tbuckley/cabot-search huggingface dataset:
Adjuvant radiotherapy (RT) and trastuzumab in stage I-IIA breast cancer: Toxicity data from North Central Cancer Treatment Group Phase III trial N9831
Authors: M. Y. Halyard, T. M. Pisansky, L. J. Solin, L. B. Marks, L. J. Pierce, A. Dueck, E. A. Perez
Journal: Journal of Clinical Oncology (2006)

523 Background: Adjuvant trastuzumab (Herceptin [H]) with chemotherapy improves outcome in HER2+ breast cancer (BC). Preclinical studies suggest H may enhance RT. We herein assess if H given with adjuvant RT increases adverse events (AE) after breast conserving surgery or mastectomy. Methods: N9831 randomized 3505 women with pT1–3N1–2M0, pT2–3N0M0, or pT1cN0M0 (ER/PR negative) HER2+ BC to doxorubicin (A) and cyclophosphamide (C) followed by weekly paclitaxel (T), AC→T→H, or AC→TH→H. Post-lumpectomy breast ± nodal RT was recommended, as was post-mastectomy chest wall + nodal RT (&gt;3 nodes +); internal mammary RT was prohibited. RT started within 5 weeks of completion of T and allowed concurrently with H. 2324 eligible patients were enrolled on study prior to April 25, 2004: 1460 patients receiving RT are available for analysis of RT-associated AEs. Also, 1286 patients on +H arms who completed T (908 +RT and 378 -RT) are available for analysis of clinical cardiac events (CE). Rates of RT-associated AEs were compared across treatment arms, and rates of CE were compared for +RT vs -RT patients within +H arms. All reported p-values are for chi-squared statistics. Results: With a median follow-up of 1.5 years, significant differences among arms in RT-associated AEs were not identified. No significant differences across arms in +RT patients existed in the incidence of skin reaction (p=0.78), pneumonitis (p=0.78), dyspnea (p=0.87), cough (p=0.54), esophageal dysphagia (p=0.26), or neutropenia (p=0.16). There was a significant difference in +RT patients in the incidence of leukopenia (p=0.02) with higher incidence rates in the arms receiving H. RT did not increase the frequency of CE. In the AC→T→H arm, the incidence of CE was 2.2% in +RT patients versus 2.9% in -RT patients. In the AC→TH→H arm, the incidence of CE was 1.5% in +RT patients versus 6.3% in -RT patients. No difference in CE was seen between left- and right-sided RT fields in +RT patients in either +H arm. Conclusion: Concurrent administration of adjuvant RT with H in early stage breast cancer patients is not associated with an increased incidence of acute RT AEs. Further follow-up is required to assess late AEs. No significant financial relationships to disclose.
Clinical translation pathway for identifying patient-specific drugs based on predictive simulation outcomes with ex vivo validation.
Authors: Nicole Adell Doudican, Shireen Vali, Annette Meredith, Anay Talawdekar, Ansu Kumar, Neeraj Singh, Anuj Tyagi, Shweta Kapoor, Zeba Sultana, Taher Abbasi, Amitabha Mazumder
Journal: Journal of Clinical Oncology (2014)

e19582 Background: The unique signature of a patient’s tumor implies that a one-size-fits-all treatment approach is suboptimal, thereby underscoring the need to rationally design therapies employing N=1 segmentation. Reuse of drugs with clinical data allows rapid translational advancement. To identify agents effective in a specific patient, we (1) employed predictive modeling using patient genomic profiling to create a simulation avatar, (2) simulated four molecularly targeted drugs with clinical data and (3) validated predictions ex-vivo in patient-derived cell lines. Methods: Clinical patient samples were analyzed for chromosomal alterations using whole genome array Comparative Genomic Hybridization (aCGH) by GenPath Diagnostics. This data were used to create a simulation avatar using Cellworks validated predictive technology, a comprehensive representation of plasma cell myeloma (PCM) physiology incorporating signaling and metabolic networks. We simulated AZD2014 (mTOR), vismodegib (Hedgehog), dasatinib (SRC) and perifosine (AKT). Simulation predictions were prospectively validated ex vivo in patient primary cells. Results: Array CGH analysis identified gains of genetic material in chromosome 1q (CKS1B) and losses in chromosomes 1p (FAF1, CDKN2C), 12p (CDKN1B) and 17p (TP53). Patient simulation predicted upregulation of the Hedgehog pathway due to 7q amplification (SMO and SHH genes) and chromosome 9 deletion (CDKN2A, CDKN2B and PTCH1). The cell cycle was upregulated due to copy number loss of cell cycle inhibitor genes and amplification of Cyclin D1 (chromosome 11q gain). The patient network indicated mTOR pathway upregulation correlating with loss of copy number of TSC1, a tumor suppressor that inhibits mTOR activation. The simulation avatar studies predicted response to vismodegib and AZD2014 and resistance to dasatinib and perifosine. Treatment of patient cells with 5µM vismodegib, AZD2014, dasatinib or perifosine alone resulted in 48%, 33%, 22% and 19% reduction in cellular proliferation, respectively. Conclusions: This study demonstrates simulation based individualization of treatment extending beyond linking point mutations to treatments.
Zika Virus Infection and Associated Neurologic Disorders in Brazil
Authors: Wanderson K de Oliveira, Eduardo H Carmo, Claudio M Henriques, Giovanini Coelho, Enrique Vazquez, Juan Cortez-Escalante, Joaquin Molina, Sylvain Aldighieri, Marcos A Espinal, Christopher Dye
Journal: New England Journal of Medicine (2017)

