tbuckley/cabot-search huggingface dataset:
A pilot chemoprevention study of isopropanolic black cohosh extract in women with ductal carcinoma in situ.
Authors: Erin Wysong Hofstatter, Karen Stavris, Nina Ruth Horowitz, Brigid K. Killelea, Theodore Tsangaris, Donald R. Lannin, Liva Andrejeva, Xiangyu Cong, Xiaopan Yao, David Rimm, Anees B. Chagpar
Journal: Journal of Clinical Oncology (2013)

TPS1609 Background: Recent evidence suggests that black cohosh (Cimicifuga racemosa) may be a potential agent for breast cancer prevention. The active ingredients in black cohosh preparations appear to be triterpene glycosides. Recent preclinical data suggest several mechanisms by which triterpenes may prevent and treat breast cancer, including anti-proliferative, pro-apoptotic, anti-estrogenic, and anti-inflammatory effects. Epidemiologic data demonstrate a significant protective effect of black cohosh against the development of breast cancer in healthy women, and prolonged disease-free survival in breast cancer patients. There is also abundant evidence demonstrating the safety and tolerability of black cohosh in several clinical trials studying its use for treatment of hot flashes. We hypothesize that efficacy of black cohosh can be demonstrated in a pilot pre-operative window trial in a cohort of women with ductal carcinoma in situ (DCIS). Methods: In this trial, we treat women with a 2-5 week pre-operative course of commercial standardized isopropanolic black cohosh extract (20 mg orally twice per day). We aim to demonstrate a reduction in breast epithelial cell proliferation as measured by Ki-67 staining in regions of DCIS using traditional IHC staining and AQUA analysis. We also assess safety and tolerability of black cohosh through monitoring of patient adherence, liver function tests and serum hormone levels. 22 patients will be enrolled onto the trial. Sample size is based on power calculations for the specific study aim of determining the mean change in the levels of Ki67, using a targeted effect size. Assuming a 10% drop-out rate, a sample size of 20 patients will achieve 91% power to detect a 0.8 standard deviation of difference with a two-sided significance level at 0.05 using Wilcoxon signed-rank test. Eligible subjects are pre- and post-menopausal women ≥ 18 years of age newly diagnosed with DCIS histologically confirmed on breast core biopsy, prior to definitive excision. Women who have recently taken any agent known to affect Ki67 levels in the breast (e.g. hormone therapy) are excluded. Enrollment is currently ongoing with 10 of 22 patients accrued. Clinical trial registry number NCT01628536. Clinical trial information: NCT01628536.
Impact of the rounding-off function of the computerized physician order entry system on dose variations of chemotherapeutic drugs.
Authors: Kenji Tsuda, Yuko Nishide Kimura, Yuji Takaba, Kensuke Okubo, Tomotaka Ishii, Tatsuo Itokawa, Takahiro Isshiki, Naoko Takei, Tetsuya Tanimoto, Masahiko Nakagawa, Tsunehiko Komatsu
Journal: Journal of Clinical Oncology (2014)

