Publications by authors named "Sujata Patil"

219 Publications

Prenatal diagnosis of vascular rings and outcome.

Ann Pediatr Cardiol 2021 Jul-Sep;14(3):359-365. Epub 2021 Feb 16.

Department of Fetal Medicine, Fernandez Hospital, Hyderabad, Telangana, India.

Background: Vascular rings (VRs) present with varied symptoms and may result in significant morbidity before an accurate diagnosis is made. Prenatal diagnosis may be useful to plan surgery after birth.

Objectives: The purpose of the study was to see the feasibility of accurate diagnosis of VR during antenatal ultrasound examination and describe their outcome.

Methods: This is a retrospective observational study between January 2014 and December 2019. Vascular rings were diagnosed on the basis of three vessel tracheal view and neck vessels arrangements on fetal echocardiogram. Postnatal evaluation by transthoracic echocardiography and computerized tomography angiogram was performed. Surgical repair was done as per standard indications.

Results: A total of 35 cases of fetal VRs (median gestational age: 24 weeks [range: 19-35]) were diagnosed during the study period. There were four dichorionic diamniotic twin gestation pregnancies. The right aortic arch (RAA) with anomalous left subclavian artery (ALSA) was suspected in 31 fetuses, double aortic arch (DAA) in 3, and circumflex aorta in 1. Twenty-six (74%) patients had successful deliveries. One patient had a spontaneous miscarriage, 2 underwent termination, and 6 were lost to follow-up. Postnatal assessment showed RAA with ALSA in 18, DAA in 5, circumflex aorta in 2, and no abnormality in 1. Twenty-two (86%) were operated (RAA with ALSA: 17, DAA: 4, and circumflex aorta: 1) and four were waiting for surgery. Two patients died due to prematurity-related complications. All survivors are symptom free during follow-up (median: 2.24; range: 0.2-5.6 years).

Conclusions: Fetal echocardiography enables prenatal diagnosis and planning of postnatal repair of VRs.
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http://dx.doi.org/10.4103/apc.APC_108_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457289PMC
February 2021

Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing.

Eur Urol Oncol 2021 Oct 12. Epub 2021 Oct 12.

Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: Despite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking.

Objective: To define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing.

Design, Setting, And Participants: We retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020.

Outcome Measurement And Statistical Analysis: The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher's exact or χ test).

Results And Limitations: Of 232 patients with early-onset RCC, 50% had non-clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non-RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non-clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non-RCC-associated genes was 0% and 9.9%, respectively.

Conclusions: Patients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing.

Patient Summary: In this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.
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http://dx.doi.org/10.1016/j.euo.2021.09.005DOI Listing
October 2021

The clinical behavior and genomic features of the so-called adenoid cystic carcinomas of the solid variant with basaloid features.

Mod Pathol 2021 Oct 1. Epub 2021 Oct 1.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Classic adenoid cystic carcinomas (C-AdCCs) of the breast are rare, relatively indolent forms of triple negative cancers, characterized by recurrent MYB or MYBL1 genetic alterations. Solid and basaloid adenoid cystic carcinoma (SB-AdCC) is considered a rare variant of AdCC yet to be fully characterized. Here, we sought to determine the clinical behavior and repertoire of genetic alterations of SB-AdCCs. Clinicopathologic data were collected on a cohort of 104 breast AdCCs (75 C-AdCCs and 29 SB-AdCCs). MYB expression was assessed by immunohistochemistry and MYB-NFIB and MYBL1 gene rearrangements were investigated by fluorescent in-situ hybridization. AdCCs lacking MYB/MYBL1 rearrangements were subjected to RNA-sequencing. Targeted sequencing data were available for 9 cases. The invasive disease-free survival (IDFS) and overall survival (OS) were assessed in C-AdCC and SB-AdCC. SB-AdCCs have higher histologic grade, and more frequent nodal and distant metastases than C-AdCCs. MYB/MYBL1 rearrangements were significantly less frequent in SB-AdCC than C-AdCC (3/14, 21% vs 17/20, 85% P < 0.05), despite the frequent MYB expression (9/14, 64%). In SB-AdCCs lacking MYB rearrangements, CREBBP, KMT2C, and NOTCH1 alterations were observed in 2 of 4 cases. SB-AdCCs displayed a shorter IDFS than C-AdCCs (46.5 vs 151.8 months, respectively, P < 0.001), independent of stage. In summary, SB-AdCCs are a molecularly heterogeneous but clinically aggressive group of tumors. Less than 25% of SB-AdCCs display the genomic features of C-AdCC. Defining whether these tumors represent a single entity or a collection of different cancer types with a similar basaloid histologic appearance is warranted.
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http://dx.doi.org/10.1038/s41379-021-00931-6DOI Listing
October 2021

Organ Preservation in Patients with Rectal Cancer Treated with Total Neoadjuvant Therapy.

Dis Colon Rectum 2021 Dec;64(12):1463-1470

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York.

Background: Retrospective studies suggest that watch-and-wait is a safe alternative to total mesorectal excision in selected patients with a clinical complete response after chemoradiotherapy.

Objective: This study aimed to determine the proportion of patients with rectal cancer who may benefit from watch-and-wait.

Design: This study is a retrospective analysis of data from prospectively maintained databases.

Setting: This study was conducted at a comprehensive cancer center.

Patients: Consecutive patients with stage II or III rectal adenocarcinoma who were treated with total neoadjuvant therapy using induction chemotherapy between 2012 and 2019 under the care of the same surgeon were included.

Intervention: Induction-type total neoadjuvant therapy consisted of 8 cycles of leucovorin-fluorouracil-oxaliplatin or 5 cycles of capecitabine-oxaliplatin before chemoradiotherapy. Patients with a clinical complete response were offered watch-and-wait, and patients with residual tumor were offered total mesorectal excision.

Main Outcomes And Measures: Tumor response was assessed with a digital rectal examination, endoscopy, and MRI. Patient characteristics and recurrence-free survival were compared between the watch-and-wait group and the total mesorectal excision group.

Results: A total of 88 patients were included in the analysis. One (1%) died during neoadjuvant therapy. Fifty-five patients (62.5%) had an incomplete clinical response and underwent surgery, 10 (18%) of the 55 developed distant metastasis, and 3 (5%) developed local recurrence. The remaining 32 patients (36.3%) had a clinical complete response and underwent watch-and-wait. On average, patients in the watch-and-wait group were older and had smaller, more distal tumors compared with patients in the surgery group. The median radiation dose, number of chemotherapy cycles, rate of adverse events, and length of follow-up did not differ substantively between the total mesorectal excision group and the watch-and-wait group. In the watch-and-wait group, 2 (6%) patients developed tumor regrowth, and one of them had distant metastasis. Recurrence-free survival was significantly higher in the watch-and-wait group.

Limitations: Generalizability, sample size, and follow-up duration were limitations of this study.

Conclusions: Approximately one-third of patients with stage II or III rectal cancer can benefit from a watch-and-wait approach with the aim of preserving the rectum if treated with induction-type total neoadjuvant therapy and followed by an experienced multidisciplinary team. See Video Abstract at http://links.lww.com/DCR/B688.

