tbuckley/cabot-search huggingface dataset:
Molecular biomarker analysis and survival in patients (pts) with advanced urothelial cancer (UC) previously treated with chemotherapy.
Authors: Bernadett Szabados, Marlon Rebelatto, Craig Barker, Alvin Milner, Arthur Lewis, Michael Stokes, Magda Zajac, Thomas Powles, Norah J Shire
Journal: Journal of Clinical Oncology (2019)

4529 Background: The biomarkers PD-L1, FOXP3, and CD8 have been explored in pts with advanced UC who progressed after platinum-based chemotherapy (CTx). However, their relevance earlier in the disease process is less well understood. Methods: The Phase 2/3 LaMB study (NCT00949455) compared maintenance lapatinib vs placebo after first-line (1L) platinum-based CTx in pts with HER1/HER2-overexpressing stage IV advanced UC. Pre-CTx archival samples from this study were retrospectively analyzed and included both randomized and screen failure pts. PD-L1 expression was assessed (VENTANA SP263 Assay) and categorized as high (≥25% of tumor cells [TC] and/or immune cells [IC]) or low/negative ( &lt; 25% TC and IC). Overall survival (OS) and progression-free survival (PFS) were estimated via Kaplan-Meier method; results were stratified by PD-L1 expression. The exploratory biomarkers CD8 and FOXP3 were also analyzed. The prognostic significance of the biomarkers was explored by multivariable Cox proportional hazards models and a bootstrap method for model selection. Results: Of 446 pts (232 randomized; 214 screened), 243 (54.5%) were assessed for PD-L1 expression, with 61 (25.1%) PD-L1 high and 158 (65.0%) PD-L1 low/negative. In PD-L1 high and low/negative pts, respectively, median OS (95% CI) was 12.0 (9.4–19.7) vs 12.5 months (10.4–15.5); median PFS (95% CI) was 6.5 (3.5–8.8) vs 5.0 months (4.3–6.3). PD-L1 expression was not associated with OS or PFS in univariate analysis or in a multivariate model for OS (hazard ratio [HR] for PD-L1 high vs low/negative 1.4 [95% CI, 0.8–2.3]). In a multivariate model for PFS, PD-L1 expression improved accuracy of the model by 23% and was a significant variable (HR, 2.1 [95% CI, 1.2–3.5]). Results of analyses of CD8 and FOXP3 will also be reported. Conclusions: Overall, these data suggest a lack of association between PD-L1 expression and survival in pts receiving 1L platinum-based CTx. Mechanisms underlying the potential association of PD-L1 expression with PFS remain unclear. CD8 and FoxP3 exploratory analyses may help to elucidate these results. Clinical trial information: NCT00949455.
Long-term survival and safety from a multi-center, open-label, pivotal phase 2 study of iobenguane I 131 in patients (Pts) with unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma (PPGL).
Authors: Richard B. Noto, Camilo Jimenez, Bennett B. Chin, Joseph S. Dillon, Lilja Solnes, Vincent A. DiPippo, Syed Mahmood, Nancy Stambler, Tess Lin, Jessica Donato Jensen, Vivien Wong, Daniel A. Pryma
Journal: Journal of Clinical Oncology (2019)

