bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of genetic markers associated with ibrutinib-related cardiovascular toxicity.
Authors: Hamadeh Issam , Jacobs Ryan , Hu Bei , Moyo Tamara Kay , Soni Amy , Park Steven I. , Patel Jai Narendra , Steuerwald Nury , Ghosh Nilanjan
Published: June 2021

7526

Background: Cardiovascular side effects (CVSEs: atrial fibrillation, hypertension, etc.) are common in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib and often lead to dose reductions or discontinuation. However, the etiology of ibrutinib related CVSEs has not been elucidated. This study sought to interrogate the association between ibrutinib related CVSEs and polymorphisms in genes of the Bruton Tyrosine Kinase (BTK) signaling pathway (identified through Ingenuity Pathway Analysis) Methods: Newly diagnosed and relapsed patients with CLL who underwent treatment with ibrutinib between December 2019 and November 2020 at Levine Cancer Institute were identified. Buccal swabs were collected through an IRB approved specimen collection protocol. Data extraction included: demographics, CLL stage, cytogenetics, previous treatments, ibrutinib start dates and dose, drug related SEs, and other medications. DNA isolated from buccal swabs was genotyped for 40 single nucleotide polymorphisms (SNPs) in GATA4, SGK1, KCNQ1, KCNA4, NPPA and SCN5A genes using a custom NGS panel. Logistic regression analysis evaluated the association between SNPs and CVSEs. Results: In 50 evaluable patients, the median age was 71 years (range:48-90) and 50% received frontline ibrutinib monotherapy. CVSEs occurred in 20% of patients (n=10). In univariate analysis, 4 SNPs in 3 genes were significantly associated with CVSEs (Table). Because the genes were in the same pathway, a genetic risk score was developed which indicated that patients with at least 2 SNPs had a 12-fold increase in risk of CVSEs (Table). Conclusions: Our findings provide insights into the genetic determinants of ibrutinib related CVSEs. If replicated in a larger study, this will facilitate utility of pharmacogenetic testing (for GATA4, KCNQ1 and KCNA5 polymorphisms ) as a clinical tool to individualize ibrutinib treatment.[Table: see text]
Post-transplant lymphoproliferative disorder in kidney transplant patients: A multicenter report.
Authors: Chong Elise A. , Tsai Daniel E. , Hughes Mitchell E. , Lim Mary Ann C , Besharatian Behdad D. , El Kassiss Yvonne , Bloom Roy , Jagadeesh Deepa
Published: June 2021

7564

Background: Post-Transplant Lymphoproliferative Disorder (PTLD) is a complication of transplantation that often arises due to reactivation of the Epstein-Bar Virus (EBV). Given the rarity of this disease, a full understanding of its presentation and optimal therapies has yet to be determined. Methods: A multicenter retrospective analysis was performed utilizing data from kidney transplant patients (pts) who developed PTLD at the Hospital of the University of Pennsylvania and the Cleveland Clinic. The association between categorical variables and clinical response were assessed via Fisher’s exact testing. Results: 117 pts had diagnoses of PTLD after kidney transplantation. The median age at PTLD diagnosis was 52 yrs (range 17-89 yrs), and the median time from transplantation to diagnosis was 3.6 yrs (range: 7 days-36 yrs). Pt characteristics included: 84% Caucasian, 57% male, and 11% combined kidney and pancreas transplant patients. 68% pts had received unrelated donor transplants; 41% had prior rejection episodes. PTLD histology was 72% monomorphic and 28% polymorphic. Polymorphic PTLD was more likely to be EBV+ than monomorphic PTLD (81% vs. 54%, p = 0.05). At diagnosis, immunosuppression included: steroids (95%), mycophenolate (44%), azathioprine (40%), sirolimus (30%), cyclosporine (46%), and/or tacrolimus (45%). Common PTLD symptoms included fever (34%), pain (38%), weight loss (30%), fatigue (30%), and/or mass (26%). The most common sites of involvement were lymph nodes (64%), kidney allograft (22%), and/or GI tract (17%). At diagnosis, 61% of patients’ tumors were EBV+ and 59% of patients had elevated serum LDH. Overall, the majority of pts responded to first-line PTLD therapy, with 61% CR and 14% PR. Reduction of immunosuppression (RI) alone (36% of pts) led to 48% CR and 12% PR; RI with rituximab (16%) led to 47% CR and 7% PR; and RI with chemotherapy (14%) resulted in 58% CR and 42% PR. Patients treated with RI as well as resection (n = 18) of their limited stage disease had better outcomes (p = 0.05). Overall survival for all patients was 10.7 years (95%CI: 5.2-13 years). PTLD patients < 40 yrs were more likely to achieve CR after first line therapy (p < 0.001), have allograft involvement (p = 0.003), and have a polymorphic histology (p = 0.002). Allograft involvement tended to occur sooner after transplant (p = 0.001) and was more likely to present with allograft failure (p = 0.007). PTLD with allograft involvement had better response to first therapy than regular PTLD (p = 0.007) and often responded well to complete resection and RI. Conclusions: Pts with PTLD may achieve a CR through different initial therapies. Younger patients and those able to undergo complete resection of disease and RI had better prognoses. Allograft involvement by PTLD carries a good prognosis and should be identified and treated differently from other presentations.
PIT-2: A multicenter phase II trail of S-1 plus cisplatin with concurrent radiotherapy followed by surgery in stage IIIA (N2) lung squamous cell carcinoma.
Authors: Takamochi Kazuya , Tsuboi Masahiro , Okada Morihito , Niho Seiji , Ishikura Satoshi , Oyamada Shunsuke , Yamaguchi Takuhiro , Tanaka Fumihiro , Yoshino Ichiro , Tsuchida Masanori , Shiono Satoshi , Oizumi Hiroyuki , Okumura Norihito , Haruki Tomohiro , Suzuki Kenji
Published: June 2021

