tbuckley/cabot-search huggingface dataset:
Metaplastic breast cancer: A single-institution experience.
Authors: Aumilto Augusto Silva, Rudinei Diogo Marques Linck, Julianne Maria da Silva Lima, Adriana Reis Brandao Matutino, Saulo Brito Silva, Maria Fernanda Vicentini, Marcelo Felizola, Debora De Melo Gagliato, Paulo Marcelo Hoff, Max S. Mano
Journal: Journal of Clinical Oncology (2016)

e12575 Background: Metaplastic breast cancer (MBC) is a rare breast cancer (BC) subtype, representing less than 1% of all BC cases. Because of its rarity, it has been traditionally treated similarly to invasive ductal carcinoma (IDC). Nevertheless, compared to IDC, evidence is accumulating in the sense that it has a worse prognosis. We sought to evaluate a MBC cohort of patients (pts) treated at our institution. Methods: Retrospective analysis of data from electronic records of 43 pts diagnosed with MBC, treated at the Instituto do Cancer do Estado de Sao Paulo, from 2006 to 2015. Patient and disease characteristics were summarized and analyzed by descriptive statistics. Results: The median age at diagnosis was 53y/o (24-92). Epithelial subtype and mixed-type represented 79% (34 pts) and 21% (9 pts) of the cases, respectively. Staging was as follows: 91% (39 pts) non-metastatic; 69% (30 pts) T3/T4 and 72% (31 pts) node positive. A total of 20 pts (51%) with localized disease were submitted to surgery upfront and 19 (79%) of them received adjuvant chemotherapy: 15 pts treated with Doxorubicin/Cyclophosphamide/weekly Paclitaxel (AC-wT); 2 pts with Docetaxel/Cyclophosphamide and 2 pts with Carboplatin/Paclitaxel. Neoadjuvant chemotherapy was given to 19 pts (39%) and AC-wT was the schedule most frequently employed (94% - 18 pts). Among them, only 1 (5%) had pathological complete response; 2 pts (10%) had progressive local disease and 16 pts (84%) had only minimal response or stable disease as best response. Recurrent disease was observed in 18 pts (46%). Systemic disease as primary recurrence was observed in 95% (17 pts) of the cases – with lung metastasis being the most common site (10 pts – 59%). One (5%) patient recurred primarily as local disease. Seventy-two percent (13 pts) of the recurrences were diagnosed in the first year of follow-up.Four pts (9%) were diagnosed with metastatic disease at the time of diagnosis, and 3 of these pts died from cancer in the first 2 years. Conclusions: In our experience, MBC is characterized by larger tumor size at presentation, poor response to systemic therapy, and high rates of recurrence. Further research is required to develop targeted treatments aiming to improve survival outcomes.
Acute obstructive hydrocephalus complicating bacterial meningitis
Authors: C. Settle, M. H Wilcox, A. Rashid, R S. Cooke, V. Patterson, L. Abernethy
Journal: BMJ (1999)

Editor—A recent lesson of the week highlighted the possibility of meningitis in childhood presenting as obstructive hydrocephalus, with cerebrospinal fluid from ventriculostomy proving sterile but subsequent lumbar fluid yielding Streptococcus pneumoniae.1 In the two paediatric cases described, treatment consisted of both a third generation cephalosporin and benzylpenicillin. In children between 3 months and 18 years of age, however, it is recommended practice for empirical treatment to consist of a third generation cephalosporin alone.2,3 The article may be misleading in giving the impression that use of two antibiotics in this type of case is routine.

There is no sound microbiological basis for using a cephalosporin and a penicillin together, with the exception of patients who may be infected with Listeria monocytogenes. Listeriosis is extremely uncommon in England and Wales, with only 64 reported cases in the first seven months of 1997, including a total of 14 neonatal cases.4 A third generation cephalosporin is adequate cover for Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus pneumoniae, or Escherichia coli, and benzylpenicillin provides no extra benefit. Two β lactam antibiotics should not be given together unless this is unavoidable: there is potential for antagonistic interaction between agents, as both act by inhibiting cell wall synthesis. It is not likely that the penicillin was used to cover the possibility of listeriosis, as the drug of choice in such cases is ampicillin (with or without an aminoglycoside).5