Conservacin De Rganos En Pacientes Con Cncer De Recto Tratados Con Terapia Neoadyuvante Total: ANTECEDENTES:Estudios retrospectivos sugieren que observar y esperar es una alternativa segura a la escisión mesorrectal total en pacientes seleccionados con una respuesta clínica completa después de la quimiorradioterapia.OBJETIVO:Determinar la proporción de pacientes con cáncer de recto que pueden beneficiarse de observar y esperar.DISEÑO:Análisis retrospectivo de datos de bases de datos mantenidas de forma prospectiva.ESCENARIO:Centro Oncológico Integral.PACIENTES:Pacientes consecutivos con adenocarcinoma de recto en estadio II o III tratados con TNT utilizando quimioterapia de inducción entre 2012 y 2019 bajo el cuidado del mismo cirujano.INTERVENCIÓN:La terapia neoadyuvante total de tipo inducción consistió en ocho ciclos de leucovorín-fluorouracilo-oxaliplatino o cinco ciclos de capecitabina-oxaliplatino antes de la quimiorradioterapia. A los pacientes con una respuesta clínica completa se les ofreció observar y esperar, y a los pacientes con tumor residual se les ofreció la escisión mesorrectal total.PRINCIPALES RESULTADOS Y MEDIDAS:La respuesta del tumor se evaluó con un tacto rectal, endoscopia y resonancia magnética. Se compararon las características de los pacientes y la supervivencia libre de recurrencia entre el grupo de observación y espera y el grupo de escisión mesorrectal total.RESULTADOS:Se incluyó en el análisis a un total de 88 pacientes. Uno (1%) murió durante la terapia neoadyuvante. Cincuenta y cinco pacientes (62.5%) tuvieron una respuesta clínica incompleta y se sometieron a cirugía; 10 (18%) de los 55 desarrollaron metástasis a distancia y 3 (5%) desarrollaron recidiva local. Los 32 pacientes restantes (36.3%) tuvieron una cCR (respuesta clínica completa) y se sometieron a observar y esperar. En promedio, los pacientes del grupo de observación y espera eran mayores y tenían tumores más pequeños y distales en comparación con el grupo de cirugía. La dosis mediana de radiación, el número de ciclos de quimioterapia, la tasa de eventos adversos y la duración del seguimiento no difirieron sustancialmente entre el grupo de escisión mesorrectal total y el grupo de observación y espera. En el grupo de observación y espera, 2 (6%) pacientes desarrollaron recrecimiento del tumor y uno de ellos tuvo metástasis a distancia. La supervivencia libre de recurrencia fue significativamente mayor en el grupo de observación y espera.LIMITACIONES:Generalizabilidad, tamaño de la muestra, duración del seguimiento.CONCLUSIONES:Aproximadamente un tercio de los pacientes con cáncer de recto en estadio II o III pueden beneficiarse de un abordaje de observación y espera con el objetivo de preservar el recto si se tratan con terapia neoadyuvante total de tipo inducción y son seguidos por un equipo multidisciplinario experimentado. Consulte Video Resumen en http://links.lww.com/DCR/B688.
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http://dx.doi.org/10.1097/DCR.0000000000002122DOI Listing
December 2021

Logistic Regression in Clinical Studies.

Int J Radiat Oncol Biol Phys 2021 Aug 17. Epub 2021 Aug 17.

Department of Quantitative Health Sciences, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio; Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio. Electronic address:

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http://dx.doi.org/10.1016/j.ijrobp.2021.08.007DOI Listing
August 2021

Evolving biological associations of upfront cytoreductive nephrectomy in metastatic renal cell carcinoma.

Cancer 2021 Nov 19;127(21):3946-3956. Epub 2021 Jul 19.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Systemic responses to cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) are variable and difficult to anticipate. The authors aimed to determine the association of CN with modifiable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors and oncological outcomes.

Methods: Consecutive patients with mRCC referred for potential CN (2009-2019) were reviewed. The primary outcome was overall survival (OS); variables of interest included undergoing CN and the baseline number of modifiable IMDC risk factors (anemia, hypercalcemia, neutrophilia, thrombocytosis, and reduced performance status). For operative cases, the authors evaluated the effects of IMDC risk factor dynamics, measured 6 weeks and 6 months after CN, on OS and postoperative treatment disposition.

Results: Of 245 treatment-naive patients with mRCC referred for CN, 177 (72%) proceeded to surgery. The CN cases had fewer modifiable IMDC risk factors (P = .003), including none in 71 of 177 patients (40.1%); fewer metastases (P = .011); and higher proportions of clear cell histology (P = .012). In a multivariable analysis, surgical selection, number of IMDC risk factors, metastatic focality, and histology were associated with OS. Total risk factors changed for 53.8% and 57.2% of the patients from the preoperative period to 6 weeks and 6 months after CN, respectively. Adjusted for preoperative IMDC risk scores, an increase in IMDC risk factors at 6 weeks and 6 months was associated with adverse OS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.13-2.19; P = .007; HR, 2.52; 95% CI, 1.74-3.65; P < .001).

Conclusions: IMDC risk factors are dynamic clinical variables that can improve after upfront CN in select patients, and this suggests a systemic benefit of cytoreduction, which may confer clinically meaningful prognostic implications.
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http://dx.doi.org/10.1002/cncr.33790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516697PMC
November 2021

PD-L1 Expression in Metaplastic Breast Carcinoma Using the PD-L1 SP142 Assay and Concordance Among PD-L1 Immunohistochemical Assays.

Am J Surg Pathol 2021 09;45(9):1274-1281

Departments of Pathology.

Immunotherapy for the treatment of programmed death-ligand 1 (PD-L1) positive locally advanced or metastatic triple negative breast cancer may benefit patients with metaplastic breast cancer (MpBC). Previous study of PD-L1 in MpBC scored tumor cells (TCs), different from Food and Drug Administration-approved scoring methods. We sought to define PD-L1 expression in MpBCs and to evaluate concordance of 3 PD-L1 assays. Primary, treatment naive MpBC treated at our Center from 1998 to 2019 were identified. PD-L1 expression was assessed using SP142, E1L3n, and 73-10. We evaluated PD-L1 expression on tumor infiltrating immune cells (IC) and also in TCs. For each assay, we scored PD-L1 expression using ≥1% IC expression according to the IMpassion130 trial criteria and using combined positive score (CPS) ≥10 according to the KEYNOTE-355 trial cutoff. A total of 42 MpBCs were identified. Most MpBC had PD-L1 positivity in ≥1% IC with all 3 assays (95%, 95%, 86%) in contrast to a maximum 71% with a CPS ≥10. PD-L1 IC expression was comparable between the SP142 and 73-10 assays and was lowest with E1L3n. PD-L1 TC expression was lowest using SP142. The overall concordance for IC scoring was 88% while 62% had concordant CPS. For each assay, the results of the 2 scoring algorithms were not interchangeable. The SP142 assay showed distinct expression patterns between IC (granular, dot-like) and TC (membranous) while 73-10 and E1L3n showed membranous and/or cytoplasmic expression in both IC and TC. Most MpBC in our cohort were positive for PD-L1 indicating eligibility for anti-PD-L1/programmed death-1 immunotherapy.
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http://dx.doi.org/10.1097/PAS.0000000000001760DOI Listing
September 2021

A phase I trial of sorafenib with whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases and a correlative study of FLT-PET brain imaging.