8543

Background: A multicenter phase II study, PIT-2 (Personized Induction Therapy-2), was performed to investigate the efficacy and safety of S-1 plus cisplatin and concurrent thoracic radiation therapy (TRT) followed by surgery in patients with stage IIIA (N2) lung squamous cell carcinoma (LSCC). To date, no clinical trials on the use of induction therapy prior to surgery have focused solely on the treatment of N2 LSCC. Methods: Eligible patients were 20 to 75 years old and had stage IIIA (pathologically proven N2) LSCC, performance status of 0-1, and no prior treatment. The patients received induction therapy consisting of three cycles of S-1 and cisplatin plus concurrent TRT (45 Gy in 25 fractions) followed by surgery. S-1 was administered orally at 40 mg/m2 twice per day, on days 1 through 14 along with an intravenous infusion of cisplatin (60 mg/m2) on day 1. The treatment cycles were repeated every four weeks. The primary endpoint was 2-year progression-free survival (PFS) rate and key secondary endpoints included overall survival (OS), the objective response rate (ORR) as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, pathological complete remission (pCR) rate, feasibility, and toxicity. Results: Of the 45 patients registered between December 2013 and September 2018, 43 received induction therapy. Of the 43 patients, 39 (91%) underwent surgery (25 lobectomies, 10 bilobectomies, three pneumonectomies, and one wedge resection). The complete resection rate was 95% (37/39). Median follow-up time was 35.7 months. The 2-year PFS and OS rates were 67% (90% CI: 54-78%) and 70% (95% CI: 53-81%), respectively. The ORR and pCR rates were 86% (37/43, 95% CI: 76-96%) and 39% (15/39, 95% CI: 23-54%), respectively. Grade (G) 3 or 4 toxicities during the induction therapy in 43 patients included neutropenia (40%), anemia (9%), thrombocytopenia (7%), and hyponatremia (7%). Severe surgical complications in 39 patients included G3/4 pneumonia (5%), G3 bronchopleural fistula (5%), and G3 pleural effusion (5%). No G3/4 intraoperative adverse events occurred. There was no 30-day postoperative mortality and one 90-day postoperative mortality in a patient who underwent right pneumonectomy and developed pneumonia after discharge. Conclusions: Induction therapy using S-1 plus cisplatin and concurrent TRT followed by surgery is a promising treatment for patients with stage IIIA (N2) LSCC. Clinical trial information: 000012413.
Genomic landscape of malignnant mesothelioma by site and histology.
Authors: Adib Elio , Akl Elie , Nassar Amin , El Zarif Talal , Abou Alaiwi Sarah , Kwiatkowski David J.
Published: June 2021

8559

Background: Malignnant mesothelioma (MM) is a highly lethal tumor that can develop in the pleura, the peritoneum, the pericardium or the testes. While the genomic features of pleural MM have been well-described overall, less is known about the distribution of genetic alterations (GAs) according to histology. In addition, few reports comparing genetic features according to disease site are available. Methods: We identified patients with pleural or peritoneal mesothelioma with mutational analysis through the GENIE registry. Patient tumor genetic data were provided by Memorial Sloan-Kettering Cancer Center (MSK)-IMPACT and Dana-Farber Cancer Institute (DFCI)-Oncopanel NGS initiatives. Patients with more than one sequenced sample were excluded. We limited our analysis to genes common to all versions of both panels and that were significantly mutated in the TCGA mesothelioma cohort. Mutation and copy number variant (CNV), collectively called GAs, were determined, and were compared using the Fisher’s Exact test and Kruskal-Wallis Test. Comparisons were made both by disease site (pleural vs. peritoneal) and histology for the pleural samples (epithelioid vs. biphasic vs. sarcomatoid). Nominal p-values were obtained, and FDR correction was employed (q<0.1). Results: We identified 439 patients with MM in the GENIE registry who fit the inclusion criteria. The median age was 70.5 years for pleural MM and 60 years for peritoneal MM (Wilcoxon-rank sum test p-value = 3e-9). 72% of patients were male. CDKN2A/CDKN2B GAs (97% and 100% being deletions in CDKN2A and CDKN2B respectively), a described prognostic marker in MM, were more common in pleural than in peritoneal MM. Among pleural MMs, tumors of epithelioid histology had less NF2 GAs than biphasic or sarcomatoid tumors, whereas sarcomatoid tumors had the lowest frequency of BAP1 GAs (Table). Conclusions: Malignnant mesotheliomas of different disease sites and/or histologies display distinct patterns of GAs. These findings may contribute in part to differences in response to treatment and survival among these subsets of MM.[Table: see text]
Application value of plasma exosomal long RNA in SCLC diagnosis and prognosis.
Authors: Liu Chang , Wang Jialei , Huang Shenglin , Yu Hui , Zhu Zhengfei , Fan Min
Published: June 2021

