

Multiinstitutional Validation Study of Cyst Fluid Protein Biomarkers in Patients With Cystic Lesions of the Pancreas.

OBJECTIVE: Prospective evaluation of 2 clinical-molecular models in patients with unknown pathology who underwent endoscopic ultrasound with fine-needle aspiration (EUS-FNA) for a cystic lesion of the pancreas. SUMMARY OF BACKGROUND DATA: Preoperative prediction of histologic subtype (mucinous vs nonmucinous) and grade of dysplasia in patients with pancreatic cystic neoplasms is challenging. Our group has previously published 2 clinical-molecular nomograms for intraductal papillary mucinous neoplasms (IPMN) that incorporated both clinical/radiographic features and cyst fluid protein markers (sFASL, CA72-4, MMP9, IL-4). METHODS: This multiinstitutional study enrolled patients who underwent EUS-FNA for a cystic lesion of the pancreas. Treatment recommendations regarding resection were based on standard clinical, radiographic, and endoscopic features. Predicted probabilities of high-risk IPMN (high-grade dysplasia/invasive cancer) were calculated using the previously developed clinical-molecular nomograms. RESULTS: Cyst fluid was obtained from 100 patients who underwent diagnostic EUS-FNA. Within this group there were 35 patients who underwent resection, and 65 were monitored radiographically. Within the group that underwent resection, 26 had low-risk IPMN or benign non-IPMN lesions, and 9 had high-risk IPMN. Within the surveillance group, no patient progressed to resection or developed cancer after a median follow-up of 12months (range: 0.5-38). Using the clinical/radiographic nomogram alone, 2 out of 9 patients with high-risk IPMN had a predicted probability >0.5. In the clinical-molecular models, 6 of 9 patients in model 1, and 6 of 9 in model 2, had scores >0.5. CONCLUSIONS: This prospective study of patients with unknown cyst pathology further demonstrates the importance of cyst fluid protein analysis in the preoperative identification of patients with high-risk IPMN. Longer follow-up is necessary to determine if this model will be useful in clinical practice.

Somatic mutations as preoperative predictors of metastases in patients with localized clear cell renal cell carcinoma - An exploratory analysis.

OBJECTIVE: Recurrent genomic alterations in clear cell renal cell carcinoma (ccRCC) have been associated with treatment outcomes; however, current preoperative predictive models do not include known genetic predictors. We aimed to explore the value of common somatic mutations in the preoperative prediction of metastatic disease among patients treated for localized ccRCC. MATERIALS AND METHODS: After obtaining institutional review board approval, data of 254 patients with localized ccRCC treated between 2005 and 2015 who underwent genetic sequencing was collected. The mutation status of VHL, PBRM1, SETD2, BAP1 and KDM5C were evaluated in the nephrectomy tumor specimen, which served as a proxy for biopsy mutation status. The Raj et al. preoperative nomogram was used to predict the 12-year metastatic free probability (MFP). The study outcome was MFP; the relationship between MFP and mutation status was evaluated with Cox-regression models adjusting for the preoperative nomogram variables (age, gender, incidental presentation, lymphadenopathy, necrosis, and size). RESULTS: The study cohort included 188 males (74%) and 66 females (26%) with a median age of 58 years. VHL mutations were present in 152/254 patients (60%), PBRM1 in 91/254 (36%), SETD2 in 32/254 (13%), BAP1 in 19/254 (8%), and KDM5C in 19/254 (8%). Median follow-up for survivors was 8.1 years. Estimated 12-year MFP was 70% (95% CI: 63%-75%). On univariable analysis SETD2 (HR: 3.30), BAP1 (HR: 2.44) and PBRM1 (HR: 1.78) were significantly associated with a higher risk of metastases. After adjusting for known preoperative predictors in the existing nomogram, SETD2 mutations remained associated with a higher rate of metastases after nephrectomy (HR: 2.09, 95% CI: 1.19-3.67, P = 0.011). CONCLUSION: In the current exploratory analysis, SETD2 mutations were significant predictors of MFP among patients treated for localized ccRCC. Our findings support future studies evaluating genetic alterations in preoperative renal biopsy samples as potential predictors of treatment outcome.