Breast Cancer Res Treat 2021 Jul 10;188(2):415-425. Epub 2021 Jun 10.

Breast Cancer Medicine Service, Evelyn Lauder Breast Center, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA.

Purpose: Sorafenib has demonstrated anti-tumor efficacy and radiosensitizing activity preclinically and in breast cancer. We examined sorafenib in combination with whole brain radiotherapy (WBRT) and explored the [18F] 3'deoxy-3'-fluorothymidine (FLT)-PET as a novel brain imaging modality in breast cancer brain metastases.

Methods: A phase I trial of WBRT + sorafenib was conducted using a 3 + 3 design with safety-expansion cohort. Sorafenib was given daily at the start of WBRT for 21 days. The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). MacDonald Criteria were used for response assessment with a correlative serial FLT-PET imaging study.

Results: 13 pts were evaluable for dose-limiting toxicity (DLT). DLTs were grade 4 increased lipase at 200 mg (n = 1) and grade 3 rash at 400 mg (n = 3). The MTD was 200 mg. The overall response rate was 71%. Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT + sorafenib and 5 WBRT) were enrolled in the FLT-PET study: baseline (n = 15), 7-10 days post WBRT (FU1, n = 14), and an additional 12 week (n = 9). A decline in average SUV of ≥ 25% was seen in 9/10 (90%) of WBRT + sorafenib patients and 2/4 (50%) of WBRT only patients.

Conclusions: Concurrent WBRT and sorafenib appear safe at 200 mg daily dose with clinical activity. CNS response was favorable compared to historical controls. This combination should be considered for further efficacy evaluation. FLT-PET may be useful as an early response imaging tool for brain metastases.

Trial And Clinical Registry: Trial registration numbers and dates: NCT01724606 (November 12, 2012) and NCT01621906 (June 18, 2012).
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http://dx.doi.org/10.1007/s10549-021-06209-4DOI Listing
July 2021

The Head and Neck Survivorship Tool (HN-STAR) Trial (WF-1805CD): A protocol for a cluster-randomized, hybrid effectiveness-implementation, pragmatic trial to improve the follow-up care of head and neck cancer survivors.

Contemp Clin Trials 2021 08 21;107:106448. Epub 2021 May 21.

Wake Forest School of Medicine, Department of Social Sciences & Health Policy, Medical Center Boulevard, Winston-Salem, NC 27157, USA.

Survivors of head and neck cancer (HNC) can have multiple health concerns. To facilitate their care, we developed and pilot-tested a clinical informatics intervention, HN-STAR. HN-STAR elicits concerns online from HNC survivors prior to a routine oncology clinic visit. HN-STAR then presents tailored evidence-based clinical recommendations as a clinical decision support tool to be used during the visit where the oncology clinician and survivor select symptom management strategies and other actions. This generates a survivorship care plan (SCP). Online elicitation of health concerns occurs 3, 6, and 9 months after the clinic visit, generating an updated SCP each time. HN-STAR encompasses important methods of improving survivorship care (e.g., needs assessment, tailored interventions, dissemination of guidelines) and will be evaluated in a pragmatic trial to maximize external validity. This hybrid type 1 implementation-effectiveness trial tests HN-STAR effectiveness while studying barriers and facilitators to implementation in community oncology practices within the National Cancer Institute Community Oncology Research Program. Effectiveness will be measured as differences in key survivorship outcomes between HNC participants who do and do not use HN-STAR over one year after the clinic visit. The primary endpoint is HNC-specific quality of life; other outcomes include patient-centered measures and receipt of guideline-concordant care. Implementation outcomes will be assessed of survivors, providers, and clinic stakeholders. The hybrid design will provide insight into a dose-response relationship between the extent of implementation fidelity and effectiveness outcomes, as well as how to incorporate HN-STAR into standard practice outside the research setting.
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http://dx.doi.org/10.1016/j.cct.2021.106448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543489PMC
August 2021

A Phase I Study of Alpelisib in Combination with Trastuzumab and LJM716 in Patients with -Mutated HER2-Positive Metastatic Breast Cancer.

Clin Cancer Res 2021 Jul 4;27(14):3867-3875. Epub 2021 May 4.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Activating mutations in promote resistance to HER2-targeted therapy in breast cancer; however, inhibition of PI3K alone leads to escape via feedback upregulation of HER3. Combined inhibition of HER2, HER3, and PI3K overcomes this mechanism preclinically.

Patients And Methods: This phase I study investigated the MTD of alpelisib given in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with -mutant HER2-positive (HER2) metastatic breast cancer (MBC) using the continual reassessment method. Secondary analyses included efficacy and exploratory correlative studies.

Results: Ten patients were treated initially with daily alpelisib (arm A). Grade ≥3 adverse events seen in ≥2 patients included diarrhea ( = 6), hypokalemia ( = 3), abnormal liver enzymes ( = 3), hyperglycemia ( = 2), mucositis ( = 2), and elevated lipase ( = 2). The MTD of alpelisib in arm A was 250 mg daily. This prompted the opening of arm B in which 11 patients received intermittently dosed alpelisib. Grade ≥3 adverse events seen in ≥2 patients included diarrhea ( = 5), hypokalemia ( = 3), and hypomagnesemia ( = 2). The MTD of alpelisib in arm B was 350 mg given 4 days on, 3 days off. Among 17 patients assessed, 1 had a partial response, 14 had stable disease, and 2 had disease progression at best response. Five patients had stable disease for >30 weeks. mRNA profiling of pre- and on-treatment tissue demonstrated target engagement by alpelisib via induction of downstream signaling and feedback pathways.

Conclusions: Combination treatment with alpelisib, trastuzumab, and LJM716 was limited by gastrointestinal toxicity. Further efforts are warranted to target the PI3K pathway in HER2 MBC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282678PMC
July 2021

PARP (Poly ADP-Ribose Polymerase) inhibitors for locally advanced or metastatic breast cancer.

Cochrane Database Syst Rev 2021 Apr 22;4:CD011395. Epub 2021 Apr 22.

NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, Australia.

Background: Locally advanced and metastatic breast cancer remains a challenge to treat. With emerging study results, it is important to interpret the available clinical data and apply the evidence offering the most effective treatment to the right patient. Poly(ADP Ribose) Polymerase (PARP) inhibitors are a new class of drug and their role in the treatment of locally advanced and metastatic breast cancer is being established.

Objectives: To determine the efficacy, safety profile, and potential harms of Poly(ADP-Ribose) Polymerase (PARP) inhibitors in the treatment of patients with locally advanced or metastatic breast cancer. The primary outcome of interest was overall survival; secondary outcomes included progression-free survival, tumour response rate, quality of life, and adverse events.

Search Methods: On 8 June 2020, we searched the Cochrane Breast Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via OvidSP, Embase via OvidSP, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) search portal and ClinicalTrials.gov. We also searched proceedings from the major oncology conferences as well as scanned reference lists from eligible publications and contacted corresponding authors of trials for further information, where needed.

Selection Criteria: We included randomised controlled trials on participants with locally advanced or metastatic breast cancer comparing 1) chemotherapy in combination with PARP inhibitors, compared to the same chemotherapy without PARP inhibitors or 2) treatment with PARP inhibitors, compared to treatment with other chemotherapy. We included studies that reported on our primary outcome of overall survival and secondary outcomes including progression-free survival, tumour response rate, quality of life, and adverse events.

