tbuckley/cabot-search huggingface dataset:
Does increasing the daily tamoxifen dose in patients with diminished CYP2D6 activity increase toxicity?
Authors: Daniel Louis Hertz, Anna C. Snavely, James P Evans, Joseph G Ibrahim, Steven M. Anderson, Kenneth J Friedman, Karen E Weck, Peter Rubin, Oludamilola A. Olajide, Susan G. Moore, Rachel Elizabeth Raab, Daniel R. Carrizosa, Steven William Corso, Garry Schwartz, Jeffrey M. Peppercorn, Mark Graham, Sean Thomas Canale, Howard L. McLeod, Lisa A. Carey, William Johnson Irvin
Journal: Journal of Clinical Oncology (2014)

561 Background: Tamoxifen treated breast cancer patients with diminished CYP2D6 activity have lower endoxifen exposure, which may lead to inferior treatment outcomes. Increasing the daily tamoxifen dose from 20 mg to 40 mg increases endoxifen in CYP2D6 poor (PM) and intermediate (IM) metabolizing patients. We previously reported that endoxifen exposure of an IM pt receiving 40 mg is similar to that of an extensive or ultra-rapid metabolizer (EM/UM) receiving 20 mg, while a PM at 40 mg continues to have lower exposure. Here we investigated whether increasing the dose to 40 mg/day in CYP2D6 PM and IM increases treatment toxicity. Methods: Patients receiving 20 mg tamoxifen for ≥ 4 months who were not taking a strong CYP2D6 inhibitor were genotyped for CYP2D6 using the Amplichip CYP450 test (Roche Diagnostics, Indianapolis, IN). PM and IM were increased to 40 mg for 120 days while EM/UM remained on 20 mg. Toxicity data was collected on the ordinal FACT-B Endocrine Subscale (0: “not at all” to 4 “very much”) at enrollment and 120 days. The prevalence of patients reporting any toxicity ≥ 3 (“quite a bit”) and the rating (0-4) of specific toxicities were compared across CYP2D6 phenotypes. Results: Of the 484 evaluable patients, 29 were PM, 293 IM and 162 EM/UM. At enrollment (all receiving 20 mg) there was a non-significant trend toward greater prevalence of toxicity as CYP2D6 activity increased (PM=55.2%, IM=57.0%, EM/UM=62.4%, p=0.25) with a significantly higher rating of vaginal dryness (PM=0.76, IM=0.84, EM/UM=1.06, p=0.03) but not hot flashes (p=0.80). After 120 days of 40 mg treatment there was a significant increase in the prevalence of toxicity in IM (change from baseline= +7.4%, p<0.001), but not PM (change=-11.7%, p=0.71). There was no significant increase in the rating of any toxicity (p>0.05). Conclusions: Increasing the daily tamoxifen dose in CYP2D6 IM, but not PM, is associated with a corresponding increase in global toxicity that cannot be attributed to any single toxicity. Analysis as to whether this impacts patients’ QOL is ongoing. Given the absence of known impact on outcomes, increasing the tamoxifen dose should be discouraged in patients with diminished CYP2D6 activity. Clinical trial information: NCT00764322.
A randomized trial of a cardiopulmonary resuscitation (CPR) video (V) in advance care planning (ACP) for progressive hepatopancreaticobiliary cancer patients.