Response to Immune Checkpoint Inhibition as Monotherapy or in Combination With Chemotherapy in Metastatic ROS1-Rearranged Lung Cancers.

INTRODUCTION: ROS1 fusions are oncogenic drivers in 1% to 3% of NSCLCs. The activity of immune checkpoint inhibitor (ICI) monotherapy or in combination with chemotherapy (chemotherapy with ICI [chemo-ICI]) in these tumors and their immunophenotype have not been systematically described. METHODS: In this multi-institutional retrospective study, tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) were evaluated in patients with ROS1-rearranged NSCLC. Time-to-treatment discontinuation (TTD) and objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) were calculated for patients treated with ICI or chemo-ICI in the metastatic setting. RESULTS: A total of 184 patients were identified. Among 146 assessable cases, PD-L1 expression was less than 1% in 60 (41%), 1% to 49% in 35 (24%), and greater than or equal to 50% in 51 tumors (35%). Of 100 (92%) TMB-assessable tumors, 92 had less than 10 mutations per megabase. TMB was significantly lower for ROS1-rearranged tumors (n = 97) compared with tumors with EGFR (n = 1250) or KRAS alterations (n = 1653) and all other NSCLC tumors (n = 2753) evaluated with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (median TMB = 2.6 versus 3.5, 7.0, and 6.1 mutations per megabase, p < 0.001). Among patients treated with ICI, median TTD was 2.1 months (95% confidence interval [CI]: 1.0-4.2 mo; n = 28) and ORR 13% (2 of 16 RECIST-assessable; 95% CI: 2%-38%). Among patients treated with chemo-ICI, median TTD was 10 months (95% CI: 4.7-14.1 mo; n = 11) and ORR 83% (5 of 6 RECIST-assessable; 95% CI: 36%-100%). There was no difference in PD-L1 expression (p = 0.91) or TMB (p = 0.83) between responders and nonresponders. CONCLUSIONS: Most ROS1-rearranged NSCLCs have low PD-L1 expression and TMB. The activity of ICI in these tumors is modest. In contrast, chemo-ICI can achieve meaningful activity.

Timing of Complication and Failure to Rescue after Hepatectomy: Single-Institution Analysis of 28 Years of Hepatic Surgery.

BACKGROUND: Morbidity after hepatectomy remains a significant, potentially preventable, outcome. Understanding the pattern of complications and rescue pathways is critical for the development of targeted initiatives intended to salvage patients after operative morbidity. STUDY DESIGN: Patients undergoing liver resection from 1991 to 2018 at a single institution were analyzed. Failure to rescue (FTR) was defined as percentage of deaths in patients with a complication within 30 days. Generalized estimating equations with log-link function assessed associations between clinical characteristics and major complications and between complications at fewer than 30 days and 30 to 90 days. Logistic regression assessed associations between complications and FTR. RESULTS: A total of 6,191 patients and 6,668 operations were identified, of which 55.6% were performed for management of metastatic colorectal cancer. Major complications (grade ≥3) occurred in 20.2% of operations (1,346 of 6,668). Ninety-day mortality was 2.2%. The most common complication was intra-abdominal abscess at 9.0% (95% CI, 8.3% to 9.7%). Ten percent of patients with a complication at 30 days had another complication between 30 and 90 days compared with 2% without an early complication (odds ratio [OR] 5.09; 95% CI, 3.97 to 6.54; p < 0.001). FTR for liver failure, cardiac arrest, abscess, and hemorrhage was 36%, 56%, 3%, and 6%, respectively. Risk of 90-day mortality was higher in patients with liver failure (53% vs 2%; OR 61.42; 95% CI, 37.47 to 100.67; p < 0.001), cardiac arrest (69% vs 2%; OR 96.95; 95% CI, 33.23 to 283.80; p < 0.001), hemorrhage (11% vs 2%; OR 5.51; 95% CI, 2.59 to 11.73; p < 0.001), and abscess (7% vs 2%; OR 4.05; 95% CI, 2.76 to 5.94; p < 0.001) compared with those without these complications. CONCLUSIONS: Morbidity after hepatectomy is frequent despite low mortality. This study identifies targets for improvement in morbidity and failure to rescue after hepatectomy. Efforts to improve recognition and intervention for infections and early complications are needed to improve outcomes.