4108 Background: PPGL, rare neuroendocrine tumors with a 5-yr survival rate as low as 12%, have a high unmet need for effective treatment options. AZEDRA, a high-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131-MIBG), is the first and only FDA- approved therapeutic radiopharmaceutical agent indicated for the treatment of adult and pediatric pts with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. Methods: Pts with advanced disease who were heavily pre-treated and were ineligible for curative surgery or chemotherapy received a dosimetric dose followed by up to two therapeutic doses (each at 296 MBq/kg to a max of 18.5 GBq). The primary endpoint, defined as the proportion of pts with at least 50% reduction of all antihypertensive medication(s) lasting ≥6 months, was met and previously reported. Updated secondary endpoints including overall survival (OS) and safety are reported. Results: A dosimetric dose of HSA I-131-MIBG was administered to 74 pts. Of those, 68 pts received one therapeutic dose and 50 received two doses of HSA I-131-MIBG. Clinical benefit rates (objective tumor responses defined by RECIST 1.0 and stable disease) were observed in 71.4% and 98.0% of pts receiving one and two therapeutic doses, respectively. As of Jan 25, 2019, median OS for all pts was 41.1 months (95% CI 31.1, 91.2). Median OS was 17.5 months (95% CI 4.0, 31.5) and 48.7 months (95% CI 33.2, 91.2) in pts receiving one and two doses, respectively. A tail of survival was observed, with OS of 73.1% at 2 yrs and 44.2% at 4 yrs. The most common (≥50%) adverse events were nausea, fatigue, and myelosuppression. Myelosuppressive events resolved within 4-8 wks without requiring stem cell transplantation. Late radiation toxicity included 8 pts with secondary malignancies (myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), colon cancer, and lung carcinoma) of which MDS, ALL and AML were considered related to I-131 radiotherapy. Conclusions: Updated results from this pivotal phase 2 study suggest that HSA I-131-MIBG is an efficacious and safe treatment for advanced PPGL. Clinical trial information: NCT00874614.
Time to surgery and overall survival after breast cancer diagnosis in a universal health system.
Authors: Yvonne L Eaglehouse, Matthew W. Georg, Craig D. Shriver, Kangmin Zhu
Journal: Journal of Clinical Oncology (2019)

e12063 Background: It is unclear whether time between breast cancer diagnosis and surgical treatment is associated with survival. In the general U.S. population, timing of treatment and clinical outcomes may be related to access to care. We aimed to evaluate the relationship between time-to-surgery (TTS) and overall survival among women with a breast cancer diagnosis in the universal-access U.S. Military Health System (MHS). Methods: Women aged 18-64 who had a pathologic diagnosis of stages I-III breast cancer between 1998 and 2007 and who received breast cancer surgery during the primary course of treatment were identified in the Department of Defense’s Central Cancer Registry and MHS Data Repository linked databases containing records through December 31, 2008. The time in days between diagnosis and breast cancer surgery was calculated as TTS. Cox regression models were used to estimate hazards ratios (HR) and 95% confidence intervals (CIs) of all-cause death associated with TTS intervals of 0 days (diagnosis and surgery on the same day), 1-21 days (≤3 weeks), 22-35 days ( &gt; 3-5 weeks), and 36 days or more ( &gt; 5 weeks), controlling for potential confounders. Results: Women (n = 6,033) had a mean age of 50.1 (SD 9.3) years at diagnosis and an average follow-up of 3.8 (SD 2.1) years. The multivariable HRs (95% CIs) of all-cause death associated with TTS intervals were 1.26 (0.97, 1.63) for 0 days, 1.22 (0.94, 1.57) for 22-35 days, and 1.55 (1.18, 2.03) for ≥36 days compared to 1-21 days as the reference. The higher risk of mortality for TTS ≥36 days was observed among patient subgroups stratified by surgery type, age at diagnosis, and tumor stage. It was also shown that women with same-day surgery (TTS 0 days) had a significantly higher risk of all-cause mortality compared to the reference group among those age 18-49 at diagnosis (HR 1.52, 95% CI 1.03, 2.26). Conclusions: In the MHS, we found that longer TTS is associated with poorer overall survival after breast cancer while same-day surgery may also have a higher risk of mortality in some patient groups. Our findings suggest the importance of timeliness in receiving surgical treatment and the need for future research on factors related to TTS and its potential effects on clinical outcomes.
Case 6-1986
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Michael A. Fifer, Frederick C. Koerner
Journal: New England Journal of Medicine (1986)