Authors: Andrew S. Epstein, Angelo E. Volandes, Kristen Gary, Ling Y. Chen, Yuelin Li, Pat Agre, Tomer Levin, Diane Lauren Reidy, Raymond D. Meng, Neil Howard Segal, Kenneth H. Yu, Yelena Yuriy Janjigian, Ghassan K. Abou-Alfa, David Paul Kelsen, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2012)

9105 Background: CPR is an important advance directive topic in patients with progressive cancer; however such discussions are challenging. Previous work by Volandes et al suggests that V images help, however whether V educational information about CPR engenders broader ACP discourse is unknown. Methods: A randomized trial of an educational V or narrative (N) in patients with progressive hepatopancreaticobiliary cancers was conducted. The V and N were 3 minutes long and contained an identical description of CPR. Primary endpoint: ACP documentation 1-month post-test (either a formal advance directive or a documented ACP discussion), 80% powered with 0.01 type-I error rate for estimated advance directive completion rates of 70% V arm vs. 25% N arm with a sample of 56 subjects. Secondary endpoints (exploratory): impressions of the study information; pre and post knowledge of and preferences for CPR and mechanical ventilation; and follow-up longitudinally (to death or 6 months post-test). Results: 56 subjects consented and analyzed. 1-month post-test ACP documentation was not significantly higher in the V arm (12/30, 40.0%) vs. the N arm (4/26, 15.4%); Fisher’s exact test, OR = 3.583 [95% CI: 0.886 – 17.937], p = 0.07. Knowledge increased in both arms after the intervention. Preferences for CPR changed in V arm but not in N arm; for mechanical ventilation, there was no change in either arm. The majority of subjects in both arms reported the information as helpful, comfortable to discuss, and recommended to others. Longitudinally, outcomes were similar between V &amp; N arms, respectively: % advance directives completed (63% &amp; 58%); median days from test to advance directive (60 &amp; 72) and advance directive to death (21 &amp; 20); median ACP documentation after 1 month (0 &amp; 1); median hospital admissions (1 &amp; 1), days of stay (5 &amp; 7), ICU stays (0 &amp; 3) and CPR/mechanical ventilation (1 &amp; 3). 52% of all subjects died by study end, the majority in hospice care. Conclusions: This first randomized trial addressing downstream ACP effects of V vs. N decision tools demonstrated a trend towards more ACP documentation in V patients. Further research into these types of educational media is needed.
Phase II trial of sunitinib as adjuvant therapy after stereotactic radiosurgery (SRS) in patients with 1-3 newly diagnosed brain metastases.
Authors: David M. Peereboom, Samuel T. Chao, John H. Suh, Ding Wang, Tom Mikkelsen, Cathy J. Brewer, Kathy N. Smolenski, Michael W. Parsons, Paul Elson, Lilyana Angelov, Gene H. Barnett, Michael A. Vogelbaum, Robert J. Weil
Journal: Journal of Clinical Oncology (2012)

2018 Background: For patients with 1-3 brain metastases, standard therapy after SRS is adjuvant whole brain radiotherapy (WBRT). SRS without WBRT carries a higher rate of brain relapse. Due to concerns about neurologic sequelae of WBRT, however, many patients and physicians opt to defer WBRT until the time of central nervous system (CNS) progression. This trial used sunitinib as an alternative to WBRT for post-SRS adjuvant therapy. Sunitinib inhibits vascular endothelial growth factor signaling, and we hypothesized that it would prevent growth of microscopic brain metastases presumed to be present. The objective was to use adjuvant sunitinib after SRS to prevent the emergence of new or progressive disease in the brain or at the site of SRS and to preserve neurocognitive function. Methods: Eligible patients had 1-3 newly diagnosed brain metastases, RTOG RPA class 1-2, and started sunitinib &lt; 1 month after SRS and baseline neuropsychological testing (NPT). Patients with controlled systemic disease were allowed to continue chemotherapy for their primary disease according to a list of published regimens (therapy + sunitinib) included in the protocol. Patients received sunitinib 37.5 or 50 mg/d days 1-28 every 42 days until CNS progression. NPT and MRIs were obtained every 2 cycles. The primary endpoint was the rate of CNS progression at 6 months (PFS 6 ) after SRS. Results: Fourteen patients enrolled. The median age was 59 (range 46-80). Main histologies: lung 36%, breast 21%, melanoma 14%. Toxicities: Grade 4: neutropenia [ANC] (1 pt); Grade 3: fatigue (5), ANC (2), rash (1). Dose reduction due to toxicity: 1 pt (to 37.5 mg/d). The CNS PFS 6 and PFS 12 were 50% + 13% and 43% + 13%, respectively. The median PFS was 6.6 months (95% C.I. 1.5-19). NPT results will be reported at the meeting. Conclusions: Sunitinib after SRS for 1-3 brain metastases was well tolerated with a PFS 6 of 50%. The use of novel agents to prevent progressive brain metastasis after SRS requires the incorporation of chemotherapy regimens to control the patient’s primary disease. Future trials should continue to explore the paradigm of secondary chemoprevention of brain metastases after definitive local therapy (surgery or SRS).