Opportunities for Improvement in the Administration of Neoadjuvant Chemotherapy for T4 Breast Cancer: A Comparison of the U.S. and Nigeria.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is an integral component of T4 breast cancer (BCa) treatment. We compared response to NAC for T4 BCa in the U.S. and Nigeria to direct future interventions. MATERIALS AND METHODS: Cross-sectional retrospective analysis included all patients with non-metastatic T4 BCa treated from 2010 to 2016 at Memorial Sloan Kettering Cancer Center (New York, New York) and Obafemi Awolowo University Teaching Hospitals Complex (Ile Ife, Nigeria). Pathologic complete response (pCR) and survival were compared and factors contributing to disparities evaluated. RESULTS: Three hundred and eight patients met inclusion criteria: 157 (51%) in the U.S. and 151 (49%) in Nigeria. All U.S. patients received NAC and surgery compared with 93 (62%) Nigerian patients. Fifty-six out of ninety-three (60%) Nigerian patients completed their prescribed course of NAC. In Nigeria, older age and higher socioeconomic status were associated with treatment receipt. Fewer patients in Nigeria had immunohistochemistry performed (100% U.S. vs. 18% Nigeria). Of those with available receptor subtype, 18% (28/157) of U.S. patients were triple negative versus 39% (9/23) of Nigerian patients. Overall pCR was seen in 27% (42/155) of U.S. patients and 5% (4/76) of Nigerian patients. Five-year survival was significantly shorter in Nigeria versus the U.S. (61% vs. 72%). However, among the subset of patients who received multimodality therapy, including NAC and surgery with curative intent, 5-year survival (67% vs. 72%) and 5-year recurrence-free survival (48% vs. 61%) did not significantly differ between countries. CONCLUSION: Addressing health system, socioeconomic, and psychosocial barriers is necessary for administration of complete NAC to improve BCa outcomes in Nigeria. IMPLICATIONS FOR PRACTICE: This cross-sectional retrospective analysis of patients with T4 breast cancer in Nigeria and the U.S. found a significant difference in pathologic complete response to neoadjuvant chemotherapy (5% Nigeria vs. 27% U.S.). Five-year survival was shorter in Nigeria, but in patients receiving multimodality treatment, including neoadjuvant chemotherapy and surgery with curative intent, 5-year overall and recurrence-free survival did not differ between countries. Capacity-building efforts in Nigeria should focus on access to pathology services to direct systemic therapy and promoting receipt of complete chemotherapy to improve outcomes.

Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma.

BACKGROUND AND AIM: Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown. APPROACH AND RESULTS: This bi-institutional study of patients with confirmed iCCA (n = 412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT-rich interactive domain-containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin-dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1-associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P < 0.0001), KRAS (P = 0.0001), and CDKN2A (P < 0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08-3.06; P = 0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95-5.94; P < 0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [P < 0.001]; regional lymph node metastases [P < 0.001]), whereas KRASmut (HR, 1.69; 95% CI, 0.97-2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P < 0.001), with high-risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8-73.5) or high-risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6-not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy. CONCLUSIONS: TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.

Urinary Outcomes for Men With High Baseline International Prostate Symptom Scores Treated With Prostate SBRT.

PURPOSE: There are limited data regarding high-dose stereotactic body radiation therapy (SBRT) for prostate cancer in patients with poor baseline urinary function. The purpose of this study was to evaluate genitourinary (GU) toxicity and changes in patient-reported symptom severity scores after prostate SBRT in men with a high pretreatment International Prostate Symptom Score (IPSS). METHODS AND MATERIALS: Seven hundred fifty-three patients treated with prostate SBRT at our institution from 2012 to 2019 were identified, of whom 72 consecutive patients with baseline IPSS ≥15 were selected for this study. GU toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) v3.0 and IPSS were prospectively documented at each follow-up visit. Univariable logistic regression was used to evaluate for potential predictors of GU toxicity. RESULTS: Median follow-up in survivors was 26.8 months. The rates of acute grade 2 and 3 GU toxicity were 20.8% and 1.4%, respectively. The rates of late grade 2 and 3 GU toxicity were 37.5% and 5.6%, respectively. The majority of grade 2+ toxicities resolved by last follow-up, and when toxicities were regraded per CTCAE v5.0, there were no longer any grade 3 adverse events. Total IPSS and individual symptom subscores improved over time. Compared with baseline, median total IPSS at 24 ± 6 months was significantly lower (18 vs 12; P < .001) and the proportion of patients with severe scores (IPSS ≥20) decreased from 29.2% to 13.9%. Pretreatment urinary urgency was associated with late grade 2+ GU toxicity (odds ratio, 2.10; 95% confidence interval, 1.33-3.31; P = .001). CONCLUSIONS: In men with baseline IPSS ≥15 managed with prostate SBRT, the rate of severe GU toxicity was low and patient-reported symptoms generally improved over time. Thus, high pretreatment IPSS should not deter clinicians from offering prostate SBRT.