8566

Background: Little research has focused on blood exosomal transcription profile in small cell lung cancer (SCLC). The aim of this study is to identify plasma exosomal specific transcriptional profile in SCLC and explore the application value of plasma exosomal long RNA (exLR) in SCLC diagnosis and prognosis. Methods: This study included 81 healthy people and 40 SCLC patients receiving standard first-line chemotherapy with etoposide and carboplatin/cisplatin. The efficacy was evaluated by progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). 19 Patients who achieved complete response (CR) or partial response (PR) as best response during the first-line therapy and had not progressed within the following 90 days after the end of first-line therapy were defined as chemosensitive. 21 Patients who achieved stable disease (SD) as best response or received progressive disease during the first-line therapy or within the following 90 days after the end of first-line therapy were defined as chemoresistant. Baseline plasma samples were collected from 40 SCLC patients (17 patients’ samples after 2 courses were collected) and 81 healthy people. Plasma exosomes were isolated and purified; exosomal RNA were extracted for high-throughout sequencing analysis. Results: We obtained plasma exLRs profiles from 81 healthy control samples and 57 SCLC samples (baseline samples from 40 patients plus samples collected by 17 patients after 2 courses). Bioinformatics analysis found that exLRs were significantly different between the SCLC and the healthy control group; between the chemosensitive and the chemoresistant group; between the baseline samples and the paired samples after 2 courses. For 40 SCLC patients receiving first-line chemotherapy, ORR was 65.0%, DCR was 90.0% and mPFS was 6.0 months (95% CI, 4.3-7.7 months). Multivariate analysis showed that baseline brain metastases and baseline bone metastases were independent predictors of poor PFS; and 223 genes were independent predictors of PFS. There were 10 genes (AC107954.1, H2AFZP2, CALB2, IFITM9P, GFPT2, PLA1A, CHST10, AC021231.2, SETP20, HILPDA) intersected in differentially expressed genes between the SCLC and the healthy control group, differentially expressed genes between the chemosensitive and the chemoresistant group and independent predictors of PFS. These 10 genes were highly expressed in both the SCLC group and the chemoresistant group, and their high expression was an independent risk factor for poor PFS. Conclusions: This study firstly identified the plasma exLRs profiles in SCLC patients, verified the feasibility and value of identifying biomarkers based on exLRs profiles in SCLC diagnosis and prognosis.
Response to selpercatinib versus prior systemic therapy in patients (pts) with RET fusion+ non-small-cell lung cancer (NSCLC).
Authors: Drilon Alexander E. , Gautschi Oliver , Besse Benjamin , Subbiah Vivek , Tan Daniel Shao-Weng , Park Keunchil , De Braud Filippo G. , Alonso Guzman , Wolf Juergen , Soldatenkova Victoria , French Pearl Plernjit , Lin Aimee K. , Goto Koichi , Solomon Benjamin J.
Published: June 2021

9032

Background: Selpercatinib, a first-in-class highly selective, potent, CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ lung or thyroid cancers. Selpercatinib demonstrated durable antitumor activity in previously treated pts with RET fusion+ NSCLC in an ongoing Phase 1/2 trial, LIBRETTO-001 (Besse et al., ASCO 2021). Methods: Pts with RET fusion+ NSCLC enrolled in the global, multicenter, LIBRETTO-001 trial (NCT03157128; 16 countries, 89 sites). Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival, duration of response, and safety. This post-hoc intrapatient analysis was based on a 30 March 2020 data cutoff date. Historical physician-reported best overall response (BOR) from last systemic therapy received prior to enrollment was compared with selpercatinib BOR by independent review committee per RECIST v1.1, with each patient serving as his/her own control. Results: In efficacy-evaluable pts (N = 218) who previously received platinum-based chemotherapy (chemo), median pt age was 61 years, the majority with ECOG of 0/1 (37%/61%), with a median of 2 (range: 1-15) prior systemic therapies. Overall, 57% of patients responded to selpercatinib while 16% responded to the immediate prior therapy. ORR improvements with selpercatinib were observed regardless of prior therapy: chemotherapy + immune checkpoint inhibitor (ICI) (57% vs 14%), single-agent ICI (48% vs 3%), or chemotherapy (58% vs 15%). A total of 108 patients (49%) did not respond to immediate prior therapy but responded to selpercatinib. Fewer patients had progressive disease as their BOR with selpercatinib (2%) compared to the immediate prior therapy (28%). The median duration of therapy for selpercatinib was notably extended compared with that of the immediate prior therapy (11.8 vs. 3.4 months, respectively). Conclusions: In pts with RET fusion+ NSCLC treated on LIBRETTO-001, systemic therapies administered prior to enrollment achieved less meaningful clinical benefit than selpercatinib. Selpercatinib demonstrated consistent efficacy regardless of the type of prior therapy. Clinical trial information: NCT03157128.
Increased risk of immune-related hepatitis among adolescent and young adults (AYAs) with melanoma during immunotherapy with checkpoint inhibitors (ICIs).
Authors: Darwin Alicia , Reed Damon R. , Tanvetyanon Tawee
Published: June 2021