Usefulness of 68Ga-DOTA-RGD (αvβ3) PET/CT Imaging in Thyroglobulin Elevation With Negative Iodine Scintigraphy
Authors: Rakhee Vatsa, Jaya Shykla, Bhagwant Rai Mittal, Priya Bhusari, Apurva Sood, Rajender Kumar Basher, Anish Bhattacharya
Journal: Clinical Nuclear Medicine (2017)

TENIS (thyroglobulin elevation with negative iodine scintigraphy) syndrome in patients with differentiated thyroid carcinoma is not a rare finding. In such patients, F-FDG PET/CT can help in disease evaluation. RGD tripeptide, used for imaging angiogenesis, may also help in disease detection in patients with negative radioiodine whole-body scan. We present 1 such case in whom Ga-RGD tripeptide imaging was helpful in disease detection in the setting of negative radioiodine whole-body scan.
Effects of Patient Preferences on Outcomes in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) Study
Authors: Boadie W. Dunlop, Mary E. Kelley, Vivianne Aponte-Rivera, Tanja Mletzko-Crowe, Becky Kinkead, James C. Ritchie, Charles B. Nemeroff, W. Edward Craighead, Helen S. Mayberg
Journal: American Journal of Psychiatry (2017)

The Predictors of Remission in Depression to Individual and Combined Treatments [PReDICT] study aimed to identify clinical and biological factors predictive of treatment outcomes in major depressive disorder among treatment-naive adults. The authors evaluated the efficacy of cognitive-behavioral therapy (CBT) and two antidepressant medications (escitalopram and duloxetine) in patients with major depression and examined the moderating effect of patients' treatment preferences on outcomes.Adults aged 18-65 with treatment-naive major depression were randomly assigned with equal likelihood to 12 weeks of treatment with escitalopram (10-20 mg/day), duloxetine (30-60 mg/day), or CBT (16 50-minute sessions). Prior to randomization, patients indicated whether they preferred medication or CBT or had no preference. The primary outcome was change in the 17-item Hamilton Depression Rating Scale (HAM-D), administered by raters blinded to treatment.A total of 344 patients were randomly assigned, with a mean baseline HAM-D score of 19.8 (SD=3.8). The mean estimated overall decreases in HAM-D score did not significantly differ between treatments (CBT: 10.2, escitalopram: 11.1, duloxetine: 11.2). Last observation carried forward remission rates did not significantly differ between treatments (CBT: 41.9%, escitalopram: 46.7%, duloxetine: 54.7%). Patients matched to their preferred treatment were more likely to complete the trial but not more likely to achieve remission.Treatment guidelines that recommend either an evidence-based psychotherapy or antidepressant medication for nonpsychotic major depression can be extended to treatment-naive patients. Treatment preferences among patients without prior treatment exposure do not significantly moderate symptomatic outcomes.
A phase II, open-label, neoadjuvant, randomized study of LCL161 with paclitaxel in patients with triple-negative breast cancer (TNBC).