We recommend that empirical treatment for patients aged between 3 months and 18 years who are suspected of having bacterial meningitis (not thought to be due to listeria or tuberculosis) should be monotherapy with high doses of a third generation cephalosporin, such as cefotaxime or ceftriaxone. Patients in the United Kingdom with a rash typical of meningococcal sepsis may be treated with a high dose of benzylpenicillin alone.
Safety, pharmacokinetics (PK), pharmacodynamics (Pd), and antitumor activity in a phase 1b study evaluating anti-ErbB3 antibody KTN3379 in adults with advanced tumors alone and with targeted therapies.
Authors: Gerald Steven Falchook, Todd Michael Bauer, Patricia LoRusso, Joseph Francis McLaughlin, Theresa LaVallee, Ronald Alan Peck, Joseph Paul Eder
Journal: Journal of Clinical Oncology (2016)

2501 Background: KTN3379 is a fully human anti-ErbB3 antibody with YTE half-life extension engineering that uniquely binds domain 3 locking ErbB3 in an inactive configuration. ErbB3 is implicated in tumor growth and treatment resistance. A phase 1b study of KTN3379 alone and in combination was undertaken to evaluate safety, PK, Pd, and efficacy (NCT02014909). Methods: Patients (pts) received KTN3379 alone at 5-20 mg/kg (N=21) or in combination at 15 or 20 mg/kg IV q3w with cetuximab (N=16), erlotinib (N=8), vemurafenib (N=4) or trastuzumab (N=9). Safety monitoring and RECIST-based tumor assessments were conducted. PK was evaluated using a two-compartment pharmacokinetic model. Pd markers included serum ErbB3. Archival tumor was tested for neuregulin (NRG) and ErbB3. Results: 58 total pts were treated. No DLTs occurred in 21 pts receiving KTN3379 alone. DLTs of diarrhea, mucositis and rash were observed in 5 of 37 pts treated with combinations. The most common adverse events across all combinations were diarrhea, fatigue, nausea and rash. KTN3379 at or above 15 mg/kg was tolerated in all combination arms. Linear PK was observed at doses between 10 and 20 mg/kg and exceeded target concentration for antitumor activity. There was a trend toward slower clearance and longer half-life of KTN3379 compared to related compounds, consistent with the engineered YTE. Responses included 1 ongoing confirmed CR with cetuximab in a pt with HNSCC who had progressed on cetuximab alone, and 2 confirmed PRs with vemurafenib in pts with BRAF-mutant NSCLC, one of which previously progressed on dabrafenib (2 of 3 responders were NRG+). Analysis of Pd correlates is in progress and will be presented at ASCO. Conclusions: KTN3379 can be safely combined with standard doses of cetuximab, erlotinib, vemurafenib or trastuzumab at 15 to 20 mg/kg. Efficacy was observed including a CR in a pt with HNSCC with cetuximab and PRs in 2 pts with BRAF-mutant NSCLC in combination with vemurafenib. A phase 2 study of the combination of cetuximab and KTN3379 in HNSCC is planned, in addition to currently ongoing phase 1b studies in SCCHN and BRAF-mutant thyroid cancer. Clinical trial information: NCT02014909.
Elimination of pelvic exams in a high-risk ovarian cancer screening program.
Authors: Kisha T Hope, Anna Everett Strohl, Patricia Smyrniotis, Jeffrey Dungan, Shohreh Shahabi, Lee P Shulman
Journal: Journal of Clinical Oncology (2016)