Presentation of CaseA 34-year-old man was admitted to the hospital because of hypertension and respiratory and renal failure.He was apparently well until five years earlier, when hypertension was found and was treated with nadolol and hydrochlorothiazide. In a 24-hour specimen of urine the vanilmandelic acid (VMA) was 2.15 mg (normal, 1 to 8). Every month or two the patient experienced bouts of nausea, vomiting, and flushing that subsided within a few hours and were associated with diuresis; these episodes were never evaluated medically. Three or four years before admission a renal angiographic examination, performed elsewhere, was reported to . . .
Pathological and genetic aggressiveness of left-sided breast cancer.
Authors: Yara Abdou, Mariko Asaoka, Kazuaki Takabe
Journal: Journal of Clinical Oncology (2019)

e12579 Background: Breast Cancer in women consistently occurs more frequently in the left breast, with the ratio of left to right sided breast cancer cases ranging from 1.05 to 1.26. In spite of the difference in frequency, prior studies have failed to show any significant difference in clinical characteristics between left sided and right sided cancer. Methods: Genomic and clinical features were collected from The Cancer Genome Atlas breast cancer project. LVI status, mitotic rate, nuclear score and tubular score were collected from pathology reports in TIES client 5.8. Fisher's exact test was used for group comparison and survival analysis was performed with Cox regression. Cytolytic activity (CYT) indicates anti-cancer immune response and was quantified from gene expression data. Hallmark gene-sets were used for gene set enrichment analysis (GSEA). Results: Among the 1081 women with unilateral invasive breast cancer, 561 had tumor on the left side compared to 520 on the right. Our results didn’t show any significant differences between left and right side with regards to tumor location, histology, race, and tumor characteristics including stage, tumor size, nodal status and receptor status. No statistical significant differences were observed in mitotic rate, LVI status and tubular score, however, the tumor grade was significantly higher in the left side. Moreover, there were no significant differences in mutation count, CYT and overall survival between both sides. GSEA revealed cell-cycle related gene sets like G2M checkpoint, Mitotic spindle, E2F targets and MYC targets which were significantly enriched in left sided tumor. Furthermore, out of the 865 genes which were highly expressed on the left side, we identified specific genes including BRCA1, BRCA2, BRIP1, CHEK2, FANCC, PALB2, TP53 and MSH6 which are associated primarily with breast cancer genesis and mostly have established clinical management guidelines. Conclusions: Our results suggest a more aggressive nature to left sided breast cancer with a higher pathological grade perhaps requiring more aggressive treatment. Such a hypothesis needs further study to confirm or refute its validity. If confirmed, it may have a major impact with regard to biology of breast cancer and its subsequent management.
The CYP2C19 rs4917623 single nucleotide polymorphism to predict tamoxifen efficacy in estrogen receptor-positive breast cancer patients.
Authors: Nobuyasu Yoshimoto, Akihiro Naito, Nobuko Kawaguchi, Miwa Kato, Naoto Kondo, Yumi Wanifuchi-Endo, Tatsuya Toyama
Journal: Journal of Clinical Oncology (2019)

e12001 Background: Tamoxifen is a selective estrogen receptor modulator that is widely used to treat estrogen receptor (ER)-positive breast cancer. However, not all patients benefit from the incorporation of tamoxifen into an adjuvant therapy. This is also the case when tamoxifen is used in chemoprevention, since only half of participants benefit from the drug. In order to improve treatment response, we attempted to identify single nucleotide polymorphisms (SNPs) that correlated with tamoxifen efficacy. Methods: ER-positive breast cancer patients at our hospital were enrolled on this study between January 2007 and September 2010. The primary endpoint was ER-positive breast cancer-free survival. We examined 17 SNPs in these patients. The survival benefit associated with each genotype was determined with a log-rank test, and the hazard ratio was analyzed using a Cox proportional-hazards model. Results: The median follow-up time of the 320 patients enrolled on the study was 3298 days. Of 240 patients who received any endocrine therapy, ER-positive breast cancer-free survival in patients with the 2q35 rs13387042 AA genotype was significantly shorter than in those who had the AG or GG genotype (p &lt; 0.0001), and the hazard ratio was significantly higher (HR 8.83; 95% CI 2.09–25.53, p = 0.0064). Of the 145 patients who received tamoxifen therapy, there was a trend among ER-positive breast cancer patients with the CYP2C19 rs4917623 TT genotype to have a shorter disease-free period (p = 0.0635) when compared to patients with TC or CC genotypes. Similarly, there was a trend for the TT genotype patients to exhibit a higher hazard ratio (HR 2.62; 95% CI 0.86–7.55, p = 0.0861). Conclusions: The rs4917623 SNP in the CYP2C19 gene, which encodes a metabolic enzyme, predicts tamoxifen efficacy. This finding will facilitate selection of ER-positive breast cancer patients for tamoxifen treatment; it may also be useful for selection of patients most likely to benefit from tamoxifen-dependent chemoprevention.
What do doctors value about attending multi-disciplinary cancer case discussions?
Authors: Paul Mitchell, Jennifer Soon, Joanne Kenny, Katherine Simons
Journal: Journal of Clinical Oncology (2019)