Authors: Marina Parton, Aditya Bardia, Sherko Kummel, Laura G Estevez, Chiun-Sheng Huang, Javier Cortes Castan, Manuel Ruiz Borrego, Melinda L. Telli, Ana Lluch, Rafael Lopez, J. Thaddeus Beck, Roohi Ismail-Khan, Shin-Cheh Chen, Sara A. Hurvitz, Ingrid A. Mayer, Rolando S. Atienza, Scott Cameron, Mizue Krygowski, Sung-Bae Kim
Journal: Journal of Clinical Oncology (2015)

1014 Background: LCL161 is a small molecule that induces apoptosis by inactivating inhibitor of apoptosis proteins (IAPs). LCL161 preferentially synergizes with paclitaxel in TNBC models with a defined gene expression signature (GS) that reflects the biology of IAP antagonists. Here we present preliminary safety and efficacy data from a completed Phase II study of neoadjuvant LCL161 with paclitaxel in patients with GS+ and GS– TNBC (NCT01617668). Methods: Women with operable, newly diagnosed TNBC (T2, N0–N2, M0) were stratified into GS+ and GS– groups upfront, then randomized to receive paclitaxel (80 mg/m2/week) ± LCL161 (1800 mg/week) for 12 weeks. Patients then received surgery to assess pathological complete response (pCR), followed by investigator’s choice of adjuvant therapy. Primary objective: To assess whether LCL161 enhances the efficacy of paclitaxel in patients with GS+ or GS– TNBC, defined by a ≥ 7.5% increase in pCR rate after 12 weeks of combination treatment vs paclitaxel alone. Results: All 209 treated patients completed the study; 17/106 patients (16.0%) in the combination arm and 17/103 patients (16.5%) in the control arm achieved pCR. In the GS+ group (30.1% of patients), 13/34 patients (38.2%) in the combination arm and 5/29 patients (17.2%) in the control arm achieved pCR; the posterior probability of a ≥7.5% increase in pCR rate was 88.8%. In the GS– group, 4/72 patients (5.6%) in the combination arm and 12/73 patients (16.4%) in the control arm achieved pCR. The most frequent adverse events (AEs; ≥ 30% of patients, all grades) are shown in the table below. Serious AEs of pyrexia (combination 17.9%; control 1.0%), pneumonia (10.4%; 1.9%), and pneumonitis (9.4%; 0%) were significantly increased in the combination arm. Conclusions: Neoadjuvant LCL161 with paclitaxel shows promising signs of efficacy in a GS+ subset of TNBC (~30% of patients), but with notable toxicity at the 1800 mg/week dose. Clinical trial information: NCT01617668. LCL161 + paclitaxel (N = 106), % Paclitaxel (N = 103), % All grades G3/4 All grades G3/4 Diarrhea 71.7 5.7 22.3 1.0 Alopecia 67.9 – 67.0 1.0 Pyrexia 48.1 4.7 9.7 – Fatigue 45.3 3.8 36.9 – Nausea 42.5 0.9 31.1 – Rash 41.5 3.8 27.2 – Neutropenia 39.6 23.6 10.7 3.9 Headache 33.0 0.9 17.5 –
Evaluation of class III beta-tubulin (bTubIII) expression as a prognostic marker in patients with resectable non-small cell lung cancer (NSCLC) treated by perioperative chemotherapy (CT) in the phase III trial IFCT-0002
Authors: G. Zalcman, G. Levallet, E. Bergot, M. Antoine, C. Creveuil, E. Brambilla, C. Dumontet, F. Morin, A. Depierre, B. Milleron
Journal: Journal of Clinical Oncology (2009)

7526 Background: IFCT-0002 phase III trial compared two timings of CT in early lung cancer, all before surgery (PRE) versus PERIoperative, and two CT regimens, CDDP-Gem vs. CBDCA-Pac. 528 patients were randomized. Paraffin embedded post- chemo pathological specimens were collected in the 490 non complete responder patients for tissue expression of the putative biomarker beta-tubulin III (bTubIII). Methods: 423 surgical pathological specimens with enough remaining viable tumor tissue after neoadjuvant chemo were processed for immunohistochemistry as published in the Bio-IALT study. A semi-quantitative score was attributed taking account the number of stained cells and the intensity of staining. Semi-quantitative scores were studied as continuous variables, without any pre- determined cut-off. Multivariate analysis for progression-free (PFS) and overall survival (OS) were corrected with Bonferroni-Holm method for multiple analyses. Median follow-up was 42 months. Results: bTubIII was the only IHC marker significantly associated with poor PFS in univariate (p=0.014) or multivariate analysis, adjusted for histology, T and stage (HR= 1.50 [1.07–2.10]; p=0.020). In patients with a pathological specimen showing a bTubIII positive immunostaining, median PFS was 30.6 months, versus 60.1 months (HR=1.46 [1.08–1.99]) for bTubIII negative patients. bTubIII IHC score remained predictive of poor OS in univariate (p= 0.0065) as in multivariate analysis (p=0.019 with Bonferroni correction, HR=1.75 [1.15–2.68] ). Median OS was not reached for bTubIII negative patients whereas it was 71.7 months in patients with bTubIII immunostaining of any intensity score (HR=1.61, [1.11–2.35]). Conclusions: This study showed a dramatic negative prognostic impact for bTubIII immunostaining in resectable early lung cancer. A subset of bTubIII expressing patients with poor prognosis did not take any advantage from perioperative chemo. Hence, those patients could rather have beneficiated from personalized adjuvant treatment with alternative approaches. No significant financial relationships to disclose.