9584

Background: Melanoma is the second most common malignancy affecting AYA patients after lymphoma. Nevertheless, AYA melanoma does constitute a minority of all melanoma cases. Additionally, the AYA population is not well represented in prospective clinical trials, including immunotherapy trials. While previous research has demonstrated the efficacy of ICIs across age groups, it remains unclear if toxicity profiles will be similar. In the general population, age-related changes in the immune milieu result in differential incidences of autoimmune diseases by age. This study aims to compare the toxicity profile between a cohort of AYA melanoma versus elderly melanoma patients receiving ICI therapy. Methods: In this single NCCN institutional study, electronic medical records of melanoma patients treated with ICIs between 01/2007-01/2019 were reviewed. Subjects receiving concurrent investigational agents or chemotherapy were excluded. The AYA cohort included those aged 15-40 years. The elderly cohort included those aged ≥65 years. Adverse events were coded according to CTC-AE version 5.0. Multivariable logistic regression analyses were performed. Results: Analyses included 184 treatment courses. In the AYA cohort (N = 57), median age at ICI initiation was 28.8 years (range: 17.9-39.3). In the Elderly cohort (N = 127), median age at ICI initiation was 72.3 years. More AYA patients (28.1% AYA vs. 7.9% Elderly) received ICI combination regimens. The most common adverse events amongst both cohorts were transaminitis (23.4%), rashes (49.5%), and diarrhea/colitis (20%). Incidences of pneumonitis, colitis, hypothyroidism, and hypophysitis did not differ significantly between cohorts. However, the AYA cohort experienced a higher incidence of transaminitis (38.6% AYA vs. 16.5% Elderly, p =0.001 ) and increased occurrence of treatment related hospitalization (26.3% AYA vs. 7.1% Elderly, p <0.001 ). Moreover, a higher proportion of severe grade ≥3 transaminitis occurred in the AYA group (27.3% AYA vs. 9.5% Elderly, p =0.004). While occurrence of transaminitis was significantly associated with combination ICIs, the association between AYA status and transaminitis remained significant after adjusting for ICI regimen (OR 2.75, 95% CI: 1.3-5.8). There was a trend toward shorter time to transaminitis onset among the AYA than Elderly cohort (median 53.0 vs. 74.5 days [non-parametric p= 0.28]). To date, median survival has not been reached in both groups ( p= 0.09). Conclusions: In this large cohort of AYA melanoma patients treated with ICI, we found a significantly higher incidence of immune-related transaminitis than in the Elderly cohort. Other immune-related AEs were comparable between cohorts. This finding was independent of ICI regimen. Further investigation will be needed to understand these differences between the AYA and Elderly cohorts.
Can Intratumoral neutrophil lymphocyte ratio (NLR) be a prognostic biomarker in breast cancer patients?
Authors: Tokumaru Yoshihisa , Oshi Masanori , Murthy Vijayashree , Katsuta Eriko , Matsuhashi Nobuhisa , Futamura Manabu , Yoshida Kazuhiro , Takabe Kazuaki
Published: June 2021

e12573

Background: In breast cancer patients, it is well known that the elevation of neutrophil lymphocyte ratio (NLR) in the blood are reported to associate with poor prognosis based on the notion that neutrophils represent pro-cancer, and lymphocytes represent anti-cancer immune cells. Tumor immune microenvironment has been demonstrated to play critical roles in the outcome of breast cancer patients. However, there is scarce evidence on the clinical relevance of intratumoral NLR in breast cancer patients. In the current study, we hypothesized that intratumoral NLR high tumors are associated with worse survival particularly in TNBC that is known to have high immune cell infiltration. Methods: A total of 1904 breast cancer patients’ data from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) and analyzed. NLR was calculated by the gene expressions of CD66b (CEACAM8) and CD8 (CD8A). NLR high and low were divided by the median. Overall Survival (OS) and Disease-Free Survival were calculated utilizing Kaplan Meier method between intratumoral NLR high and low groups. xCell algorithm was used to analyze the infiltrated immune cells within the tumor immune microenvironment as we have previously published. Results: Intratumoral NLR high group was associated with worse OS in whole, ER-positive/HER2-negative, and triple negative (TN) subtypes, in agreement with the previous studies. TN subtype alone demonstrated worse DFS of NLR high group. Surprisingly, gene set enrichment analysis (GSEA) demonstrated no gene set enrichment to NLR high group, which implicates that there is no distinctive mechanism that associate with worse survival. Whereas, immune response-related gene sets significantly enriched to NLR low group in TN subtype. This enrichment was consistent in ER-positive/HER2-negative. Compared with ER-positive/HER2-negative subtype, anti-cancer immune cells such as CD4+ T cells, CD8+ T cells, M1 macrophage, and helper T helper type 1 cells were significantly infiltrated in TN patients (p < 0.001 for all genes), where M2 macrophages and neutrophils were less and regulatory T cells and T helper type 2 cells were more infiltrated in TN subtype. Furthermore, intratumoral NLR was significantly lower in TN compared with ER-positive/HER2-negative subtype (p < 0.001). These results suggest that intratumoral NLR low group is associated with better survival due to favorable tumor immune microenvironment in TN subtype rather than NLR high group has worse survival. Conclusions: Intratumoral NLR low tumor demonstrated more favorable OS and more favorable DFS in TN patients. Intratumoral NLR low breast cancer was associated with enhanced immune response and higher infiltration of anti-cancer immune cells were observed in TN subtype compared to ER-positive/HER2-negative which may contribute to the favorable outcome of in TN breast cancer.
Breast cancer surgical delays in a racially and ethnically diverse California cancer registry cohort.
Authors: Navarro Stephanie , Yang Yifei , Ochoa Carol , Kim Sue , Liu Lihua , Lerman Caryn , Farias Albert
Published: June 2021