e13059 Background: The Northwestern Ovarian Cancer Early Detection and Prevention Program (NOCEDPP) was established in 1998 to monitor woman at increased risk for epithelial ovarian cancer (EOC). The goals of the NOCEDPP are: 1) to create an effective early detection program, and 2) identify new prevention strategies and therapies to improve the quality of life for both high-risk women as well as women affected by ovarian cancer. Methods: Program eligibility includes women ages 18-80 years with a personal or family history of ovarian cancer, BRCA mutation carriers, and women with germ-line mutations causing Lynch, Li-Fraumeni, and Cowden syndromes. The initial NOCEDPP screening protocol included up to four visits per year, consisting of a pelvic bimanual exam (PBE), CA-125 blood test, transvaginal ultrasound (TVUS), breast exam, and symptom assessment. In 2010, PBEs were removed from the protocol as the exams were considered redundant in light of universal TVUS at all visits. The objective is to evaluate the utility of PBEs in epithelial ovarian cancer detection in a high-risk screening program. Results: We identified 2051 individuals who met all inclusion criteria and were referred to the program. The average annual clinic visit was twice a year. Ovarian cancer detection and mortality rates in the NOCEDPP were compared prior to and after the elimination of the pelvic exam from the protocol and no significant difference in EOC detection or mortality was found. No cases of EOC were detected in the NOCEDPP population before and after the elimination of bimanual pelvic exams. Conclusions: The utility of pelvic exams in EOC screening is under scrutiny. Recent national guidelines omit pelvic exams from national screening guidelines in hereditary breast and/or ovarian cancer syndrome. Furthermore, performance of unnecessary, invasive exams are associated with increased anxiety in high-risk populations. The results of this study found no difference in epithelial ovarian cancer detection or mortality with omission of the PBE from routine screening in a high-risk patient population, suggesting elimination of pelvic exams is safe. Future studies should focus on patient experience and anxiety in response to these changes. Clinical trial information: NCT00005095.
A novel MGMT methylation-based prognostic score in patients with glioblastoma.
Authors: Lorenzo Gerratana, Giuseppe Lombardi, Elisa De Carlo, Vanessa Buoro, Giovanna De Maglio, Raffaella Marcato, Miriam Isola, Monica Cattaneo, Luisa Bellu, Giacomo Pelizzari, Lorena Gurrieri, Alessandro Follador, Fabio Puglisi, Stefano Pizzolitto, Gianpiero Fasola, Vittorina Zagonel, Simona Rizzato
Journal: Journal of Clinical Oncology (2017)

2048 Background: The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has been associated with improved outcome in glioblastoma (GBM) patients (pts). Pyrosequencing (PSQ) has been reported to be an accurate method for quantitative detection of CpG islands (CpGs) methylation, but the role of methylation heterogeneity among different CpGs sites is still unclear. Aim of this study was to evaluate on a large multicentric cohort a novel prognostic score based on the evaluation of the MGMT promoter methylation at 10 different CpGs sites. Methods: We retrospectively analyzed a series of 185 pts with GBM treated at the University Hospital of Udine and Istituto Oncologico Veneto in Padua between 2006 and 2015. The methylation level of 10 CpGs (74 – 83) was determined by PSQ. The cut-off point of 9% was used to define a CpG as methylated. One point was assigned to each methylated CpG, with a total score from 0 (all CpGs &lt; 9%) to 10 (all CpGs ≥ 9%). A threshold capable to detect a favorable outcome (Overall Survival, OS &gt; 24 months) has been identified through ROC analysis as 6 by a previous study conducted at our center. The prognostic impact was explored through Cox regression. Results: After a median follow-up of 59 months, the median OS and Progression Free Survival (PFS) in the whole population were 16.41 and 9.67 months, respectively. A score ≥ 6 identified pts with a considerably better median OS (24.85 vs 12.99 months, p &lt; .0001) and PFS (11.44 vs 8.22 months, p &lt; .0001). On multivariate analysis, it remained independently associated with a favorable prognosis (HR 0.38, 95% CI 0.27-0.55, p &lt; 0.0001) after adjustment for IDH1 mutational status (HR 0.42, 95% CI 0.20-0.87, p = .02), age ( &gt; 70 vs ≤ 70 years HR 2.20, 95% CI 1.48-3.28, p = .0001) and ECOG performance status (2-3 vs 0-1 HR 2.35, 95% CI 1.59-3.49, p &lt; .0001). The score’s prognostic value was maintained in all the explored subgroups. Conclusions: Combining methylation data from multiple CpGs increases the prognostic value of the MGMT promoter methylation assessment. The study confirmed the independent prognostic value of a novel score system based on the evaluation of the MGMT promoter methylation at 10 different CpGi sites.
Analysis of tumor infiltrating lymphocytes in HER2-positive primary breast cancer treated with neoadjuvant lapatinib and trastuzumab: The NeoLath study (JBCRG-16).
Authors: Kosuke Kawaguchi, Eiji Suzuki, Tatsuki R Kataoka, Masahiro Hirata, Shinji Ohno, Hiroko Bando, Hiroshi Ishiguro, Kenichi Inoue, Naohito Yamamoto, Katsumasa Kuroi, Satoshi Morita, Norikazu Masuda, Masakazu Toi
Journal: Journal of Clinical Oncology (2016)