A retrospective single institution review of 90 pancreatic adenosquamous cancer (PASC) patients (pts).
Authors: Jennifer Brooke Goldstein, Graciela M. Nogueras-Gonzalez, Milind M. Javle, Matthew H. G. Katz, Gauri R. Varadhachary, David R. Fogelman, Michael J. Overman, Robert A. Wolff, Rachna T. Shroff
Journal: Journal of Clinical Oncology (2015)

4125 Background: PASC is a rare and aggressive subset of pancreatic cancer. PASCs are more likely to have poorly differentiated histology and positive lymph nodes. No separate treatment guidelines exist for PASC, however platinum-based therapy (tx) is commonly used based on a few published case series. The molecular signature of PASC has been reported in small studies and mirrors that of pancreatic adenocarcinoma (PA), with genetic mutations commonly involving TP53, CDKN2A, KRAS and loss of SMAD4 and the recently reported UPF1. These genomic analyses have been limited to genes known to be important in PA. Methods: We retrospectively reviewed the medical records of pts with PASC that were seen at M.D. Anderson Cancer Center from 1990 to 2014. Pts were chosen based on a pathologic diagnosis of PASC either in the primary tumor or metastasis. Descriptive statistics and survival analysis were performed using Stata 13.1. Results: A total of 90 pts were identified as having PASC, 75 diagnosed from the primary tumor and 15 from a metastatic site. Median age was 65 years (40-86), 62% were male, and 67% had locally advanced or metastatic disease at presentation. The median overall survival (OS) was 8.8 mths [95%CI (6.8-10.3)]. Of 29 pts who underwent surgical resection, the median time to recurrence was 6.7 mths [95%CI (3.4-Not Estimable)]. First line platinum-based tx did not impact OS (HR 1.07, 95% CI 0.66-1.75, P=0.785). 6 pts had genomic testing performed. All 6 had mutations in codon 12 of KRAS (three G12D, two G12R, and one G12V), 4 had mutations in TP53, all at different loci. One pt had CDKN2A loss, while another had a point mutation in the gene. Additionally, 2 of 6 pts showed FGF 3 and 19 amplification. Conclusions: Our results demonstrate that PASC has a poor prognosis. Pts undergoing surgical resection are at a high risk for relapse and neoadjuvant tx may be utilized to stratify pts who would benefit from resection. Next generation sequencing of tumors show the classically described KRAS and TP53 mutations seen in PA, but a potentially novel amplification of FGF 3 and 19, which could play a role in tumorigenesis. Further molecular profiling may demonstrate potential targets for tx not traditionally seen in PA.
Cellular immunotherapy as maintenance therapy and overall survival in patients with small cell lung cancer in extensive stage.