e17600 Background: EGMAIN-GX (Fujitsu Ltd., Tokyo, Japan) is a popular computerized physician order entry (CPOE) system in Japan. Version 2 was used since 2009, but the newly introduced version 4 has been used since 2012. Notable among the new features is the automatic rounding-off of the calculated dose of anticancer drugs to the nearest whole number. We conducted a study to examine the effect of the rounding-off function on dose variations with CPOE version 4 compared to version 2. Methods: Twelve physicians ordered 5 predefined chemotherapeutic regimens for a hypothetical patient: idarubicin and cytarabine; fludarabine and busulfan; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; cyclophosphamide, doxorubicin, vincristine, and dexamethasone; and rituximab, etoposide, cytarabine, cisplatin, and methylprednisolone. Data were entered twice for each regimen, using versions 2 and 4, and 1392 drugs were prescribed. We calculated the ratio of actual to ideal doses of chemotherapeutic drugs and compared the median ratios and standard deviations (SD) of the 2 groups using the Wilcoxon signed rank sum test. Results: The Table shows the median ratios of actual to ideal doses and SDs with versions 2 and 4. EGMAIN-GX version 4 yielded a significantly higher ratio than did version 2 (1.0097 and 0.9997, respectively; p < 0.01) and a lower SD (0.0275 and 0.0290, respectively). SDs were consistently small for most drugs, except for rituximab and cytarabine. Conclusions: The rounding-off function of CPOE decreased the dose variations of chemotherapeutic drugs. Median ratios of actual to ideal doses and their SDs with versions 2 and 4. Version 2 Version 4 Drug Median SD Median SD Cytarabine 1.0000 0.0134 1.0250 0.0137 Fludarabine 1.0018 0.0388 1.0036 0 Busulfan 0.9856 0.01498 1.0096 0 Rituximab 1.0125 0.0554 0.9225 0.0810 Cisplatin 1.0250 0.0152 0.9994 0.0129 Doxorubicin 1.0000 0.0128 0.9994 0.0052 Vincristine 1.0000 0.0406 1.0000 0.0406 Etoposide 0.99230 0.0229 0.9609 0 Cyclophosphamide 1.0018 0.0271 1.0036 0.0028 Idarubicin 1.0000 0.0353 1.0143 0.0042 Total 0.9997 0.0290 1.0097 0.0275
Abstract 13554: Highest Exercise Circulatory Equivalents are Reproducible in Heart Failure Patients Despite Wide Differences in Ramp Rate Increments
Authors: James E Hansen, T. Scott Bowen, Klaus K Witte, Harry D Rossiter
Journal: Circulation (2012)

BACKGROUND: Gas exchange measurements during exercise in chronic heart failure (CHF) provide important prognostic and diagnostic information, but are infrequently used, in part due to their complex...
The risk of febrile neutropenia and need for G-CSF primary prophylaxis with the adjuvant docetaxel and cyclophosphamide in patients with early-stage breast cancer: A meta-analysis.
Authors: Tran Do, Polly Ann Niravath, Meghana Trivedi
Journal: Journal of Clinical Oncology (2015)

e20707 Background: The reported febrile neutropenia (FN) rates with the regimen of docetaxel 75mg/m2 plus cyclophosphamide 600mg/m2 (TC) given every 3 weeks vary from 4% to 69% in early-stage breast cancer patients. This greatly impacts the recommendations for granulocyte colony-stimulating factor primary prophylaxis (G-CSFpp) based on various guidelines. We conducted a meta-analysis of published studies to determine FN rates with the TC regimen, its dependence on patients’ age, and the efficacy of G-CSFpp in reducing the FN risk in early-stage breast cancer patients. Methods: We systematically searched the literature via PUBMED using the following terms: ‘docetaxel’, ‘cyclophosphamide’, ‘febrile neutropenia’, and ‘breast cancer’, with the search limit ‘title/abstract’. Inclusion criteria were full text peer-reviewed clinical studies in English reporting FN rates with TC regimen in relationship to G-CSFpp. Results: Our systematic search of the literature yielded 104 articles, of which 8 studies (N = 1,542 patients) were included in our analysis. The studies were well matched for disease stage, drug dosage regimen, and definition of FN. Out of 883 patients not receiving G-CSFpp, 194 patients (22%) had FN; whereas only 36 patients (5.5%) out of 659 patients receiving G-CSFpp, had FN (p < 0.0001, Fisher’s exact test). The FN rates were not significantly different in patients < 65 y/o compared to those ≥ 65 y/o when G-CSFpp was not given with TC regimen (21% vs. 18.6%, p = 0.58, Fisher’s exact test; N = 788 in 4 studies). In 5 studies reporting the performance status, all the patients had Karnofsky performance status of ≥ 80% and ECOG performance status of 0-2. Comorbidities were not reported in most studies for evaluating the probability of FN within specific disease populations. Conclusions: Our meta-analysis of the published studies demonstrated ≥ 20% FN rate with TC regimen and a significant benefit from G-CSFpp. The discrepancy in the reported FN rates with TC regimen was not related to patients’ age or performance status. G-CSFpp should be strongly considered for all early-stage breast cancer patients receiving TC regimen.
Cancer stemness inhibition and chemosensitization: Phase 1b/II study of cancer stemness inhibitor napabucasin (BBI-608) with FOLFIRI +/- bevacizumab (Bev) administered to colorectal cancer (CRC) patients (pts).
Authors: Johanna C. Bendell, Bert H. O'Neil, Alexander Starodub, Derek J. Jonker, Thorvardur Ragnar Halfdanarson, William Jeffery Edenfield, Bassel F. El-Rayes, Joleen Marie Hubbard, Henry C. Pitot, Timothy J. Hobday, Youzhi Li, Yuan Gao, Axel Grothey, Laura Borodyansky, Chiang Li
Journal: Journal of Clinical Oncology (2017)