e18324 Background: Discussion of cancer cases at multi-disciplinary meetings (MDMs) for treatment planning is expected standard care in Australia. There has been rapid uptake of MDMs in the last 10 - 15 years and in the state of Victoria approximately 70% of cancer cases are discussed. MDMs have strong support from medical staff and we investigated their motivation in attending MDMs. Methods: Over 12 months, Austin Health in Melbourne, Victoria, hosted 452 cancer MDMs discussing 5943 patients. MDMs covered 15 tumour areas: 11 solid tumour, one lymphoma and three haematological. Over a 4-week period, medical staff attending MDMs were surveyed and asked to rank what they valued most about cancer MDMs, over and above the benefits for patients. Results: Responses were received from 84% of the 285 medical staff surveyed, which included consultants as well as trainees (registrars and fellows). For 75% of respondents the highest ranking was given to multi-disciplinary communication, 9% gave the highest ranking to quality assurance and governance, 5% ongoing learning for consultants, 5% collegiate relationships, 2% learning and teaching for non-consultant staff, 2% peer support 1% job satisfaction and 1% clinical trials engagement. Similar results were obtained for consultant staff and for registrars / fellows. For consultant medical staff, if multidisciplinary communication was excluded, 44% of respondents gave the highest ranking to quality assurance and governance, 23% to collegiate relationships, 20% ongoing learning for consultants, 10% peer support and 3% clinical trials engagement. Conclusions: When we asked doctors what they valued most about attending cancer MDMs, besides the benefits for patients, communication between disciplines was clearly the most valued aspect. The benefits for quality and governance was the next most valued, then collegiate relationships and peer support, and ongoing learning.
Case 21-1984
Authors: Richard H. Meade, David L. Gang
Journal: New England Journal of Medicine (1984)

Presentation of CaseA girl was admitted to the hospital at the age of 10 years and 8 months because of episodic abdominal pain and fever.She was in excellent health until 45 months earlier, when coryza and headache developed, followed by intermittent fever with rise of the temperature to 38.9°C and midline lower abdominal pain. Her mother noticed cervical lymphadenopathy. During the next two weeks the patient was irritable and anorectic, with loss of an unknown amount of weight. Her symptoms worsened, and she entered another hospital. An ultrasound study of the abdomen showed a questionable abscess cavity in . . .
Approach to Evaluation of Multiple Liver Lesions—Reply
Authors: Adam Mikolajczyk, Lindsay Yassan, Anjana Pillai
Journal: JAMA (2019)

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Circulating-free DNA analysis from long-term surviving metastatic colorectal cancer patients undergoing surgery for resectable disease.
Authors: Michele Ghidini, Jens Claus Hahne, Chiara Senti, Andrea Lampis, Margherita Ratti, Claudio Pizzo, Angela Gobbi, Gianluca Tomasello, Rodolfo Passalacqua, Nicola Valeri
Journal: Journal of Clinical Oncology (2019)