599 Background: The presence of tumor-infiltrating lymphocytes (TILs) is associated with better outcomes in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) patients who are treated with adjuvant or neoadjuvant trastuzumab-based systemic therapy. Precise subset analysis of TILs is important to understand the role of TILs in the breast tumor microenvironment. We examined the correlation between TILs and treatment outcomes of neoadjuvant dual-HER2 blockage therapy with paclitaxel in HER2-positive EBC. Our aim was to achieve a robust understanding of the predictive value of neuropilin-1 (NRP1), an active CD4 T cell marker, and FOXP3, a well-known regulatory T cell marker, on TILs. Methods: The NeoLath study is a randomized, phase II, five-arm study evaluating the efficacy and safety of lapatinib and trastuzumab followed by lapatinib and trastuzumab plus weekly paclitaxel with or without prolongation of anti-HER2 therapy prior to chemotherapy (18 weeks vs. 6 weeks). The primary endpoint was the comprehensive pathological complete response (pCR) rate. We evaluated the %TILs, %NRP1/TILs and %FOXP3/TILs using core biopsy sections taken at diagnosis, and in surgical specimens after dual HER2 blockage therapy in the prospectively defined, retrospective analysis. Results: A total of 222 tumor samples from 74 patients were used for the present analysis. The mean level of TILs was 20.0% and pCR rate was 56.8%. Univariate analysis showed that %TILs and %NRP1/TILs were associated with pCR and multivariate analysis showed that %NRP1/TILs was significantly associated with pCR (adjusted odds ratio, 1.08 [95% CI, 1.04–1.13]; P < .0001) (table). Conclusions: In addition to TIL evaluation, analysis of NRP1 expression of TILs is important to explore prognosis in HER2-positive EBC patients who are treated with neoadjuvant dual-HER2 blockage therapy for pCR. Clinical trial information: 000007576.Multivariate analysis Effect Odds Ratio P value 95% CI Age 1.00 0.82 0.95–1.07 ER 0.44 0.21 0.12–1.61 Nodal status 0.58 0.41 0.16–2.13 TILs 0.99 0.66 0.96–1.03 Tumor size 0.95 0.07 0.90–1.00 NRP1 1.08 <0.0001 1.04–1.13
Phase I study of alpelisib and T-DM1 in trastuzumab-refractory HER2-positive metastatic breast cancer.
Authors: Sarika Jain, Lauren Elizabeth Nye, Cesar Augusto Santa-Maria, Hannah Garrett, Ellen Dammrich, Amanda Williams, Lauren Bontemps, Lisa E. Flaum, Francis J. Giles, William John Gradishar
Journal: Journal of Clinical Oncology (2016)