e12589

Background: Surgical delays for invasive breast cancer have been increasing over time and are associated with an increased risk of mortality. Black and Hispanic breast cancer patients are more likely to experience surgical delays than white patients; however, surgical delays among Asian ethnic subgroups remain unstudied. Methods: We used data from the population-based California Cancer Registry to identify all females diagnosed with stage I-III invasive breast cancer from 2012-2017. Our main independent variable was patient race/ethnicity, including five Asian ethnic subgroups. Covariates captured tumor, treatment-related, and patient sociodemographic characteristics. We conducted multivariable logistic regression to determine the odds of receiving surgery within 30 and 90 days of diagnosis and multivariable Cox proportional hazards regression to determine the risk of shorter time to surgical treatment. Results: Of 106,441 breast cancer patients, 57.5% were non-Hispanic white (NHW), 20.7% were Hispanic, 5.9% were non-Hispanic black (NHB), and 12.6% were Asian (consisting of 33.7% Filipino, 24.6% Chinese, 8.1% Asian Indian or Pakistani (AIP), 7.7% Japanese, 6.7% Korean, and 19.2% other Asian (OA) patients). Compared to NHWs, Hispanics and NHBs were less likely to receive surgical treatment within 30 and 90 days of diagnosis (Hispanic, 30-day: OR = 0.94, 95% CI = 0.89-0.98; Hispanic, 90-day: 0.89, 0.85-0.92; NHB, 30-day: 0.91, 0.85-0.98; NHB, 90-day: 0.86, 0.80-0.92). However, Chinese and AIP patients were more likely than NHWs to receive surgery within 30 and 90 days of diagnosis (Chinese, 30 day: OR = 1.30, 95% CI = 1.19-1.41; Chinese 90-day: 1.26, 1.08-1.47; AIP 30-day: 1.29, 1.11-1.50; AIP 90-day: 1.34, 1.17-1.53). In addition, Koreans were more likely than NHWs to receive surgery within 90 days of diagnosis (OR = 1.26, 95% CI = 1.08-1.47). Hispanics, NHBs, and OAs were less likely to receive timely treatment compared to NHWs (Hispanic: HR = 0.95, 95% CI = 0.94-0.97; NHB: 0.91, 0.89-0.94; OA: 0.95, 0.92-0.99), while Chinese, AIP, and Korean patients were more likely to receive timely treatment compared to NHWs (Chinese: HR = 1.15, 95% CI = 1.11-1.20; AIP: 1.10, 1.04-1.17; Korean: 1.10, 1.03-1.17). Lastly, patients diagnosed in 2017 were 14% less likely to receive timely treatment than those diagnosed in 2012 (HR: 0.86, 95% CI = 0.84-0.88). Conclusions: In this population-based cohort of female breast cancer patients in California, Hispanics and NHBs continue to experience surgical treatment delays and Asian American minority subgroups experience similar delays compared to NHWs. In addition, increasing delays over time could potentially exacerbate racial/ethnic disparities in breast cancer mortality. Continued work investigating the causes of breast cancer treatment delays among Asian ethnic subgroups is necessary to fully elucidate and target racial/ethnic treatment disparities.
Targeted axillary lymph node dissection in breast cancer patients using I-125 microseeds for prostate cancer brachytherapy.
Authors: Emelyanov Alexander , Petr Krivorotko , Pesotskiy Roman , Bessonov Alexander , Gorelov Viktor , Semiglazov Vladimir
Published: June 2021

e12601

Background: To date, targeted axillary lymph node dissection is one of the possible methods of de-escalation of surgical aggression on the areas of regional lymph flow in breast cancer patients with confirmed metastases in the axillary lymph nodes prior to the neoadjuvant chemotherapy. There are no specialized microseeds for targeted axillary dissection. The purpose of our study was to determine the possibility of using I-125 microseed for prostate cancer brachytherapy for targeted axillary dissection. Methods: A prospective study of patients with biopsy-confirmed nodal axillary metastases with a I-125 microseed placed in the node was performed. I-125 microseed for prostate cancer brachytherapy was used to mark the axillary lymph node. After neoadjuvant therapy, patients underwent targeted axillary lymph node dissection in combination with SLNB with pathomorphological examination of marked lymph node and total axillary lymph node dissection with pathomorphological examination of over lymph nodes for FNR evaluation. Results: 45 breast cancer patients stage cT1-3N1M0 were enrolled in the study. The frequency of reaching ypN0 was 58%. Residual disease identified in 19 patients. The clipped node revealed metastases in 18 patients, resulting in an FNR of 5.26% (95% CI, to 20.6) for the clipped node. CIs for FNR were calculated using exact (Clopper-Pearson) confidence limits for the binomial proportion. Conclusions: Marking the biopsy-confirmed lymph node using a I-125 microseed prior neoadjuvant chemotherapy and performing targeted axillary lymph node dissection in combination with SLNB is a safe method for diagnosing axillary lymph nodes and allows you to abandon routine ALD for ypN0 patients. Advantages of I-125 microseed for prostate cancer brachytherapy: fixation in the lymph node without migration, the ability to use a standard gamma-probe to locate the microseed during the operation, these microseeds are registered for the treatment of cancer patients.
SGK1 regulated apoptosis in invasive breast carcinoma.
Authors: Song Yuxin , Li Lei , Fei YinJiao , Chen Wenquan , Wo Guan qun , Tang Jinhai
Published: June 2021