Data Collection And Analysis: We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity.

Main Results: We identified 49 articles for qualitative synthesis, describing five randomised controlled trials that were included in the quantitative synthesis (meta-analysis). A sixth trial was assessed as eligible but had ended prematurely and no data were available for inclusion in our meta-analysis. Risk of bias was predominately low to unclear across all studies except in regards to performance bias (3/5 high risk) and detection bias for the outcomes of quality of life (2/2 high risk) and reporting of adverse events (3/5 high risk). High-certainty evidence shows there may be a small advantage in overall survival (HR 0.87, 95% CI 0.76 to 1.00; 4 studies; 1435 patients). High-certainty evidence shows that PARP inhibitors offer an improvement in PFS in locally advanced/metastatic HER2-negative, BRCA germline mutated breast cancer patients (HR 0.63, 95% CI 0.56 to 0.71; 5 studies; 1474 patients). There was no statistical heterogeneity for these outcomes. Subgroup analyses for PFS outcomes based on trial level data were performed for triple-negative breast cancer, hormone-positive and/or HER2-positive breast cancer, BRCA1 and BRCA2 germline mutations, and patients who had received prior chemotherapy for advanced breast cancer or not. The subgroup analyses showed a persistent PFS benefit regardless of the subgroup chosen. Pooled analysis shows PARP inhibitors likely result in a moderate improvement in tumour response rate compared to other treatment arms (66.9% vs 48.9%; RR 1.39, 95% CI 1.24 to 1.54; 5 studies; 1185 participants; moderate-certainty evidence). The most common adverse events reported across all five studies included neutropenia, anaemia and fatigue. Grade 3 or higher adverse events probably occur no less frequently in patients receiving PARP inhibitors (59.4% for PARP arm versus 64.5% for non-PARP arm, RR 0.98, 95% CI 0.91 to 1.04; 5 studies; 1443 participants; moderate-certainty evidence). Only two studies reported quality of life outcomes so this was not amenable to meta-analysis. However, both studies that did assess quality of life showed PARP inhibitors were superior compared to physician's choice of chemotherapy in terms of participant-reported outcomes.

Authors' Conclusions: In people with locally advanced or metastatic HER2-negative, BRCA germline mutated breast cancer, PARP inhibitors offer an improvement in progression-free survival, and likely improve overall survival and tumour response rates. This systematic review provides evidence supporting the use of PARP inhibitors as part of the therapeutic strategy for breast cancer patients in this subgroup. The toxicity profile for PARP inhibitors is probably no worse than chemotherapy but more information is required regarding quality of life outcomes, highlighting the importance of collecting such data in future studies. Future studies should also be powered to detect clinically important differences in overall survival and could focus on the role of PARP inhibitors in other relevant breast cancer populations, including HER2-positive, BRCA-negative/homologous recombination repair-deficient and Programmed Death-Ligand 1 (PDL1) positive.
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http://dx.doi.org/10.1002/14651858.CD011395.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092476PMC
April 2021

Endoscopic Feature and Response Reproducibility in Tumor Assessment after Neoadjuvant Therapy for Rectal Adenocarcinoma.

Ann Surg Oncol 2021 Sep 1;28(9):5205-5223. Epub 2021 Apr 1.

Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: The watch-and-wait approach may be safe for selected rectal cancer patients who achieve a complete clinical response after neoadjuvant treatment. Endoscopic examination is critical in determining completeness of tumor response but has not been systematically studied.

Methods: Two cross-sectional surveys, each containing endoscopic photos of rectal cancers treated with neoadjuvant therapy, were distributed to surgeons. The first survey assessed the reproducibility of eight endoscopic criteria using 41 unique endoscopic photos. The percentage of surgeons selecting each of the prespecified endoscopic criteria for each photo was calculated to determine the reproducibility of endoscopic criteria in assessing treatment and tumor response grade across multiple surgeons. The second survey included endoscopic pairs of pre- and post-neoadjuvant treatment photos of 17 patients. The surgeons were assigned a tumor response grade (clinical complete response [cCR], near complete clinical response [nCR], incomplete [iCR] clinical response), and percentages of correct diagnostic assignment were calculated.

Results: The findings showed significant inter- and intra-surgeon variation in the selection of predefined endoscopic features used to grade tumor response as well as significant inter- and intra-surgeon variation in the selection of the tumor response grade (cCR, nCR, or iCR). However, individual endoscopic features and tumor response grades clustered together, suggesting consistency in tumor response interpretation. Surgeons were more accurate in identifying patients with a complete response (82%) than in identifying patients with an incomplete response (68%).

Conclusions: Despite inter- and intra-surgeon variation, endoscopic features were well-selected in terms of tumor response grade, suggesting consistency in endoscopic interpretation. Surgeons tended to underestimate the degree of tumor response, identifying complete responses more accurately than incomplete responses.
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http://dx.doi.org/10.1245/s10434-021-09827-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355052PMC
September 2021

Interpreting the RAPIDO trial: factors to consider.

Lancet Oncol 2021 03;22(3):e87-e88

Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(21)00061-9DOI Listing
March 2021

Comprehensive Molecular Characterization and Response to Therapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

Clin Cancer Res 2021 May 3;27(10):2910-2919. Epub 2021 Mar 3.

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking.

Experimental Design: We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic mutation plus IHC evidence of FH loss, were included.

Results: A total of 28 of 32 included patients (median age 46; range, 20-74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic germline variant. Five (16%) were negative for germline mutations; all had biallelic somatic loss. Somatic NGS (31/32 patients) revealed co-occurring mutation most frequently ( = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination ( = 18, ORR 44%), VEGF monotherapy ( = 15, ORR 20%), checkpoint inhibitor therapy ( = 8, ORR 0%), and mTOR monotherapy ( = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3-33.8] and 8.7 months (95% CI: 4.8-12.3), respectively.

Conclusions: Although most FH-RCC tumors are due to germline alterations, a significant portion result from biallelic somatic loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127353PMC
May 2021

Four Cycles of Etoposide plus Cisplatin for Patients with Good-Risk Advanced Germ Cell Tumors.

Oncologist 2021 06 12;26(6):483-491. Epub 2021 Mar 12.

Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York, USA.

Background: The National Comprehensive Cancer Network recommends either three cycles of bleomycin, etoposide, and cisplatin or four cycles of etoposide and cisplatin (EPx4) as initial chemotherapy for the treatment of good-risk germ cell tumors (GCTs). To assess the response, toxicity, and survival outcomes of EPx4, we analyzed our experience.

Material And Methods: Response and survival outcomes, selected toxicities, and adherence to chemotherapy dose and schedule were assessed in patients with good-risk GCT who received EPx4 at Memorial Sloan Kettering Cancer Center between 1982 and 2016. The results were compared with our past results and published data.