588 Background: Constitutive activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a mechanism of trastuzumab resistance in HER2-positive metastatic breast cancer (MBC). Alpelisib (BYL-719) is the first oral PI3K inhibitor that selectively inhibits the PI3K alpha isoform. We aimed to determine the maximum tolerated dose (MTD), safety, and activity of alpelisib in combination with ado-trastuzumab emtansine (T-DM1) in HER2-positive MBC. Methods: This phase I study enrolled patients who received alpelisib daily (cohort 1: 300 mg, (-)1: 250 mg) and T-DM1 3.6 mg/m2on Day 1 every 21 days using a 3+3 design with dose expansion at MTD. Dose-limiting toxicity (DLT) was defined as CTCAE Grade 3/4 adverse events (AE) during cycle 1. Blood was collected for pharmacokinetic (PK) and pharmacodynamic (PD) markers. Imaging and echocardiogram were obtained every 3 cycles. Data cut-off is Jan. 1, 2016. Results: Fifteen patients have been enrolled. Median age was 53 (40-66). Median prior lines of therapy in metastatic setting was 4.5 (range 0-13) including 9 patients who progressed on prior T-DM1 (after median 8 cycles). Median number of metastatic sites was 3 (range 1-5) including brain, liver, and lung. Median number of cycles per patient who completed at least 1 cycle was 7 (range 1-15). Five patients were enrolled in cohort 1 with 2 DLTs (grade 3 rash), leading to cohort (-)1, in which there were no DLTs. The most common alpelisib-related AEs were hyperglycemia (n = 9, 64%), fatigue (n = 8, 57%), nausea (n = 8, 57%), and rash (n = 6, 43%). Grade 3 AEs included rash (n = 6), hyperglycemia (n = 2), anorexia (n = 2), lymphocyte count decrease (n = 1), hypertension (n = 1) and thrombocytopenia (n = 1). Grade 3 rash occurred during cycle 1, which resolved with interruption and subsequent dose reduction of alpelisib and use of steroids. Grade 3 hyperglycemia was reversible with oral anti-diabetic treatment. One Grade 4 AE occurred (thrombocytopenia) most likely due to T-DM1. MTD for alpelisib was established as 250 mg daily. Efficacy data will be reported. PK/PD and PIK3CA mutation testing are pending. Conclusions: The combination of alpelisib and T-DM1 appears to be safe in HER2-positive MBC patients. A phase II study is planned. Clinical trial information: NCT02038010.
Germline hypomorphic CARD11 mutations in severe atopic disease
Authors: Chi A Ma, Jeffrey R Stinson, Yuan Zhang, Jordan K Abbott, Michael A Weinreich, Pia J Hauk, Paul R Reynolds, Jonathan J Lyons, Celeste G Nelson, Elisa Ruffo, Batsukh Dorjbal, Salomé Glauzy, Natsuko Yamakawa, Swadhinya Arjunaraja, Kelsey Voss, Jennifer Stoddard, Julie Niemela, Yu Zhang, Sergio D Rosenzweig, Joshua J McElwee, Thomas DiMaggio, Helen F Matthews, Nina Jones, Kelly D Stone, Alejandro Palma, Matías Oleastro, Emma Prieto, Andrea R Bernasconi, Geronimo Dubra, Silvia Danielian, Jonathan Zaiat, Marcelo A Marti, Brian Kim, Megan A Cooper, Neil Romberg, Eric Meffre, Erwin W Gelfand, Andrew L Snow, Joshua D Milner
Journal: Nature Genetics (2017)
Outcomes of Turkish National Breast Cancer Registry.
Authors: Saadettin Kilickap, Mahmut Gumus, Dogan Uncu, Metin Ozkan, Irfan Cicin, Tamer E. Elkiran, Abdurrahman Isikdogan, Aziz Karaoglu, Berna Oksuzoglu, Feyyaz Ozdemir, Hande Turna, Ruchan Uslu, Ozgur Ozyilkan, Alper Erdogan, Burce Goktas, Oguz Kara
Journal: Journal of Clinical Oncology (2017)