e13061

Background: Worldwide, breast cancer is the most common type of cancers and the presentation of drug resistance is often associated with poor prognosis. Previous studies have shown the mechanism of drug resistance was affected by apoptosis at different levels in the signaling cascades. This article is aimed to explore the relationship between the serum and glucocorticoid-regulated kinase 1 (SGK1) and apoptosis in invasive breast cancer (IBC). Methods: We evaluated the expression of SGK1 in IBC using publicly available data from The Cancer Genome Atlas (TCGA) and Curtis Breast program. TaqMan probe-based qRT-PCR assay and Western Blot analysis were performed to quantitatively detect the expression of SGK1 at RNA and protein levels in the IBC specimens. Clinicopathologic characteristics associated with overall survival were tested by Cox regression. Gene Set Enrichment Analysis (GSEA) was performed to mine the biological pathways involved in IBC pathogenesis related SGK1 regulatory network using MSigDB database. Immunohistochemistry staining (IHC) was used to detect apoptotic markers Fas, Bcl2 and SGK1 in the IBC specimens. Results: Totally 1109 IBC samples with SGK1 expression data were downloaded from TCGA databases for analyzed. SGK1 expression was elevated in normal breast tissues compared with both invasive ductal carcinoma and invasive lobular carcinoma (p < 0.0001). Among them, SKG expression in 112 tumor tissues was significantly lower than that in paracancerous tissues, especially in advanced patients with TNM stage IV. Western Blot and qRT-PCR assay confirmed that SGK1 expression in IBC was distinctly lower than normal. The Kaplan-Meier survival analysis showed that decreased expression of SGK1 was significantly correlated with the clinical stage (p = 0.036). In Curtis Breast program, we further verified SGK1 gene expression was reduced in stage IV than stage I. The univariate analysis demonstrated that clinicopathologic variables associated with poor survival include age, advanced stage, lymph nodes, distant metastasis and deep myometrial invasion. GSEA revealed that apoptosis was differentially enriched when SGK1 was highly expressed. Similarly, TCGA data indicated that the positive rate of SGK1 was higher in Fas positive IBCs, and the same result was also obtained by IHC in the IBC specimens. Conclusions: Expression of SGK1 regulated apoptosis in invasive breast carcinoma, which might be a potential therapeutic target to overcome refractory and drug-resistant breast cancer.
Treatment patterns of older adults with metastatic breast cancer in community practices.
Authors: McShane Melissa , Dotan Efrat , Obeid Elias , Handorf Elizabeth A.
Published: June 2021

e13063

Background: The median age at diagnosis of breast cancer is 62 with 45% of patients over the age of 65. At diagnosis, up to 5% of patients will have metastatic breast cancer (MBC) and up to 30% of patients with early-stage disease will develop MBC. There are no clear guidelines on how to treat older adults with MBC (OA-MBC) due to their poor representation in clinical trials. This lack of recommendations can often lead to under treatment of OA-MBC. This study evaluated the self-reported treatment patterns of practitioners in community practices for OA-MBC and evaluated the actual treatment their OA-MBC patients received. Methods: This is a secondary analysis of a multi-phase trial which initially evaluated the gaps in practice patterns that exist in the assessment and management of OA-MBC and did a prospective comparison between the older patient’s geriatric assessment and provider’s clinical assessment. In this analysis we focused on the practice patterns in the community. Physicians completed questionnaires detailing their front-line treatment choices for each subcategory of MBC in women over the age of 65. Data was then collected on patients in these physicians’ practices including their current line of treatment, treatment regimen, comorbidities, performance status and demographics. The appropriateness of treatment choice was then evaluated based on MBC subcategory and line of treatment using the NCCN guidelines for breast cancer. Patient and physician characteristics and treatment choices were summarized using descriptive statistics. Results: 44 providers from 9 community practices located in PA, DE, NJ, MT, and WA participated. Majority of providers were Caucasian (57%) and had been in practice for >11 years (53%). 100 patients were evaluated from these practices between December 2016 – April 2019. Median age 73 (65-90). In response to front-line therapy choices, 27/44 (61%) providers selected endocrine only therapy for HR+ but in practice, 29/37 (78%) of HR+ patients were treated with combination endocrine & CDK 4/6 inhibitors. For HER2+, 20/44 (45%) providers selected trastuzumab + chemotherapy for front-line therapy and in practice 8/8 (100%) of patients received this combination. For TNBC, 37/44 (84%) providers agreed with sequential single agent chemotherapy over combination and in practice 6/7 (86%) patients received this. Including all lines of therapy, 84/100 patients were treated in accordance with NCCN guidelines. Conclusions: Despite the lack of older adult guidelines, our community-based practitioners are treating the majority of their OA-MBC patients appropriately and in accordance with NCCN guidelines. In our cohort of OA-MBC there was no evidence of under treatment, however, due to the lack of sufficient data in this patient population it is not clear that this approach is beneficial. Additional research is needed to refine the treatment approach of this unique patient population.
Relationship between tumor size and metastatic site in patients with stage IV breast cancer: A large SEER-based study.
Authors: Dong Qian , Zhang Mi , Jiang Da
Published: June 2021

e13065

Background: To analyze the correlation between tumor size and metastatic site in first-diagnosed stage IV breast cancer patients. Methods: Stage IV breast cancer patients diagnosed from 2010 to 2015 were screened by the Surveillance, Epidemiology, and End Results (SEER) database. The characteristics of clinical variables were represented by a frequency table, and the Chi-square test was used for comparison. At the same time, the Chi-square test was used to analyze the relationship between tumor size and organ metastasis. Correlation between tumor size and the prognosis of patients was contributed by KM curve and Log-rank test. Results: Regardless of tumor size, the proportion of bone metastasis was higher and brain metastasis was lower in breast cancer patients. There were significant differences in the site of metastases based on different subtype. Luminal A and Luminal B breast cancer had the highest proportion of bone metastases; brain metastasis accounted for the highest proportion in triple-negative breast cancer (TNBC); while the incidence of liver metastasis was the highest in Her-2(+) breast cancer. At the same time, the results indicated that Luminal A breast cancer with a tumor size > 5 cm was more likely to develop multi-site metastasis and lung metastasis, while Luminal B breast cancer with a tumor size ≤ 5 cm was more likely to develop liver metastasis. The results also revealed that TNBC patients with a tumor size of 0 - 2cm were more likely to develop bone metastasis than those with a tumor size > 5 cm, and the incidence of lung metastasis in triple-negative patients showed an increasing trend with the increase of tumor size. Conclusions: Based on subtype, we found that there was a significant difference between tumor size and metastatic site in patients with stage IV breast cancer, and the difference was statistically significant. This study provided evidence-based basis for decision-making of stage IV breast cancer treatment.
Feasibility of using data collected through the St. Jude Pediatric Oncology Facility integrated local evaluation (PrOFILE) tool to determine previously defined levels of pediatric hematology-oncology care.
Authors: Udoko Aniekan , Mazotti-Roso Pedro , Suriano Enrico , Silva-Perez Fernando , Forrest Heather , Bass Madison , Gonzalez-Guzman Miriam , Friedrich Paola
Published: June 2021