Results: Between 1982 and 2016, 944 patients with GCT were treated with EPx4, 289 who were previously reported plus 655 treated between January 2000 and August 2016. A favorable response was achieved in 928 of 944 patients (98.3%). Five-year progression-free, disease-specific, and overall survival rates were 93.9%, 98.6%, and 97.9%, respectively. Median follow-up was 7.3 years (range, 2.8 months to 35.5 years). Viable, nonteratomatous malignant GCT was present in 3.5% of 432 postchemotherapy retroperitoneal lymph node dissection specimens from patients with nonseminomatous GCT. Febrile neutropenia and thromboembolic events occurred in 16.0% and 8.9%, respectively, with one treatment-related death. In the more recent 655-patient cohort, full-dose EPx4 was administered to 631 (96.3%), with deviations from planned treatment driven mainly by vascular (n = 13), hematologic (n = 11), renal (n = 7), or infectious (n = 5) events.

Conclusion: EPx4 is highly effective and well tolerated in patients with good-risk GCTs and remains a standard of care.

Implications For Practice: Four cycles of etoposide and cisplatin (EPx4) is a standard-of-care regimen for all patients with good-risk germ cell tumors with a favorable response rate and disease-specific survival of 98%. Full-dose administration of etoposide and cisplatin and complete resection of residual disease lead to optimal outcomes. EPx4 should be the recommended regimen in active smokers, patients with reduced or borderline kidney function, and patients aged 50 years or older, which are patient groups at increased risk for bleomycin pulmonary toxicity. Because of a risk of acquired severe pulmonary illness, EPx4 may also be favored for patients who vape or use e-cigarettes and during ongoing transmission of severe acute respiratory syndrome coronavirus 2.
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http://dx.doi.org/10.1002/onco.13719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176973PMC
June 2021

Prognosis of Incidental Brain Metastases in Patients With Advanced Renal Cell Carcinoma.

J Natl Compr Canc Netw 2021 04 12;19(4):432-438. Epub 2021 Feb 12.

1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Metastatic renal cell carcinoma (mRCC) management guidelines recommend brain imaging if clinically indicated and the rate of occult central nervous system (CNS) metastasis is not well-defined. Early detection could have major therapeutic implications, because timely interventions may limit morbidity and mortality.

Patients And Methods: A retrospective review was performed to characterize patients with mRCC incidentally diagnosed with asymptomatic brain metastases during screening for clinical trial participation at Gustave Roussy and Memorial Sloan Kettering Cancer Center. Descriptive statistics and time-to-event methods were used to evaluate the cohort.

Results: Across 68 clinical trials conducted between 2001 and 2019 with a median 14.1-month follow-up, 72 of 1,689 patients (4.3%) with mRCC harbored occult brain metastases. The International Metastatic RCC Database Consortium (IMDC) risk status was favorable (26%), intermediate (61%), and poor (13%), and 86% of patients had ≥2 extracranial sites of disease, including lung metastases in 92% of patients. CNS involvement was multifocal in 38.5% of patients, and the largest brain metastasis was >1 cm in diameter in 40% of the cohort. Localized brain-directed therapy was pursued in 93% of patients, predominantly radiotherapy. Median overall survival was 10.3 months (range, 7.0-17.9 months), and the 1-year overall survival probability was 48% (95% CI, 37%-62%). IMDC risk and number or size of lesions did not correlate with survival (log-rank, P=.3, P=.25, and P=.067, respectively).

Conclusions: This large multi-institutional mRCC cohort study identified occult brain metastasis in a notable proportion of patients (4.3%) and highlights that the risk of asymptomatic CNS involvement extends to those with favorable risk features per IMDC risk assessment. These data provide rationale for brain screening in patients with advanced RCC.
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http://dx.doi.org/10.6004/jnccn.2020.7634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407454PMC
April 2021

Comparative analysis of the Memorial Sloan Kettering Bowel Function Instrument and the Low Anterior Resection Syndrome Questionnaire for assessment of bowel dysfunction in rectal cancer patients after low anterior resection.

Colorectal Dis 2021 Feb 10;23(2):451-460. Epub 2021 Feb 10.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York City, New York, USA.

Aim: Neoadjuvant therapy and total mesorectal excision (TME) for rectal cancer are associated with bowel dysfunction symptoms known as low anterior resection syndrome (LARS). Our study compared the only two validated instruments-the LARS Questionnaire (LARS-Q) and the Memorial Sloan Kettering Bowel Function Instrument (MSK-BFI)-in rectal cancer patients undergoing sphincter-preserving TME.

Methods: One hundred and ninety patients undergoing sphincter-preserving TME for Stage I-III rectal cancer completed the MSK-BFI and LARS-Q simultaneously at a median time of 12 (range 1-43) months after restoration of bowel continuity. Associations between the MSK-BFI total/subscale scores and the LARS-Q score were investigated using Spearman rank correlation (r ). Discriminant validity for the two questionnaires was assessed, and the questionnaires were compared with the European Quality of Life Instrument.

Results: Major LARS was identified in 62% of patients. The median MSK-BFI scores for no LARS, minor LARS and major LARS were 76.5, 70 and 57, respectively. We found a strong association between MSK-BFI and LARS-Q (r -0.79). The urgency/soilage subscale (r -0.7) and the frequency subscale (r -0.68) of MSK-BFI strongly correlated with LARS-Q. Low correlation was observed between the MSK-BFI diet subscale and LARS-Q (r -0.39). On multivariate analysis, both questionnaires showed worse bowel function in patients with distal tumours. A low to moderate correlation with the European Quality of Life Instrument was observed for both questionnaires.

Conclusions: The MSK-BFI and LARS-Q showed good correlation and similar discriminant validity. As the LARS-Q is easier to complete, it may be considered the preferred tool to screen for bowel dysfunction.
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http://dx.doi.org/10.1111/codi.15515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023229PMC
February 2021

Primary Tumor-Related Complications and Salvage Outcomes in Patients with Metastatic Rectal Cancer and an Untreated Primary Tumor.

Dis Colon Rectum 2021 01;64(1):45-52

Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: For rectal cancer with unresectable metastases, current practice favors omitting interventions directed at the primary tumor in asymptomatic patients.

Objective: This study aimed to determine the proportion of patients with primary tumor-related complications, characterize salvage outcomes, and measure survival in patients with metastatic rectal cancer who did not undergo upfront intervention for their primary tumor.

Design: This is a retrospective analysis.

Setting: This study was conducted at a comprehensive cancer center.

Patients: Patients who presented between January 1, 2008, and December 31, 2015, with synchronous stage IV rectal cancer, an unresected primary tumor, and no prior primary tumor-directed intervention were selected.

Main Outcome Measures: The main outcome measured was the rate of primary tumor-related complications in the cohort that did not receive any primary tumor-directed intervention. The Kaplan-Meier method and Cox regression analysis were used to determine whether complications are associated with survival.

Results: The cohort comprised 358 patients with a median age of 56 years (22-92). Median follow-up was 26 months (range, 1-93 months). Among the 168 patients (46.9%) who eventually underwent elective resection of the primary tumor, the surgery was performed with curative intent in 66 patients (18.4%) and preemptive intent in 102 patients (28.5%). Of the 190 patients who did not undergo an upfront or elective intervention for the primary tumor, 68 (35.8%) experienced complications. Nonsurgical intervention for complications was attempted in 34 patients with an overall success rate of 61.8% (21/34). Surgical intervention was performed in 47 patients (including 13 patients for whom nonsurgical intervention failed): diversion in 26 patients and resection in 21 patients. Of those 47 patients, 42 (89.4%) ended up with a colostomy or ileostomy.