Authors: Jiuwei Cui, Xiao Ding, Guanjun Wang, Haofan Jin, He Cao, Dan Li, Xiao Chen, Ziling Liu, Hua He, Wei Li
Journal: Journal of Clinical Oncology (2014)

e14007 Background: Small cell lung cancer (SCLC) is the most devastating type of human lung cancer. These patients usually present with disseminated disease to many organs (extensive stage). Their initial response to therapy is rapidly followed by a relapse with drug resistance. Patients with SCLC are found to have functional deficiency in a variety of immunocytes. Thus, cellular immunotherapy (CIT) would improve the immune state to afford a potential value in enhancing the therapeutic outcome for SCLC patients. In this study, we investigated the efficiency and safety of application of NK cells, γδT cells and cytokine-induced killer (CIK) cells, to the patients with SCLC as maintenance therapy, to overcome the multiple limitations in immune responses in the patients. Methods: Thirty- eight patients with SCLC in extensive stage who got response after six cycles of chemotherapy (EP regimen: cisplatin and etoposide), were divided into two groups: control group (19 patients) and study group (receiving cellular immunotherapy, 19 patients). Autologous mononucler cells were collected from the peripheral blood by apheresis, and then induced into NK cells, γδT cells and CIK cells. These cells were infused intravenously to study group patients for 3 to 6 courses. The tumor status of the patients was evaluated with CT every two month after recruitment. Progression-free survival (PFS), overall survival (OS), and adverse effects were examined. This study was approved by the Ethical Committee of the First Hospital of Jilin University. Results: The characteristics of the patients in the two groups were well balanced. Application of CIT after chemotherapy significantly improved the PFS in the study group, as compared with control group (8 vs 5.7 months, p=0.049). OS in the study group was superior to the control group (17.5 vs 12 months, p=0.045). No significant adverse reaction was found in the patients with CIT. Conclusions: These preliminary results suggest that cellular immunotherapy as maintenance therapy prolongs survival in patients with SCLC in extensive stage was efficient and safe. It would provide a novel strategy for the treatment of SCLC, although further studies were needed.
Potential risk of asbestos exposure among Japanese general population: Japanese general screening study for asbestos-related diseases (JGSARD).
Authors: Nobuhiko Seki, Takuhiro Yamaguchi, Kenji Eguchi, Masahiro Kaneko, Masahiko Kusumoto
Journal: Journal of Clinical Oncology (2012)

1530 Background: The number of patients with pleural mesothelioma and lung cancer associated with asbestos exposure has recently been increasing in Japan. The aim of this study was to evaluate the results of screening for asbestos-related diseases in a group of Japanese general population. Methods: This prospective study was approved by the institutional review board. From 2006 to 2008, 9810 subjects (5283 men and 4527 women; mean age, 57 years) underwent chest radiography and low-dose CT examinations in 26 institutions in Japan. Among them, 6286 (64.1%) subjects underwent subsequent CT examinations after 2 years of interval. Clinical information such as histories of smoking and asbestos exposure was reviewed. Images were interpreted independently by 15 experienced pulmonologists or chest radiologists. Results: The history of asbestos exposure was definitely present in 1253 (12.8%) subjects, possibly present in 2058 (21.0%), and absent in 6499 (66.2%). On chest radiograph, pleural plaque and thickening were seen in 61 (0.6%) and 65 (0.6%) subjects, respectively. On low-dose CT, pleural plaque and thickening were identified in 264 (2.7%) and 245 (2.5%) subjects, respectively, and non-calcified pulmonary nodule/mass was seen in 1003 (10.2%). Furthermore, lung cancer was identified in 29 (0.3%) subjects. The history of asbestos exposure was not confirmed in 77 out of 264 subjects (29.2%) having pleural plaques on low-dose CT. Based on the logistic regression analysis, pleural plaque on low-dose CT was significantly correlated with male, age more than 60 years, smoking, and a history of asbestos exposure. Especially, total residential period in asbestos factory area as well as asbestos exposure work period showed significantly increased relative risk every 10 years. Similarly, lung cancer was significantly correlated with age more than 60 years, a history of asbestos exposure, and presence of pleural plaques. Conclusions: Our results indicate the presence of pleural plaques on low-dose CT among Japanese general population is closely associated with potential risk of asbestos exposure. However, about 30% of such subjects are not aware of a history of asbestos exposure.