593 Background: Cancer stem cells or stemness-high cancer cells are considered to be fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting Stat3-driven gene transcription. Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapeutics and targeted agents. Methods: This study was performed to assess signs of anti-tumor activity of napabucasin in combination with FOLFIRI +/- Bev in CRC pts. Napabucasin was administered at 240 mg BID. FOLFIRI (5-FU 400 mg/m 2 bolus with 2400 mg/m 2 , irinotecan 180 mg/m 2 , and leucovorin 400 mg/m 2 infusion) +/- Bev 5 mg/kg was administered biweekly until disease progression or other discontinuation criterion. pSTAT3 status of archival tumor tissue was assayed by immunohistochemistry using the H-score with pSTAT3 high defined as ≥ 5% pSTAT3+ cancer cells and tumor stroma staining at ≥ 2+ intensity. Results: 63 CRC pts with an average of &gt;2 prior therapy lines were enrolled. No pharmacokinetic interactions or dose-limiting toxicity was observed. Most common adverse events (AEs) included grade 1/2 diarrhea, nausea, vomiting and fatigue. 25 pts had grade 3 AEs, including diarrhea (14), fatigue (4), dehydration (2), electrolyte imbalance (4), nausea (1) and weight loss (1) resolved with dose reduction and supportive care. Among 63 pts enrolled who received RECIST evaluation, disease control (CR+PR+SD) was observed in 49 pts (86%) with an overall response (CR+PR) of 28% with 1 pt achieving CR. Clinical trial information: NCT02024607. Conclusions: This phase Ib/II study suggests napabucasin may sensitize chemorefractory CRC to FOLFIRI +/- Bev. Encouraging signs of synergistic activity between napabucasin and FOLFIRI was observed in CRC pts regardless of pSTAT3 status.[Table: see text]
Transdermal delivery of atorvastatin calcium from novel nanovesicular systems using polyethylene glycol fatty acid esters: Ameliorated effect without liver toxicity in poloxamer 407-induced hyperlipidemic rats
Authors: Mohamed O. Mahmoud, Heba M. Aboud, Amira H. Hassan, Adel A. Ali, Thomas P. Johnston
Journal: Journal of Controlled Release (2017)
Chemotherapy and survival benefit in elderly patients with advanced gastric cancer.
Authors: Aya Sugimoto, Tsutomu Nishida, Kei Takahashi, Kaori Mukai, Tokuhiro Matsubara, Shiro Hayashi, Masashi Yamamoto, Sachiko Nakajima, Koji Fukui, Masami Inada
Journal: Journal of Clinical Oncology (2017)