Limitations: This study was conducted at a single center.

Conclusion: A significant proportion of patients with metastatic rectal cancer and untreated primary tumor experience primary tumor-related complications. These patients should be followed closely, and preemptive intervention (resection, diversion, or radiation) should be considered if the primary tumor progresses despite systemic therapy. See Video Abstract at http://links.lww.com/DCR/B400. COMPLICACIONES RELACIONADAS CON EL TUMOR PRIMARIO Y RESULTADOS DE RESCATE EN PACIENTES CON CÁNCER DE RECTO METASTÁSICO Y UN TUMOR PRIMARIO NO TRATADO: Para el cáncer de recto con metástasis no resecables, la práctica actual favorece la omisión de las intervenciones dirigidas al tumor primario en pacientes asintomáticos.Determinar la proporción de pacientes con complicaciones relacionadas con el tumor primario, caracterizar los resultados de rescate y medir la supervivencia en pacientes con cáncer rectal metastásico que no se sometieron a una intervención inicial para su tumor primario.Análisis retrospectivo.Centro oncológico integral.Pacientes que se presentaron entre el 1 de enero de 2008 y el 31 de diciembre de 2015 con cáncer de recto en estadio IV sincrónico, un tumor primario no resecado y sin intervención previa dirigida al tumor primario.Tasa de complicaciones relacionadas con el tumor primario en la cohorte que no recibió ninguna intervención dirigida al tumor primario. Se utilizó el método de Kaplan-Meier y el análisis de regresión de Cox para determinar si las complicaciones están asociadas con la supervivencia.La cohorte estuvo compuesta por 358 pacientes con una mediana de edad de 56 años (22-92). La mediana de seguimiento fue de 26 meses (rango, 1 a 93 meses). Entre los 168 pacientes (46,9%) que finalmente se sometieron a resección electiva del tumor primario, la cirugía se realizó con intención curativa en 66 pacientes (18,4%) y con intención preventiva en 102 pacientes (28,5%). De los 190 pacientes que no se sometieron a una intervención inicial o electiva para el tumor primario, 68 (35,8%) experimentaron complicaciones. Se intentó una intervención no quirúrgica para las complicaciones en 34 pacientes con una tasa de éxito global del 61,8% (21 de 34). La intervención quirúrgica se realizó en 47 pacientes (incluidos 13 pacientes en los que falló la intervención no quirúrgica): derivación en 26 pacientes y resección en 21 pacientes. De esos 47 pacientes, 42 (89,4%) terminaron con una colostomía o ileostomía.Único centro.Una proporción significativa de pacientes con cáncer de recto metastásico y primario no tratado experimentan complicaciones relacionadas con el tumor primario. Se debe hacer un seguimiento estrecho de estos pacientes y considerar la posibilidad de una intervención preventiva (resección, derivación o radiación) si el tumor primario progresa a pesar de la terapia sistémica. Consulte Video Resumen en http://links.lww.com/DCR/B400.
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http://dx.doi.org/10.1097/DCR.0000000000001803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931667PMC
January 2021

Measuring Tumor Epichaperome Expression Using [I] PU-H71 Positron Emission Tomography as a Biomarker of Response for PU-H71 Plus Nab-Paclitaxel in HER2-Negative Metastatic Breast Cancer.

JCO Precis Oncol 2020 17;4. Epub 2020 Nov 17.

Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Epichaperome network maintenance is vital to survival of tumors that express it. PU-H71 is an epichaperome inhibitor that binds to the ATP-binding site of HSP90 and has demonstrated antitumor activity in breast cancer xenograft models and clinical safety in patients. PU-positron emission tomography (PET) is a theragnostic imaging tool that allows visualization of the epichaperome target. In this phase Ib trial, we present safety and tolerability for PU-H71 plus nab-paclitaxel in HER2-negative patients with metastatic breast cancer (MBC) and the utility of PU-PET as a noninvasive predictive biomarker.

Methods: We performed a 3 + 3 dose-escalation study with escalating PU-H71 doses and standard nab-paclitaxel. The primary objective was to establish safety and determine maximum tolerated dose (MTD)/recommended phase 2 dose. Secondary objectives were to assess pharmacokinetics and clinical efficacy. Patients could enroll in a companion PU-PET protocol to measure epichaperome expression before treatment initiation to allow exploratory correlation with treatment benefit.

Results: Of the 12 patients enrolled, dose-limiting toxicity occurred in one patient (G3 neutropenic fever) at dose level 1; MTD of PU-H71 was 300 mg/m plus nab-paclitaxel 260 mg/m administered every 3 weeks. Common toxicities included diarrhea, fatigue, peripheral neuropathy, and nausea. PU-H71 systemic exposure was not altered by nab-paclitaxel administration. Two of 12 patients had partial response (overall response rate, 17%) and the clinical benefit rate was 42% (5 of 12). Time to progression was associated with baseline epichaperome positivity and PU-H71 peak standard uptake value (SUV), with more durable disease control observed with high epichaperome levels.

Conclusion: The combination of PU-H71 and nab-paclitaxel was well tolerated, with evidence of clinical activity. More durable disease control without progression was observed in patients with high baseline epichaperome expression. A phase II trial of this combination with PU-PET as a companion diagnostic for patient selection is currently planned.
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http://dx.doi.org/10.1200/PO.20.00273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713524PMC
November 2020

Quantitative assessment of tumor-infiltrating lymphocytes in mismatch repair proficient colon cancer.

Oncoimmunology 2020 11 11;9(1):1841948. Epub 2020 Nov 11.

Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Tumor infiltrating lymphocytes (TIL), which represent host adaptive response to the tumor, were first identified at scanning magnification to select areas with the highest counts on hematoxylin and eosin slides, quantitated per high-power field (HPF), and analyzed for association with recurrence-free survival (RFS) in 848 patients. Highest TIL in a single HPF was analyzed as a continuous and categorical variable, and optimal cutoff analysis was performed to predict RFS. Highest TIL count in a single HPF ranged from 0 to 45, and the optimal cutoff for TIL high vs TIL low was determined to be ≥ 3 vs < 3 with a concordance probability estimate of 0.74. In the entire cohort, 5-year RFS was 90.2% (95% CI = 83.7-94.2) in TIL high compared to 78.9% (95% CI = 74.1-82.9) in TIL low (log rank < .0001). TIL remained significant in the mismatch repair-proficient (pMMR) cohort where 5-year RFS was 94.6% (95% CI = 88.3-97.5) in TIL high compared to 77.9% (95% CI = 69.2-84.4) in TIL low ( = .008). On multivariable analysis, TIL and AJCC Stage were independently associated with RFS in the pMMR cohort. Qualitatively in the pMMR cohort, RFS in Stage II TIL high patients was similar to that in Stage I patients and RFS in Stage III TIL high was similar to that in Stage II TIL low patients. Assessment of TIL in a single HPF using standard H&E slides provides important prognostic information independent of MMR status and AJCC stage.
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http://dx.doi.org/10.1080/2162402X.2020.1841948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671050PMC
November 2020

Use of patient-reported controls for secular trends to study disparities in cancer-related job loss.