e13530

Background: Pediatric hematology and oncology (PHO) facilities are not all equally equipped to diagnose and treat the full range of childhood cancers. Proposed facility tier models have been published to facilitate the context-based adaptation of PHO diagnostic and treatment guidelines. However, a tool to assist facilities in identifying their level of PHO care does not exist. We assessed the feasibility of using the St. Jude Pediatric Oncology Facility Integrated Local Evaluation (PrOFILE) tool to identify (1) facility levels as defined by the International Society of Pediatric Oncology (SIOP) and the Lancet Oncology Commission (LOC) for sustainable care for children with cancer, and (2) treatment strata in the Adapted Resource and Implementation Application (ARIA) Guide. Methods: This study employed a multi-step mapping approach. We mapped the 1,279 PrOFILE tool variables to the nine SIOP service lines, ten LOC domains, and ten ARIA resource groups. Mapping was performed by two teams and carried out in two different rounds. The first round aimed to define if an indicator was fully or partially covered by PrOFILE. Multiple PrOFILE variables could be assigned to each concept to meet its content specificity. Various cut-offs were applied when necessary to assign mutually exclusive responses to each tier. The second round consisted of expert validation for each indicator previously identified. Results: Most (97%) of SIOP’s indicators were partially or fully covered in the PrOFILE tool (Table). Radiation therapy tools and appointment scheduling and call back system could not be mapped. Of the LOC indicators, 89% were covered (Table). Pathology technical staff, chemotherapy complexity (low, moderate, and high), lymph node biopsy, organ preservation, liver transplantation, intensity-modulated radiotherapy, and research infrastructure could not be mapped. Finally, 77% of the indicators used by the ARIA Guide were covered (Table). The ophthalmology resource group could not be fully mapped. Conclusions: This exercise demonstrates the feasibility of using PrOFILE tool variables to identify facility PHO care levels as defined by SIOP and LOC. The tool also contains most of the variables necessary to apply the ARIA Guide to diagnose, treat, and manage childhood cancer. Future PrOFILE versions will address concepts that are not covered or are partially covered in its current version.[Table: see text]
Evaluation of in silico tools for variant classification in clinically actionable NSCLC variants.
Authors: Kim Eugene , Duarte Samantha , Fridland Stas , Nam Myungwoo , Hwang Jin Young , Lee Alice Daeun , Lee Grace , Yu Emma , Chae Young Kwang
Published: June 2021

e13545

Background: Genetic variants beyond FDA-approved drug targets are often identified in NSCLC patients. To address this challenge, in silico variant classification tools are available to determine whether specific variants contribute to disease pathogenicity or remain benign. Although the performance of in silico tools has been analyzed in previous studies, it has not been analyzed for actionable targets of FDA-approved therapies for NSCLC. The aim of this study is to compare the performance of commonly used in silico tools in classifying the pathogenicity of actionable variants in NSCLC. Methods: We evaluated the performance of several in silico tools: PolyPhen-2, Align-GVGD, and MutationTaster2. A curated set of targetable NSCLC missense variants (n = 179) was used. The dataset consisted of variants in the BRAF, EGFR, ERBB2, KRAS, MET, ALK, and ROS1 genes based on their indications as molecular targets in the NCCN Guidelines for NSCLC. Pathogenic variants (n = 80) were curated based on available literature and annotations according to the NCCN Guidelines, OncoKB, My Cancer Genome, and AACR Project GENIE. Benign variants (n = 99) were curated from the dbSNP database with the inclusion criteria of a benign or likely benign ClinVar assertion. The overall accuracy, sensitivity, specificity, and Matthews correlation coefficient (MCC) of each in silico tool were determined. The performance of each in silico tool in predicting pathogenicity for subsets of sensitizing (n = 18) and resistant (n = 57) variants was also evaluated. Results: PolyPhen-2 HumVar demonstrated the highest overall accuracy (0.80), specificity (0.69), and MCC (0.63) of the in silico tools analyzed. PolyPhen-2 HumDiv (0.75) and MutationTaster2 (0.69) had similar overall accuracies while Align-GVGD (0.50) had the lowest overall accuracy. Align-GVGD also had the lowest MCC (0.08), with the other in silico tools ranging from 0.50 to 0.63. All the in silico tools achieved high sensitivities, with MutationTaster2 performing the highest (1.00) and Align-GVGD performing the lowest (0.86). The specificities were remarkably low (0.20-0.69) for all the in silico tools, with the lowest specificity demonstrated by Align-GVGD. The overall accuracies when classifying the subsets of sensitizing and resistant variants were generally high, ranging from 0.84 to 1.00. Conclusions: These results suggest that the performance of the evaluated in silico tools to predict the pathogenicity of clinically actionable NSCLC missense variants is not fully reliable. The tools analyzed in this study could be acceptable to rule out pathogenicity in variants given their higher sensitivities, but are limited when it comes to identifying pathogenicity in variants due to low specificities.
A systematic evaluation of models predicting short-term mortality for cancer patients to highlight uncertainty about model performance and high risk of bias.
Authors: Lu Sheng-Chieh , Xu Cai , Nguyen Chandler , Meyer Larissa , Sidey-Gibbons Chris
Published: June 2021