45 Background:There is little evidence if chemotherapy (CT) offer survival benefit for elderly patients (EP) with advanced gastric cancer (AGC). Methods: This was a single-centre retrospective study. A total of 118 patients with AGC were hospitalized at our hospital from April 2012 to June 2016. Of them, EP older than 75 years with AGC were eligible for inclusion in the study. Basically, the treatment strategy, chemotherapy (CT) or best supportive care (BSC) were comprehensively decided according to their background. We evaluate the risk factors for survival using the Cox proportional hazard model and explored the optimal indication for CT for EP. Results: Of 118 patients with AGC, 47 patients were enrolled as EP [63% men; mean age, 81 years]. Of EP, 26 patients (55%) received CT and 21 patients received BSC. As first-line CT, 13 patients received S1 monotherapy, the others treated with combination agents. The median overall survival time (MST) was 138 days. There was no significant difference between CT and BSC group (172 vs. 118 days, p = 0. 1087). Univariate analysis revealed the following 5 factors for poor prognosis were significant (defined as p-value &lt; 0.1): Performance status (PS) 3 a 2 (HR3.7, 95% CI: 1.5-8.5), C-reactive protein levels 3 a 1mg/dL (HR4.0, 95% CI: 1.8-9.4), albumin level &lt; 3g/dL (HR2.1, 95% CI: 1.1-4.3), neutrophil/lymphocyte ratio (NLR) 3 a 4 (HR3.7, 95% CI: 1.7-8.5), and diffuse type (HR1.8, 95% CI: 0.9-3.8). As each poor risk factor of 5 and age factor 3 a 80 years represents point 1, we calculated total points (0-6) for each patient. Median total points of CT and BSC were 2 and 4, respectively (p = 0.0196). Therefore, we set cut-off point of 3. Then, EP with a total point of 3 and more were classified as high risk group (HR: N = 25) and the others were as low risk group (LR: N = 22). There was significantly longer MST in LR than HR (all EP; 457 vs 105 days, HR: 0.23, p = 0.0002 and EP with CT; 232 vs 113 days, HR:0.26, p = 0.0085). Conclusions: Our findings using the scoring system including 6 factors suggest that EP with a total point 3 and more, were poor prognosis and may not receive benefit from CT for AGC. When judging indication for CT in EP with AGC, this scoring system may be useful, and in case of LR (total point 0-2) may be considered an indication for CT.
Angiogenic Mechanisms of Human CD34 <sup>+</sup> Stem Cell Exosomes in the Repair of Ischemic Hindlimb
Authors: Prabhu Mathiyalagan, Yaxuan Liang, David Kim, Sol Misener, Tina Thorne, Christine E. Kamide, Ekaterina Klyachko, Douglas W. Losordo, Roger J. Hajjar, Susmita Sahoo
Journal: Circulation Research (2017)

Rationale: Paracrine secretions seem to mediate therapeutic effects of human CD34 + stem cells locally transplanted in patients with myocardial and critical limb ischemia and in animal models. Earlier, we had discovered that paracrine secretion from human CD34 + cells contains proangiogenic, membrane-bound nanovesicles called exosomes (CD34Exo). Objective: Here, we investigated the mechanisms of CD34Exo-mediated ischemic tissue repair and therapeutic angiogenesis by studying their miRNA content and uptake. Methods and Results: When injected into mouse ischemic hindlimb tissue, CD34Exo, but not the CD34Exo-depleted conditioned media, mimicked the beneficial activity of their parent cells by improving ischemic limb perfusion, capillary density, motor function, and their amputation. CD34Exo were found to be enriched with proangiogenic miRNAs such as miR-126-3p. Knocking down miR-126-3p from CD34Exo abolished their angiogenic activity and beneficial function both in vitro and in vivo. Interestingly, injection of CD34Exo increased miR-126-3p levels in mouse ischemic limb but did not affect the endogenous synthesis of miR-126-3p, suggesting a direct transfer of stable and functional exosomal miR-126-3p. miR-126-3p enhanced angiogenesis by suppressing the expression of its known target, SPRED1 , simultaneously modulating the expression of genes involved in angiogenic pathways such as VEGF (vascular endothelial growth factor), ANG1 (angiopoietin 1), ANG2 (angiopoietin 2), MMP9 (matrix metallopeptidase 9), TSP1 (thrombospondin 1), etc. Interestingly, CD34Exo, when treated to ischemic hindlimbs, were most efficiently internalized by endothelial cells relative to smooth muscle cells and fibroblasts, demonstrating a direct role of stem cell–derived exosomes on mouse endothelium at the cellular level. Conclusions: Collectively, our results have demonstrated a novel mechanism by which cell-free CD34Exo mediates ischemic tissue repair via beneficial angiogenesis. Exosome-shuttled proangiogenic miRNAs may signify amplification of stem cell function and may explain the angiogenic and therapeutic benefits associated with CD34 + stem cell therapy.
Apolipoprotein L1 Variants and Blood Pressure Traits in African Americans
Authors: Girish N. Nadkarni, Geneviève Galarneau, Stephen B. Ellis, Rajiv Nadukuru, Jinglan Zhang, Stuart A. Scott, Claudia Schurmann, Rongling Li, Laura J. Rasmussen-Torvik, Abel N. Kho, M. Geoffrey Hayes, Jennifer A. Pacheco, Teri A. Manolio, Rex L. Chisholm, Dan M. Roden, Joshua C. Denny, Eimear E. Kenny, Erwin P. Bottinger
Journal: Journal of the American College of Cardiology (2017)
Commentary: Statistical aspects
Authors: Michael J Campbell
Journal: BMJ (2004)