J Cancer Surviv 2021 10 26;15(5):685-695. Epub 2020 Oct 26.

Immigrant Health and Cancer Disparities Service, Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, 485 Lexington Avenue, Second Floor, New York, NY, 10017, USA.

Purpose: Racial/ethnic minorities experience greater job loss than whites during periods of economic downturn and after a cancer diagnosis. Therefore, race/ethnicity-matched controls are needed to distinguish the impact of illness on job loss from secular trends METHODS: Surveys were administered during and 4-month post-completion of breast cancer treatment. Patients were pre-diagnosis employed women aged 18-64, undergoing treatment for stage I-III breast cancers, who spoke English, Chinese, Korean, or Spanish. Each patient was asked to: (1) nominate peers who were surveyed in a corresponding timeframe (active controls), (2) report a friend's work status at baseline and follow-up (passive controls). Both types of controls were healthy, employed at baseline, and shared the nominating patient's race/ethnicity, language, and age. The primary outcome was number of evaluable patient-control pairs by type of control. A patient-control pair was evaluable if work status at follow-up was reported for both individuals.

Results: Of the 180 patients, 25% had evaluable active controls (45 patient-control pairs); 84% had evaluable passive controls (151 patient-control pairs). Although patients with controls differed from those without controls under each strategy, there was no difference in the percentage of controls who were working at follow-up (96% of active controls; 91% of passive controls). However, only 65% of patients were working at follow-up.

Conclusions: The majority of patients had evaluable passive controls. There was no significant difference in outcome between controls ascertained through either method IMPLICATIONS FOR CANCER SURVIVORS: Passive controls are a low-cost, higher-yield option to control for secular trends in racially/ethnically diverse samples.
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http://dx.doi.org/10.1007/s11764-020-00960-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071836PMC
October 2021

Everolimus plus bevacizumab is an effective first-line treatment for patients with advanced papillary variant renal cell carcinoma: Final results from a phase II trial.

Cancer 2020 12 25;126(24):5247-5255. Epub 2020 Sep 25.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: We previously reported on a phase 2 study of everolimus plus bevacizumab across various nonclear cell renal cell carcinoma (nccRCC) histologies and observed encouraging activity among patients with papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component. We subsequently expanded the study to enroll additional patients with pRCC variants.

Methods: Everolimus plus bevacizumab was administered at standard doses until disease progression or intolerance to therapy. The primary endpoint was the 6-month progression-free survival (PFS) rate; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Correlative analyses included next-generation sequencing (NGS) from tumor and germline across >341 genes of interest.

Results: In addition to 19 patients with pRCC variants in the original cohort, 20 patients with similar features were enrolled on the expansion cohort (uRCC with papillary features [n = 24], pRCC [n = 14], and translocation-associated RCC with papillary features [n = 1]). Among 37 evaluable patients, the 6-month PFS rate was 78%, the median PFS was 13.7 months (95% CI, 10.8-16.4 months), and the ORR was 35%. With a median follow-up of 17.6 months, the median OS was 33.9 months (95% CI, 23.3-71.9). Tolerance was consistent with prior reports for everolimus plus bevacizumab. NGS results (n = 33) identified responses in patients with a wide spectrum of genomic alterations, including ARID1A, FH, and MET mutations.

Conclusion: The expansion cohort results confirm robust activity of everolimus plus bevacizumab in metastatic pRCC variants, supporting this regimen as a standard option for this patient population.
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http://dx.doi.org/10.1002/cncr.33148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366407PMC
December 2020

Optimization and kinetic study of ultrasound assisted deep eutectic solvent based extraction: A greener route for extraction of curcuminoids from Curcuma longa.

Ultrason Sonochem 2021 Jan 18;70:105267. Epub 2020 Aug 18.

Department of Chemical Engineering, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India. Electronic address:

The use of deep eutectic solvents (DESs) as a new extraction medium is a step towards the development of green and sustainable technology. In the present study, nine DESs based on choline chloride acids, alcohols, and sugar were screened to study the extraction of curcuminoids from Curcuma longa L. Choline chloride and lactic acid DES at 1:1 M ratio gave the maximum extent of extraction. Further, DES based extraction was intensified using ultrasound. The impact of various process parameters such as % (v/v) water in DES, % (w/v) solid loading, particle size, ultrasound power intensity, and pulse mode operation of ultrasound was studied. The maximum curcuminoids yield of 77.13 mg/g was achieved using ultrasound assisted DES (UA-DES) based extraction in 20% water content DES at 5% solid loading and 0.355 mm particle size with 70.8 W/cm power intensity and 60% (6 sec ON and 4 sec OFF) duty cycle at 30 ± 2 °C in 20 min of irradiation time. Kinetics of UA-DES extraction was explained using Peleg's model and concluded that it is compatible with the experimental data. Additionally, anti-solvent (water) precipitation technique was applied, which resulted in 41.97% recovery of curcuminoids with 82.22% purity from UA-DES extract in 8 h of incubation at 0 °C. The comparison was made between conventional Soxhlet, batch, DES and UA-DES based processes on the basis of yield, time, solvent requirement, temperature, energy consumption, and process cost. The developed UA-DES based extraction can be an efficient, cost effective, and green alternative to conventional solvent extraction for curcuminoids.
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http://dx.doi.org/10.1016/j.ultsonch.2020.105267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786552PMC
January 2021

Laccase immobilized peroxidase mimicking magnetic metal organic frameworks for industrial dye degradation.

Bioresour Technol 2020 Dec 18;317:124035. Epub 2020 Aug 18.

Department of Chemical Engineering, Institute of Chemical Technology, Mumbai, India. Electronic address:

In the present work, laccase was successfully immobilized in peroxidase mimicking magnetic metal organic frameworks (MMOFs) within 30 min using a facile approach. The integration of magnetic nanoparticles during synthesis significantly eases the separation of prepared biocatalyst using an external magnet. The immobilization of laccase was confirmed using different characterization techniques. The [email protected] found spherical in nature with an average particle size below 100 nm. The synthesized laccase embedded framework exhibits supermagnetic property with the saturation magnetization (Ms) of 34.12 emu/gm. The prepared bio-metallic frameworks maintain high surface area and thermal stability. The [email protected] was successfully exploited for the degradation of industrial dyes in batch and continuous mode with an average degradation efficiency of 95%. The prepared laccase structure had an excellent recyclability retaining upto 89% residual activity upto 10 cycle and can be stored at room temperature upto 30 days without any significant loss of activity.
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http://dx.doi.org/10.1016/j.biortech.2020.124035DOI Listing
December 2020

Alterations in and promote clinical resistance to alpelisib plus aromatase inhibitors.

Nat Cancer 2020 Apr 23;1(4):382-393. Epub 2020 Mar 23.

Human Oncology and Pathogenesis Program, MSKCC, New York, NY.

Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function mutations in 25% of patients with resistance. activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight loss as a recurrent mechanism of resistance to PI3Kα inhibition.
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http://dx.doi.org/10.1038/s43018-020-0047-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450824PMC
April 2020

Rapid extraction of watermelon seed proteins using microwave and its functional properties.

Prep Biochem Biotechnol 2021 31;51(3):252-259. Epub 2020 Aug 31.

Department of Chemical Engineering, Institute of Chemical Technology, Mumbai, India.