e14545 Background: Liquid biopsies (LB) allow monitoring of genetically different and co-occurring cancer cell clones present in primary tumor and all metastatic sites in parallel. In metastatic colorectal cancer (mCRC), circulating-free DNA (cfDNA) can be relevant for monitoring treatment and identification of molecular alterations resulting in disease relapse often earlier than radiological examinations. Methods: Patients with mCRC at diagnosis and treated with chemotherapy (CT) in combination with antibodies (bevacizumab, cetuximab or panitumumab) before undergoing surgery for resectable disease were included in this study. LB were collected before therapy start, every four weeks during treatment, within ten days of radiological disease evaluation, at radiological relapse and until two months after relapse. Next generation sequencing based on plasma samples was performed (testing for mutations and copy number variations covering 77 genes). Results: From February 2016 to October 2018, 14 patients having surgery after first line treatment were included herein; median follow-up was 21.5 months. Five of them had RAS wild-type disease and received CT plus anti-EGFR treatment, while nine RAS mutated mCRC patients received bevacizumab. Surgery was radical in 10 cases, with no further treatment. In four cases, surgery was not radical and required further treatment. Disease relapse happened in seven cases, with subsequent death in three cases. In six out of seven cases, gene alterations were already detected in the pre-operative cfDNA. In the seven cases without disease relapse, gene variants were detected even after the surgery in two patients despite receiving radical resection. Median number of gene variants was two. Beside the well-established mutations in TP53 gene, both APC and ROS1 gene mutations were frequent, while further evaluations are required for the other variants detected. Conclusions: Evaluation of cfDNA mutations in LB from mCRC may be a useful tool for monitoring clinical response and predict treatment outcome. Moreover, this molecular analysis can help to subgroup patients with regard to risk of relapse after radical surgery. Indeed, cfDNA mutations present before surgery seem to be an indication for a higher risk of post-surgery disease relapse.
Patterns of local extension and nodal involvement from 1300 nasopharyngeal carcinoma patients: An imaging-based predictor of distant metastases.
Authors: Dan Fan, Ying Wang, Yifu Tian, Nancy Y. Lee, Liangfang Shen
Journal: Journal of Clinical Oncology (2019)

e17516 Background: Distant metastasis is a main determinant of prognosis in patients with nasopharyngeal carcinoma(NPC). We explored the patterns of disease spread in NPC patients and identified the pattern correlates with distant metastases. Methods: The imaging documents of 1300 consecutive newly diagnosed nasopharyngeal carcinoma between 2012 and 2016 were reviewed. According to the incidence rates of tumor invasion, the anatomic sites were classified into high-risk group (≥50%), medium-risk group (≥10%~ &lt; 50%) and low-risk group ( &lt; 10%). The location of lymph nodes was determined by 2013 updated guidelines for neck node levels. Additionally, we developed a novel classification based on tumor spreading patterns, as shown in Table. Moreover, we validated the prognostic accuracy of the classification in a validation cohort from a different institution, 241 non-metastatic NPC patients were retrospectively enrolled. Kaplan-Meier method and log-rank test were used to analyze all time-to-event data. Results: The incidence rates of tumor invasion were 0.2% ~91.2%, 95.2% cases across the midline. If anatomic sites in high-risk group or median-risk group were involved, the incidence rates in adjacent medium-risk sites or low-risk group were increased. On the contrary, the incidence rates were decreased when the adjacent high-risk sites or median-risk group were not involved. 85.9% cases had involved lymph nodes. Only 3.9% had skip metastases. The incidence rates of nodal involvement were increased when adjacent upper nodal level was involved. In validation cohort, distant metastases were present in 32/241 NPC patients (13.3%) and 3-year distant metastasis-free survival(DMFS) in local, superior, inferior, and mixed type were 95.0%, 91.3%, 89.0%, and 78.7%, respectively. Cumulative survival curves for former three patterns were relatively similar and were clearly separated from mixed type. DMFS was significantly lower for patients with mixed type pattern than for those with other patterns(P = 0.018). Conclusions: Local disease in NPC patients spreads stepwise from proximal sites to more distal sites. The frequency of metastases in the jugular lymph node chains decreased in the cranio-caudal direction. Based on the patterns of tumor extension, an imaging-based predictor of distant metastases was developed and may be used as a prognostic marker for selecting patients to further systemic treatments. [Table: see text]