The main issue in this study is the use of an n of 1 trial for the evaluation of treatments for nausea and vomiting in pregnancy. These trials are used to decide what treatment benefits an individual patient and are a more scientific method of decision making than the usual method used by general practitioners: asking the patient to return if the first treatment doesn't work and trying a second one.1 As I have pointed out before, R A Fisher, one of the greatest statisticians, discussed at length an n of 1 trial investigating whether a woman could tell whether milk was added before or after the tea,2 and this has even become the title of a book.3 They are usually used in chronic illness, such as arthritis, to evaluate the best long term treatment for a patient. A recent good example showed that paracetemol may be used instead of non-steroidal anti-inflammatory drugs in some patients with osteoarthritis.4

However it is worth mentioning a few problems associated with n of 1 trials.5 In terms of design an investigator needs to decide:



How many treatment periods


How long to treat within each period.






Since nausea in pregnancy obviously has a limited duration, few treatment periods will be available, and a compromise will have to be made about the number of periods compared with the length of each one. The trial had only five pairs of treatment periods, and so did not have much power to detect an effect unless it was large. However, that is what we would be hoping for in this case. To accommodate even five pairs of treatment periods within the time span, the treatment was given for only two days, and several respondents commented that two days of active treatment is unlikely to be enough to correct a vitamin deficiency.

N of 1 trials are crossover trials, and like crossover trials they are also vulnerable to carry over effects, where the effect of treatment extends to the next treatment period. This may be a problem in this case, because if the treatment did in fact cure the deficiency, it is unlikely to reappear again after two days.

An interesting problem (discussed at length by statisticians since it affects the P value) is what Ms Reynolds knew of the allocation. Was she simply told that she was going to be treated for 25 days with either vitamin B-6 or placebo allocated at random or did she know that there were five matched periods? Despite these caveats, it would be nice to see more general practitioners conducting these type of trials.
COX2, p16, and Ki67 expression in DCIS, microinvasive and early invasive breast carcinoma with extensive intraductal component.
Authors: Michaela Bartova, Frantisek Ondrias, Iveta Meciarova, Muy-Kheng Maria Tea, Marie Therese Kastner, Christian F. Singer, Kamil Pohlodek
Journal: Journal of Clinical Oncology (2014)