Solid food industry waste like watermelon seed is an excellent source of value-added components such as proteins, oil, and carbohydrate. In the present study, protein extraction was carried out using microwave energy from defatted watermelon seeds (DWS), containing 50% of proteins. Microwave-assisted extraction (MAE) was optimized with different parameters, namely, solid to solvent ratio (1:10-1:40), pH (7-10), microwave power (30 W, 50 W, 70 W), extraction time (30 s-8 min) and moisture content or pre-leaching effect. Maximum protein recovery was achieved with 50 W microwave power, solid to solvent ration of 1:30, and pH 10 in 2 minutes of microwave irradiation time. MAE gave higher yield in less time compared to conventional extraction. SDS-PAGE confirmed the molecular weight of watermelon seed proteins (WSP) in the range of 25-250 kDa. A comparative study showed 90% protein recovery with MAE in 2 min with 1:30 (w/v) solid to solvent ratio, whereas ultrasound gave 87% in 9 min with 1:50 (w/v) ratio and batch 72% in 25 min with 1:70 (w/v) ratio. Watermelon seed proteins obtained from MAE method possess excellent functional properties with reference to conventional extraction method indicating its application in food products.
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http://dx.doi.org/10.1080/10826068.2020.1808792DOI Listing
July 2021

Systemic therapy for advanced clear cell renal cell carcinoma after discontinuation of immune-oncology and VEGF targeted therapy combinations.

BMC Urol 2020 Jul 2;20(1):84. Epub 2020 Jul 2.

Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), 300 East 66th Street, New York, NY, 10065, USA.

Background: Several phase 3 studies reported positive results for combinations of Immune-Oncology (IO) and Vascular Endothelial Growth Factor (VEGF) targeted therapies in patients with metastatic clear cell Renal Cell Carcinoma (ccRCC). However, there are limited data on outcomes to systemic therapy after IO-VEGF combinations.

Methods: A retrospective analysis was performed on patients with metastatic ccRCC treated at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic who initiated systemic therapy post IO-VEGF including combinations with VEGF receptor (VEGFR) tyrosine kinase inhibitors (IO-TKI) and combinations with the anti-VEGF monoclonal antibody bevacizumab (IO-Bev). The study objectives were to evaluate the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) on systemic therapy post IO-VEGF. RECIST v1.1 criteria were used to determine radiological responses and progression. Survival estimates were evaluated with the Kaplan-Meier methods and the log-rank test from the start of systemic therapy post IO-VEGF to the event of interest.

Results: A total of fifty-nine patients were treated post discontinuation of IO-VEGF regimens which included IO-Bev (n = 35; 59%) and IO-TKI (n = 24; 41%). Fifty-eight patients (98%) received IO-VEGF regimens as part of a clinical trial. Subsequent therapies included cabozantinib (n = 22; 37%), axitinib (n = 18; 31%), pazopanib (n = 4; 7%), lenvatinib and everolimus (n = 4; 7%), mTOR inhibitor monotherapy (n = 3; 5%), axitinib and dalantercept (n = 2; 3%), sunitinib (n = 1; 2%), sorafenib (n = 1; 2%), and treatment with agents on unreported clinical trials (n = 4; 7%). Patients treated on unreported clinical trials were excluded from the efficacy analysis. Post IO-VEGF, the ORR was 25% and median PFS was 12.0 months (95% CI, 8.2-24.5). Median OS was 24.5 months (95% CI, 12-NE) and 12 months OS rate was 63.3% (95% CI, 48.6-74.9). We observed no differences post IO-VEGF OS when comparing IO- TKI vs IO-Bev (Log-rank p = 0.73).

Conclusions: Post IO-VEGF, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs demonstrated clinical activity and remain a viable option for salvage therapy after progression on IO-VEGF.
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http://dx.doi.org/10.1186/s12894-020-00647-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331268PMC
July 2020

Clinical and pathologic features associated with PD-L1 (SP142) expression in stromal tumor-infiltrating immune cells of triple-negative breast carcinoma.

Mod Pathol 2020 11 1;33(11):2221-2232. Epub 2020 Jul 1.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The Ventana PD-L1 SP142 immunohistochemistry (IHC) assay is the FDA-approved companion diagnostic assay for atezolizumab therapy selection for patients with PD-L1-positive locally advanced or metastatic triple-negative breast carcinoma (TNBC). We aimed to elucidate clinical, pathologic, and molecular features associated with PD-L1 expression in TNBCs. Clinical, pathologic, and next-generation sequencing (NGS)-based molecular data for TNBCs tested with PD-L1 (SP142) IHC at our institution between 11/2018 and 12/2019 were retrieved and reviewed. PD-L1 positivity was defined as ≥1% IC staining. Patients with metastatic TNBC treated at first line with atezolizumab regimens were evaluated for treatment response and for time to treatment failure (TTF). Among 156 TNBCs, PD-L1 was positive in 47.4% of cases. Primary TNBCs were significantly more frequently PD-L1 positive, compared with recurrent/metastatic samples (p = 0.002). PD-L1-positive TNBCs had increased stromal IC, compared with PD-L1-negative samples (p < 0.001). The repertoire of somatic genetic alterations of PD-L1-positive and PD-L1-negative TNBCs was similar. Matched primary and recurrent/metastatic TNBC samples were available for eight patients, in whom four had discordant results. Thirty patients with metastatic TNBC were treated with atezolizumab regimens, with treatment failure occurring in 16 patients and a median TTF of 5.1 months in this early evaluation. The findings of this study show stromal ICs in primary TNBCs are more likely to show PD-L1 positivity than in recurrent or metastatic samples. This information should guide selection of samples suitable for testing. Further studies are needed to identify other features associated with PD-L1-positive breast carcinomas and clinical benefit of treatment.
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http://dx.doi.org/10.1038/s41379-020-0606-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234788PMC
November 2020

DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy.

J Immunother Cancer 2020 06;8(1)

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

Background: Loss-of-function alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may determine benefit from immune-oncology (I/O) agents as shown in colon cancer. However, biologic significance and relevance to I/O in metastatic clear cell RCC (ccRCC) are unknown.

Methods: Genomic data and treatment outcomes were retrospectively collected for patients with metastatic ccRCC. Tumor and germline DNA were subject to targeted next generation sequencing across >400 genes of interest, including 34 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) deleterious DDR gene alterations present (Del DDR); (2) wild-type (WT) and variants of unknown significance (VUS) DDR gene alterations present (WT/VUS DDR). Association between DDR status and therapeutic benefit was investigated separately for I/O and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy.

Results: Del DDR were detected in 43/229 patients (19%). The most frequently altered genes were and . Clonality analysis was performed in 27 somatic DDR mutations and 17 were clonal (63%). For patients with I/O treatment, Del DDR status was associated with superior overall survival (log-rank p=0.049); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Del DDR was 0.41 (95% CI: 0.14-1.14; p=0.09). No association was seen with VEGF-TKI treatment (log-rank p=0.903).

Conclusion: Del DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Loss-of-function events in these genes may affect outcome with I/O therapy in metastatic RCC, and these hypothesis-generating results deserve further study.
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http://dx.doi.org/10.1136/jitc-2019-000230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311069PMC
June 2020
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