To the Editor: The first cases of a new illness involving fever and rash that was deemed to have been caused by Zika virus (ZIKV) infection in Brazil were reported in 2014, and the presence of the virus was confirmed in April 2015.In October 2015, an unusual increase in the number of cases of microcephaly among newborn infants was reported in Brazil; this disorder was apparently linked to ZIKV infection.From the first investigations of microcephaly, and from subsequent studies in Brazil and elsewhere, it is now clear that ZIKV is a cause of a range of neurologic disorders, including the Guillain-Barré syndrome (GBS) in adults and abnormalities in fetuses and newborn infants, including microcephaly. 1 Here, we use routinely collected surveillance data and medical records to show how the spread of ZIKV in Brazil was associated with an increase in the incidence of GBS and microcephaly during 2015 and 2016.We also highlight the limitations of routinely collected data, which cannot yet explain, for example, why there were many fewer cases of microcephaly than expected in 2016.To explore the temporal and geographic distribution of ZIKV infection, we used data provided by municipalities and states in each of the five regions of Brazil, as compiled by the Ministry of Health.These data describe the number of suspected and confirmed cases of ZIKV infection and of cases reported as GBS and microcephaly (Sections 1 and 2 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).The number of suspected cases of ZIKV infection began to increase in the northeast region of Brazil starting in March 2015 (week 9) (Fig. 1A).Cases were subsequently reported in the other four regions, beginning in late 2015 and greatly expanding in 2016.Together with phylogenetic analysis of viral RNA sequences, 2 these findings suggest that ZIKV was dispersed widely after a single introduction of infection in the northeast region.The spread of ZIKV in Brazil has been associated with an increase in the incidence of neurologic disorders, most visibly in cases reported as GBS and microcephaly.Weekly reports of cases from hospitals reveal that the incidence of GBS was markedly higher in the northeast region in 2015 and 2016 and in other areas of Brazil in
ESTUDIO RETROSPECTIVO SOBRE LA EFICACIA Y SEGURIDAD DE LA CPRE EN LA POBLACIÓN ANCIANA
Authors: D Bonillo Cambrodón, A Granja Navacerrada, M Hernandez Tejero, P Bernal Checa, P Valer Lopez, A Bermejo Abati, A Algaba, A Carneros José, F García Durán, F Bermejo San Jose
Journal: Endoscopy (2015)

El envejecimiento de la sociedad Española, ha provocado un crecimiento en el peso de la población anciana. Por ello la OMS ha subcategorizado a las personas ancianas en: Tercera edad (3 °edad) 60 – 74años, Cuarta edad (4 °edad) 75 – 89años y Longevos (LOG) (90 – 99años). Surge la necesidad de evaluar la eficacia de la terapeutica actual, en esta población.
Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial
Authors: Toshiaki Takahashi, Takeharu Yamanaka, Takashi Seto, Hideyuki Harada, Hiroshi Nokihara, Hideo Saka, Makoto Nishio, Hiroyasu Kaneda, Koichi Takayama, Osamu Ishimoto, Koji Takeda, Hiroshige Yoshioka, Motoko Tachihara, Hiroshi Sakai, Koichi Goto, Nobuyuki Yamamoto
Journal: The Lancet Oncology (2017)
Estimated Perinatal HIV Infection Among Infants Born in the United States, 2002-2013
Authors: Allan W. Taylor, Steven R. Nesheim, Xinjian Zhang, Ruiguang Song, Lauren F. FitzHarris, Margaret A. Lampe, Paul J. Weidle, Patricia Sweeney
Journal: JAMA Pediatrics (2017)