Background: The aim of this registry was to collect demographic, diagnostic, treatment, and outcome information about Turkish patients with breast cancer (BC). Methods: It was designed as a multicenter, cross-sectional, non-interventional study conducted on new and previously diagnosed BC cases applied to 28 medical oncology outpatient clinics between 2012 and 2015. A total of 16841 male (n = 153) and female (n = 16688) patients &gt; 18 years were included. Results: Mean age of BC patients was 52.0±11.5 years. Among women, 53.7% were postmenopausal, and 24.4% were receiving hormone replacement (HRT) and/or oral contraceptive therapies (OCT). At time of diagnosis, 18.2% of patients presented with Stage 1, 48.5% with Stage 2, 25.5% with Stage 3, and 7.9% with Stage 4 BC. In 79,8% of the patients histopathology was invasive ductal carcinoma. Estrogen (ER) and progesterone receptors (PR) were positive in 74.7%, and 69.4% of patients, respectively. Diagnostic immunohistochemistry (IHC) was performed in 90.4% of patients. HER2+ was found in 30.2% of patients. HER2+ was observed in 27.6% Stage I, 27.6% Stage II, 36.2% Stage III, and in 41.7% Stage 4 BC. ER and PR positivity were 62.4% and 56.4% among HER2+ patients, respectively. Neoadjuvant therapy was administered in 10.6% and adjuvant therapy was administered in 73.2% of patients. Between 2010 and 2015, trastuzumab was administered in 68.3% of adjuvant (n = 1959), and 7.5% of neoadjuvant (n = 215) HER2+ patients. Conclusions: BC is a major health concern. Majority of the patients are diagnosed in stage 2 or 3, therefore screening should be improved to diagnose patients at earlier stages. In HER2 positive patients, neoadjuvant trastuzumab usage is limited despite its known advantages.
Impact of landmark responses on 3-year (yr) outcomes with ponatinib in heavily pretreated CP-CML patients (pts).
Authors: Martin C. Müller, Michele Baccarani, Michael W.N. Deininger, Francois Guilhot, Andreas Hochhaus, Timothy P. Hughes, Neil P. Shah, Moshe Talpaz, Stephanie Lustgarten, Victor M Rivera, Timothy Piers Clackson, Frank G. Haluska, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2016)

7053 Background: PON, a potent oral TKI, is active against native and mutant BCR-ABL1 and approved for pts with refractory CML or Ph+ALL, or with the T315I mutation. Pt responses at early landmark time points have been correlated with positive long-term (LT) outcomes in 1st and 2nd-lines. Here we evaluate the impact of early responses with PON on 3-yr outcomes in heavily pretreated pts (primarily ≥3rd line) with CP-CML in the ongoing Ph2 PACE trial. Methods: Molecular and cytogenetic responses at 3, 6 and 12 mo and their association with outcomes at 3 yrs were examined among CP-CML (n=267) pts in a posthoc analysis. P values: calculated using log-rank test. Data: as of 3 Aug 2015. Results: Median time from diagnosis was 7 yrs (range 0.5-27) and median age was 60 yrs (range 18-94); 61% had received ≥3 prior TKIs. At 3, 6, and 12 mo, 48%, 62% and 71% of pts, respectively, achieved MCyR, and 14%, 29% and 39%, respectively, achieved MMR, among pts evaluable at each landmark. Greater reductions in BCR-ABL1 transcript levels at most landmark time points were associated with improved PFS and OS at 3 yrs (Table), as was MCyR. Deeper responses at all landmark time points were also associated with the achievement of MR4.5 over time. Conclusions: Deep, early reductions in BCR-ABL1 transcripts were positively associated with LT survival in this refractory population. These data demonstrate the prognostic value of achieving early landmark cytogenetic and molecular responses with PON in heavily pretreated pts. Clinical trial information: NCT01207440.Estimated PFS and OS at 3 years past landmark by BCR-ABL1 level. Landmark/Response n PFS *p –value n OS *p –value 3 mo BCR-ABL1 ≤0.1% 32 97% — 33 97% — BCR-ABL1 >0.1–1% 47 70% .39 48 85% .60 BCR-ABL1 >1%–10% 51 61% .0080 55 81% .13 BCR-ABL1 >10% 82 54% .0003 overall: 0.0013 94 78% .16 overall: 0.34 6 mo BCR-ABL1 ≤0.1% 58 91% — 61 93% — BCR-ABL1 >0.1–1% 42 60% .0023 44 83% .036 BCR-ABL1 >1%–10% 30 61% <.0001 32 90% .33 BCR-ABL1 >10% 57 53% <.0001 overall: 0.0001 74 78% .0076 overall: 0.029 12 mo BCR-ABL1 ≤0.1% 63 91% — 63 97% — BCR-ABL1 >0.1–1% 26 74% .011 27 85% .039 BCR-ABL1 >1%–10% 19 70% .0041 22 96% .18 BCR-ABL1 >10% 41 56% <.0001 overall: 0.0001 50 80% .0020 overall: 0.012 *Calculated across the entire post-landmark timespan and unadjusted for multiple comparisons.