Predictors for post-treatment biopsy outcomes after prostate stereotactic body radiotherapy.

PURPOSE: To investigate predictors associated with post-treatment biopsy outcomes after stereotactic body radiotherapy (SBRT) for localized prostate cancer. MATERIALS AND METHODS: 257 patients treated with prostate SBRT to dose levels of 32.5 Gy to >40 Gy in 5-6 fractions underwent a post-treatment biopsy performed approximately two years after treatment to evaluate local control status. 73 had% intermediate-risk disease (n = 187) and the remaining 17% (n = 43) and 10% (n = 27) had low-risk and high-risk disease, respectively. RESULTS: The incidence of positive, negative, and treatment-effect post-treatment biopsies were 15.6%, 57.6%, and 26.8%, respectively. The incidence of a positive biopsy according to dose was 37.5% (n = 9/24), 21.4% (n = 6/28), 19.4% (n = 6/31), and 10.9% (n = 19/174) for 32.5 Gy, 35 Gy, 37.5 Gy, and >40 Gy, respectively. In a multivariable model, patients treated with SBRT doses of <40 Gy and those with unfavorable-intermediate-risk or high-risk disease had higher likelihood of a positive post-treatment biopsy. A positive post-SBRT biopsy was associated with a significantly higher likelihood of subsequent PSA relapse at five years (Positive biopsy: 57%, 95% CI: 29-77% compared to negative biopsy: 7%, 95% CI: 3-14%; p < 0.001). CONCLUSION: Based on two-year post-SBRT biopsies, excellent tumor control was achieved when dose levels of 40 Gy or higher were used. Standard SBRT dose levels of 35-37.5 Gy were associated with a higher likelihood of a positive post-treatment biopsy. Two-year positive post-treatment biopsies pre-dated the development of PSA failure in the majority of patients.

Lack of survival advantage among re-resected elderly glioblastoma patients: a SEER-Medicare study.

BACKGROUND: The survival benefit of re-resection for glioblastoma (GBM) remains controversial, owing to the immortal time bias inadequately considered in many studies where re-resection was treated as a fixed, rather than a time-dependent factor. Using the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database, we assessed treatment patterns for older adults and evaluated the association between re-resection and overall survival (OS), accounting for the timing of re-resection. METHODS: This retrospective cohort study included elderly patients (age ≥66) in the SEER-Medicare linked database diagnosed with GBM between 2006 and 2015 who underwent initial resection. Time-dependent Cox regression was used to assess the association between re-resection and OS, controlling for age, gender, race, poverty level, geographic region, marital status, comorbidities, receipt of radiation + temozolomide, and surgical complications. RESULTS: Our analysis included 3604 patients with median age 74 (range: 66-96); 54% were men and 94% were white. After initial resection, 44% received radiation + temozolomide and these patients had a lower hazard of death (hazard ratio [HR]: 0.28, 95% confidence interval [CI]: 0.26-0.31, P < .001). In total, 9.5% (n = 343) underwent re-resection. In multivariable analyses, no survival benefit was seen for patients who underwent re-resection (HR: 1.12, 95% CI: 0.99-1.27, P = .07). CONCLUSIONS: Re-resection rates were low among elderly GBM patients, and no survival advantage was observed for patients who underwent re-resection. However, patients who received standard of care at initial diagnosis had a lower risk of death. Older adults benefit from receiving radiation + temozolomide after initial resection, and future studies should assess the relationship between re-resection and OS taking the time of re-resection into account.