e13559

Background: Short-term cancer mortality prediction has many implications concerning care planning. An accurate prognosis allows healthcare providers to adjust care plans and take appropriate actions, such as initiating end-of-life conversations. Machine learning (ML) techniques demonstrated promising capability to support clinical decision-making via providing reliable predictions for a variety of clinical outcomes, including cancer mortality. However, the evidence has not yet been systematically synthesized and evaluated. The objective of this review was to examine the performance and risk-of-bias for ML models trained to predict short-term (≤ 12 months) cancer mortality. Methods: We identified relevant literature from five electronic databases: Ovid Medline, Ovid EMBASE, Scopus, Web of Science, and IEEE Xplore. We searched each database with predefined MeSH terms and keywords of oncology, machine learning, and mortality using AND/OR statements. Inclusion criteria included: 1) developed/validated ML models for predicting oncology patient mortality within one year using electronic health record data; 2) reported model performance within a dataset that was not used to train the models; 3) original research; 4) peer-reviewed full paper in English; 5) published before 1/10/2020. We conducted risk of bias assessment using prediction model risk of bias assessment tool (PROBAST). Results: Ten articles were included in this review. Most studies focused on predicting 1-year mortality (n = 6) for multiple types of cancer (n = 5). Most studies (n = 7) used a single metric, the area under the receiver operating characteristic curve (AUROC), to examine their models. The AUROC ranged from .69 to .91, with a median of .85. Information on samples (n = 10), resampling methods (n = 6), model tuning approaches (n = 9), censoring (n = 10), and sample size determinations (n = 10) were incomplete or absent. Six studies have a high risk of bias for the analysis domain in the PROBAST. Conclusions: The performance of ML models for short-term cancer mortality appears promising. However, most studies report only a single performance metric that obfuscates evaluation of a model’s true performance. This is especially problematic when predicting rare events such as short-term mortality. We found little-to-no information on a given model’s ability to correctly identify patients at high risk of mortality. The incomplete reporting of model development poses challenges to risk of bias assessment and reduces the confidence in the results. Our findings suggest that future studies should report comprehensive performance metrics using a standard reporting guideline, such as transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD), to ensure sufficient information for replication, justification, and adoption.
Electronic patient reported outcome in Brazil: Insurance provider impact on adherence.
Authors: Jorge Thiago William Carnier , Filho César , Campagnaro Melina , Cartolano Lorenzo , Singh Jean , Sena Kamila , dos Prazeres Luiz Felipe , Guerrero Juliana , Ansarah Simone
Published: June 2021

e13590

Background: Routine monitoring of cancer patients' symptoms during their journey can improve symptom management, quality of life, and survival. Wecancer App is an electronic patient-reported outcome tool, which also provides on-demand multidisciplinary digital support by nurses, psychologists and nutritionists. It also encompasses real time remote patient monitoring, symptoms diary to patient and medical staff, symptom monitoring, medication control and a content hub with reliable information. It is free to any patient who download the app. In this study, we aim to understand if insurance provider type (private, public or out of pocket) impact on app adherence. Methods: This study examined daily symptom reporting (with electronic patient-reported outcomes [e-PROs]) patterns in breast cancer patients, according to insurance provider. The following were observed: app adherence, numbers of reports, chat interactions, specific symptoms, symptoms alerts and wellness reports. Patients could report sixteen common symptoms through a mobile application, on their smartphones and tablets, for monitoring, symptom management and follow-up with a specialized nurse, determining care based on digital support clinical protocols through online chat. The nursing team action started at the moment of patient inclusion with the tutorial to download the App and training it with the patient/caregiver. The alerts made through the chat system guided the clinical actions of the nursing team in relation to online clinical management that can stratify the risk by crossing the intensity of symptoms by the CTCAE grading scale and PRO-CTCAE Measurement System and promote preventive educational conduct of vigilance and risk mitigation. Results: From January 2020 to January 2021, 543 female eligible patients downloaded the app. The e-PRO completion rates were superior to 90% at baseline, and 55.47% completed all on-treatment assessments. The app adherence for private insurance patients (PIP), 37.06% for public insurance patients (PIP) and 7.45% for out of pocket patients (OPP). 2,626 reports were made (46.41% IP; 28.58% OPP; 25% PHP); 1008 chat interactions (52.18% IP; 40.28% PHP; 7.54% OPP); 1144 number of symptoms reported (46,41% IP; 28.58% OPP; 25% PHP); specific symptoms most reported in all kind of service was tiredness, pain, nausea, tingling; 547 symptoms alerts (54.84% IP; 35.46% PHP; 9.7% OPP) and 451 wellness reports (55.43% IP; 35.03% PHP; 9.53% OPP). Conclusions: Private insurance patients are more adherent to ePROS than public insured or out of pocket patients. Lack of free internet access and digital literacy could be impacting on adherence and, ultimately, quality of life and survival. Further studies are warranted to understand how to improve equality for digital health tools.