Perinatal transmission of human immunodeficiency virus (HIV) can be reduced through services including antiretroviral treatment and prophylaxis. Data on the national incidence of perinatal HIV transmission and missed prevention opportunities are needed to monitor progress toward elimination of mother-to-child HIV transmission.
Cutaneous septic emboli from <i>Candida glabrata</i> in a haematological patient
Authors: Andrea Lombardi, Giorgio Alberto Croci, Valeria Brazzelli, Marco Vecchia, Valentina Zuccaro, Marco Sciarra, Raffaele Bruno
Journal: American Journal of Hematology (2017)

A 62-year-old-man, with an EBV-associated extranodal NK/T-cell lymphoma, stage IV-B, nasal type, was admitted to our unit for persistent fever. He had received one cycle of CHOP chemotherapy before undergoing SMILE combination chemotherapy. At admission to our ward, blood cultures resulted positive after 52 h for Candida glabrata, susceptible to azoles, echinocandins, and polyenes; the time to positivity (TPP) of blood cultures is in accord with what is presented by Kim et al., who showed a median TPP for C. glabrata of 50 h.1 Antimycotic therapy with anidulafungin was started, in accordance with the 2016 IDSA (Infectious Diseases Society of America) guidelines.2 In the following days, the patient's condition improved, with the disappearance of fever, reduction of inflammation markers, and persistently negative procalcitonin levels. Fundus oculi examination revealed the presence of several white spots compatible with Candida emboli. On day 6 of therapy, the patient developed a papulo-nodular lesion with a superimposed vesicle, associated with a linear swelling and light hard erythema, along the lateral surface of the left arm (Figure 1A). A culture of the liquid collected from the vesicle showed the presence of C. glabrata at high load. (A) Papulo-nodular lesion with a superimposed vesicle, associated with a linear swelling and light hard erythema, along the lateral surface of the left arm. (B) Pseudoepitheliomatous hyperplasia with erosion and an underlying dermo-hypodermic, diffuse inflammatory infiltrate comprising granuloctyes, small lymphocytes, plasma cells and histiocytes, with small foci of necrosis (HE 10×; C, PAS-diastase 40×). (C) Histiocytes with their cytoplasm engulfed with PAS-positive fungal spores (3-5 µm of diameter) (inset, PAS-diastase 100×). Histopathology of a punch biopsy showed features of superficial and deep dermatitis, with the presence of histiocytes engulfed with PAS (Periodic-acid Schiff stain) positive fungal spores (3-5 µm of diameter). No features of lymphoma localization were documented and the picture was consistent with skin involvement by systemic mycosis (Figure 1B,C). Patients with hematologic malignancies are at high risk of developing invasive fungal infections caused by yeast, and Candida species represent the most common pathogens among them.3 C. glabrata appears to be the Candida species associated with the highest mortality rate in these patients.4 Clinicians should be aware of that in patients with hematological malignancies as C. glabrata can be responsible for systemic disease and might be associated with embolic cutaneous involvement. These emboli are detectable with an accurate skin examination and fundus oculi study; skin lesion cultures and histopathology studies can represent an integration to blood cultures in the identification of systemic mycotic infection. None related to the content of this article.
Pathologic complete response to cisplatin with dose-dense paclitaxel as neoadjuvant chemotherapy for locally advanced cervical cancer: Preliminary results of a multicenter phase II study with additional mutation analysis of adeno/adenosquamous carcinoma.
Authors: Maki Tanioka, Satoshi Yamaguchi, Shinya Sato, Shoji Nagao, Kazuhiro Takehara, Masato Nishimura, Tamotsu Sudo, Satoshi Morita, Hironobu Minami, Shunichi Negoro, Muneaki Shimada, Junzo Kigawa, Kiyoshi Fujiwara
Journal: Journal of Clinical Oncology (2013)