e11519 Background: Biological potential of premalignant lesions of the breast remains unclear. Ductal carcinoma in situ (DCIS) represents heterogeneous group of lesions and reliable prognostic markers are still missing. Numerous studies focus on elucidating the pathways of carcinogenesis and understanding the lesions‘ origin or future behaviour. Recent studies have drawn attention to the prognostic value of p16, COX-2 and Ki67 as markers of locoregional invasive recurrences in DCIS due to abrogated response to cellular stress. In addition, the influence of the microenvironment seem to be important in determining lesions‘ future behaviour. In our case-control study we compared expression levels of the three promising prognostic markers (p16, COX-2, Ki67) in in situ lesions, existing as part of different tumors – in situ lesions within pure DCIS, microinvasive tumor (T1mic) and invasive tumor with extensive intraductal component (IDC with EIC). We hypothesized different expression phenotype according to progression level of the surrounding tumors. Methods: Immunohistochemical examination was used to evaluate expression of COX-2, p16 and Ki67 in three subgroups of tumors (with and without invasive component): DCIS, T1mic and IDC with EIC. Expression was measured exclusively in in situ compounds. We examined 37 tumors operated at our clinic in 2000-2010. Results: We found increasing expression of COX-2 and p16 with rising severity of the diagnosis (gradually rising prevalence of overexpression from DCIS to T1mic and IDC). Prevalence of p16 expression score 1 was the highest within DCIS, the lowest in IDC and p16 overexpression maintained the same tendency (overexpression in DCIS<T1mic<IDC), although this was not significant. Combination of COX-2 and p16 overexpression (COX-2+p16+) was higher within invasive carcinoma in comparison to DCIS and T1mic and was rising gradually with severity of the diagnosis. Conclusions: The data support different expression pattern of COX-2 and p16 markers in in situ lesions according to surrounding tumors. Further examinations on larger cohorts are needed. This might help to understand different character and behaviour of in situ lesions.
Proposal of size-based surgical indication criteria for liver hemangioma based on a nationwide survey in Japan.
Authors: Yoshihiro Sakamoto, Norihiro Kokudo, Takeyuki Watadani, Junji Shibahara, Masakazu Yamamoto, Hiroki Yamaue
Journal: Journal of Clinical Oncology (2017)

265 Background: Although hepatic hemangioma is one of the most frequent benign tumors in the liver, surgical indication for this neoplasm remains unclear. The objective of the present study was to conduct a nation-wide survey on resected cases of liver hemangioma and propose evidence-based surgical indication criteria for this disease (Research project of Japanese Society of Hepato-Biliary-Pancreatic Surgery). Methods: Of a total of 510 patients undergoing surgical resection for liver hemangioma in 118 Japanese centers between 1998 and 2012, abdominal symptoms, coagulopathy, diagnostic accuracy and surgical outcomes were analyzed according to the tumor status. Results: The patients were classified into 4 groups based on the tumor size; Group A) ≤ 5cm (n = 122, 24%), B) 5-10cm (n = 164, 32%), C) 10-15cm (n = 124, 24%), and D) &gt; 15cm (n = 100, 20%) Hemangioma in Group A was most frequently diagnosed as a malignant tumor (43.5%) due to absence of typical imaging findings as cavernous hemangioma and with highest incidence of positive of HBV (15.7%). Diagnostic accuracy was 98.4% in Groups B-D. In Group B, 71% of patients presented no abdominal symptoms or Kasabach-Merritt syndrome. Symptoms associated with hemangioma increased in proportion as the size increased, and the incidence of abdominal distension, tumor rupture, and Kasabach-Merritt syndrome were 55%, 2.0%, and 26%, respectively, in Group D. The incidence of liver failure after hepatectomy was higher in Group D than in Groups A-C (3.0% vs. 0.5%, p = 0.02). There was only one operative death (0.2%) in Group D. Conclusions: In patients with = /&lt; 5cm hemangioma, surgical resection is indicated when malignant tumor can not be ruled out. However, surgical indications for 5-10cm asymptomatic hemangiomas should be limited because preoperative diagnosis of benign disease is trustworthy in this subgroup. Tumor size &gt; 10cm would be candidate for surgery when accompanied with abdominal symptom or coagulopathy, and hepatectomy for tumors &gt; 15cm should be performed in high volume centers by experienced hepatic surgeons to avoid serious morbidity or mortality.