Intraductal Papillary Mucinous Neoplasms: Have IAP Consensus Guidelines Changed our Approach?: Results from a Multi-institutional Study.

OBJECTIVE: To evaluate the influence of consensus guidelines on the management of intraductal papillary mucinous neoplasms (IPMN) and the subsequent changes in pathologic outcomes. BACKGROUND: Over time, multiple guidelines have been developed to identify high-risk IPMN. We hypothesized that the development and implementation of guidelines should have increased the percentage of resected IPMN with high-risk disease. METHODS: Memorial Sloan-Kettering (MSK), Johns Hopkins (JH), and Massachusetts General Hospital (MGH) databases were queried for resected IPMN (2000-2015). Patients were categorized into main-duct (MD-IPMN) versus branch-duct (BD-IPMN). Guideline-specific radiographic/endoscopic features were recorded. High-risk disease was defined as high-grade dysplasia/carcinoma. Fisher's exact test was used to detect differences between institutions. Logistic regression evaluated differences between time-points [preguidelines (pre-GL, before 2006), Sendai (SCG, 2006-2012), Fukuoka (FCG, after 2012)]. RESULTS: The study included 1210 patients. The percentage of BD-IPMN with ≥1 high-risk radiographic feature differed between centers (MSK 69%, JH 60%, MGH 45%; P < 0.001). In MD-IPMN cohort, the presence of radiographic features such as solid component and main pancreatic duct diameter ≥10 mm also differed (solid component: MSK 38%, JH 30%, MGH 18%; P < 0.001; duct ≥10 mm: MSK 49%, JH 32%, MGH 44%; P < 0.001). The percentage of high-risk disease on pathology, however, was similar between institutions (BD-IPMN: P = 0.36, MD-IPMN: P = 0.48). During the study period, the percentage of BD-IPMN resected with ≥1 high-risk feature increased (52% pre-GL vs 67% FCG; P = 0.005), whereas the percentage of high-risk disease decreased (pre-GL vs FCG: 30% vs 20%). For MD-IPMN, there was not a clear trend towards guideline adherence, and the rate of high-risk disease was similar over the time (pre-GL vs FCG: 69% vs 67%; P = 0.63). CONCLUSION: Surgical management of IPMN based on radiographic criteria is variable between institutions, with similar percentages of high-risk disease. Over the 15-year study period, the rate of BD-IPMN resected with high-risk radiographic features increased; however, the rate of high-risk disease decreased. Better predictors are needed.

Clinical trial of proton craniospinal irradiation for leptomeningeal metastases.

BACKGROUND: Leptomeningeal metastases (LM) are associated with limited survival and treatment options. While involved-field radiotherapy is effective for local palliation, it lacks durability. We evaluated the toxicities of proton craniospinal irradiation (CSI), a treatment encompassing the entire central nervous system (CNS) compartment, for patients with LM from solid tumors. METHODS: We enrolled patients with LM to receive hypofractionated proton CSI in this phase I prospective trial. The primary endpoint was to describe treatment-related toxicity, with dose-limiting toxicity (DLT) defined as any radiation-related grade 3 non-hematologic toxicity or grade 4 hematologic toxicity according to the Common Terminology Criteria for Adverse Events that occurred during or within 4 weeks of completion of proton CSI. Secondary endpoints included CNS progression-free survival (PFS) and overall survival (OS). RESULTS: We enrolled 24 patients between June 2018 and April 2019. Their median follow-up was 11 months. Twenty patients were evaluable for protocol treatment-related toxicities and 21 for CNS PFS and OS. Two patients in the dose expansion cohort experienced DLTs consisted of grade 4 lymphopenia, grade 4 thrombocytopenia, and/or grade 3 fatigue. All DLTs resolved without medical intervention. The median CNS PFS was 7 months (95% CI: 5-13) and the median OS was 8 months (95% CI: 6 to not reached). Four patients (19%) were progression-free in the CNS for more than 12 months. CONCLUSION: Hypofractionated proton CSI using proton therapy is a safe treatment for patients with LM from solid tumors. We saw durable disease control in some patients.