5528 Background: We report efficacy and safety of neoadjuvant cisplatin plus dose-dense paclitaxel (ddTP) within a phase II trial (UMIN-CTR ID: UMIN000006440), designed to investigate recurrence-free survival of neoadjuvant ddTP plus radical hysterectomy followed by adjuvant ddTP without radiotherapy for patients (pts) with stage IB2, IIA2, and IIB cervical cancer, whose driver mutations have been poorly understood. Methods: All enrolled pts received 3 cycles of cisplatin 75 mg/mq on day1 with paclitaxel 80 mg/mq on days 1, 8, and 15 every 21 days. Pathologic complete response (pCR) was defined as no evidence of malignancy in all surgical specimens observed. Using a selected panel of 535 oncogenes (Otogenetics, Norcross, GA), mutations of pretreatment biopsy tissues were analyzed in 6 non-pCR pts with adeno/adenosquamous carcinoma (AC/ASC). Results: Among 51 enrolled pts, 50 were evaluable (40 with squamous cell carcinoma [SCC], 9 with AC/ASC, and 1 with small cell carcinoma). Median age was 52 years (range 30-70), the FIGO stage was IB2 in 14 pts, IIA2 in 3, and IIB in 34. Eighteen pts achieved complete response and 29 pts achieved partial response, with response rate of 94% (47/50). A total of 14 pts (28%; 13 with SCC, 1 with AC) achieved pCR. Grade 3/4 adverse events were neutropenia (34%), nausea (12%), appetite loss (10%), fatigue (6%), and anemia (6%). Febrile neutropenia was uncommon (2%). The analysis of oncogenes revealed that all 6 pts had mutations in the mixed-lineage leukemia (MLL3) gene, a histone methyltransferase, whose mutations have recently been reported in breast, pancreas, and colorectal cancers. Specifically, in MLL3 gene, identical frameshift mutation was found in 2 pts and 2 common non-synonymous point mutations were found in 4 pts, despite no relevance to the ddTP response. No mutations were detected in TP53 and PIK3CA genes. Conclusions: The pCR rate with neoadjuvant ddTP for locally advanced cervical cancer was one of the highest reported in a prospective trial setting. Novel mutations of the MLL3 gene were identified in non-pCR pts with AC/ASC. Clinical trial information: UMIN000006440.
Frequency of clinically relevant genomic alterations using comprehensive genomic profiling (CGP) for the management of advanced gynecologic malignancies in a community setting.
Authors: Luis Rojas, Casey B. Williams, Siraj Mahamed Ali, Kirstin Anne Williams, David Starks, Mark Bailey, Jie He, Julia Andrea Elvin, Norma Alonzo Palma, Nandini Dey, Pradip De, Philip J. Stephens, Vincent A. Miller, Jeffrey S. Ross, Brian Leyland-Jones
Journal: Journal of Clinical Oncology (2015)

e22068 Background: The management challenges of advanced gynecologic malignant neoplasms are often intensified in a community setting. We utilized comprehensive genomic profiling (CGP) of advanced gynecologic malignancies to identify routes of possible benefit from targeted therapy. Methods: DNA was extracted from 40 microns of FFPE sections of advanced gynecologic malignancies. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of > 500x for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. All classes of genomic alterations (GA) were evaluated, and clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The 30 female patients had a median age of 62 years (range 32-88). There were 16 (56%) ovarian carcinoma, 9 (30%) endometrial carcinoma, and 1 (3.3%) case each of uterine sarcoma, uterine carcinosarcoma, leiomyosarcoma, vaginal melanoma, and peritoneal carcinoma. CGP revealed 80.00% (24/30) of cases harbored at least 1 CRGA, for an average of 1.83 CRGA per case, and 100% of cases harbored at least one GA, for a total of 137 GA, for an average of 4.56 GA/case. The most frequently detected GA was in TP53 (52%), and the most common CRGA were in PTEN 36% (11/30), PIK3R1 28% (9/30), CDKN2A 12% (4/30), KRAS 12% (4/30) and PIK3CA 12% (4/30), respectively. There were 8 evaluable ovarian carcinoma patients that received therapy based on assay results, and 3/8 cases had complete responses and another 4/8 had partial responses with median duration of response of 31 weeks (range 2-43 weeks) and ongoing. The remaining evaluable patient had PD as a result of noncompliance. Conclusions: In this group of patients with advanced gynecologic malignancies, CGP uncovered a high frequency of CRGA that lead to preliminary successes in multiple ovarian carcinoma patients. Further application of CGP in gynecologic cancers as a route to precision treatment for these patients appears warranted.
A phase II study of muscadine grape skin extract in men with biochemically recurrent prostate cancer.
Authors: Channing Judith Paller, Elisabeth I. Heath, Mary-Ellen Taplin, Mark N. Stein, Glenn J. Bubley, Roberto Pili, Tina M. Mayer, Xian Chong Zhou, Tamaro Hudson, Muneer Abbas, Nicole Anders, Donna Dowling, Serina KIng, Charles G. Drake, Emmanuel S. Antonarakis, Mario A. Eisenberger, Samuel R. Denmeade, Michelle A. Rudek, Gary L. Rosner, Michael Anthony Carducci
Journal: Journal of Clinical Oncology (2017)

248 Background: Pulverized muscadine grape ( Vitis rotundifolia) skin (MPX) is a potential therapeutic option for men with biochemically recurrent (BCR) prostate cancer (PCa) wishing to defer androgen deprivation therapy. MPX demonstrated antitumor effects in PCa through antioxidant activity of its principal polyphenol components, ellagic acid, quercetin, and resveratrol. A Phase I trial demonstrated safety of MPX in doses up to 4000 mg/day. Methods: This is a 12-month, multi-center, placebo-controlled, two-dose, double-blinded trial of MPX (manufactured by Muscadine Naturals Inc. in Warsaw, NC) in 125 men with BCR PCa. Participants were stratified by baseline PSADT and Gleason score, with no restrictions for PSADT and no upper limit PSA value. Patients were randomly assigned 2:2:1 to receive 4000 mg (8 capsules) of MPX, 500 mg (1 capsule) of MPX plus 7 capsules of placebo, or 8 capsules of placebo. PSA levels were obtained every 3 months The trial was powered to detect a statistically significant between-group difference of around 6 months (low dose) and 12 months (high dose) in PSADT relative to placebo. Results: The intention to treat (ITT) population included 116 patients, of which 97% were treated for up to 6 and 58% were treated for up to 12 months. This ITT population was 79% white, with median age 68 years, 47% with Gleason score ≤ 6 or 3+4, and 12% with ECOG status of 1. Median PSADT in the ITT population lengthened from 7.5 months at baseline (range 1.4 to 74.6) to 9.8 months after treatment (range 2.3 to 151.5) (p &lt; 0.001). There was no significant treatment difference in PSADT between the control and the treatment groups (p = 0.84). Eighteen percent (21/116) of men had a post-baseline PSADT of more than 200% of baseline. No clinically significant toxicities were seen. Conclusions: These data suggest that both 500 and 4000 mg of MPX are safe. The lengthening PSADT in patients treated with MPX is not significantly greater than that provided by placebo. A subgroup analysis of patients more likely to benefit (those with the AA genotype of MnSOD) is ongoing. Clinical trial information: NCT01317199.
Safety and immunologic correlates of allogeneic melanoma GVAX (MelGVAX), a genetically engineered whole-cell melanoma vaccine.
Authors: Evan J. Lipson, William Howard Sharfman, Shuming Chen, Tracee L. McMiller, Theresa Salay Pritchard, January T. Salas, Susan Sartorius-Mergenthaler, Sowmya Ravi, Hao Wang, Janis M. Taube, Drew M. Pardoll, Suzanne Louise Topalian
Journal: Journal of Clinical Oncology (2014)

e20001 Background: Cytokine-transduced whole tumor cell vaccines have the potential to induce or enhance antitumor immunity. This first-in-human study investigated the safety, tolerability and immunologic correlates of MelGVAX, a lethally irradiated granulocyte-macrophage colony stimulating factor (GM-CSF)-secreting allogeneic whole-cell melanoma vaccine, administered in the adjuvant setting with or without low-dose cyclophosphamide (CPM) to pts with resected stage IIB-IV melanoma. Methods: MelGVAX was administered intradermally every 28 days for 4 doses, at 5E7 cells/dose (n=3), 2E8 cells/dose (n=9), or 2E8 cells/dose plus 200 mg/m2 of CPM one day prior to each vaccine (n=8). Blood was collected before each vaccination and at 4 and 6 months after treatment initiation. Vaccine injection site biopsies and additional blood samples were obtained 2 days after the 1st and 4th vaccines. Results: Among 20 treated pts, 18 completed 4 vaccinations. Systemic vaccine-related adverse events included fatigue, chills and joint pain (grade 1) and rash (grade 2). One patient developed vitiligo. Localized vaccine site reactions included grade 1 erythema, induration, tenderness, swelling and pruritus. Vaccine site biopsies demonstrated complex inflammatory infiltrates. Serum GM-CSF increased significantly in a dose-dependent manner 48 hrs after vaccination (P=0.0086), accompanied by increased numbers and activation (HLA-DR expression) of circulating monocytes (P<0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+, CD11b+, HLA-DR low or negative; P=0.002). No difference in numbers of circulating T regulatory cells was observed in the vaccine+CPM cohort versus vaccine alone. No significant changes in anti-melanoma immunity were observed in peripheral T cells (ELIPSOT) or immunoglobulins (serum Western blotting). Conclusions: MelGVAX demonstrated safety and tolerability in the adjuvant setting. Pharmacodynamic testing revealed a favorable profile of circulating monocytic cell subsets. These findings support further optimization of MelGVAX and potential development of combinatorial regimens with synergistic agents. Clinical trial information: NCT01435499.