tbuckley/cabot-search huggingface dataset:
Phase III study evaluating safety and efficacy of the addition of veliparib plus carboplatin versus the addition of carboplatin to standard neoadjuvant chemotherapy in subjects with early-stage triple-negative breast cancer (TNBC).
Authors: Gunter Von Minckwitz, Joyce O'Shaughnessy, Eric P. Winer, Norman Wolmark, Charles E. Geyer, Jens Bodo Huober, Sibylle Loibl, William M. Sikov, Michael Untch, Mark D. McKee, Vincent L. Giranda, Hope S. Rugo
Journal: Journal of Clinical Oncology (2014)

TPS1149 Background: Emerging data suggests that TNBC may be sensitive to DNA-damaging chemotherapy agents, including carboplatin (Cb). Veliparib (V; ABT-888), a potent, competitive poly (ADP-ribose) polymerase (PARP)-1 and -2 inhibitor, enhances the activity of several DNA-damaging agents. In I-SPY2, the addition of V and Cb to standard neoadjuvant therapy for early TNBC doubled the pathologic complete response (pCR) rate (52% vs. 26%). This study will evaluate the addition of Cb or V + Cb to neoadjuvant paclitaxel (P) followed by doxorubicin + cyclophosphamide (AC). Methods: A phase 3, randomized, placebo-controlled, double-blinded, multinational, multicenter study will enroll 624 patients (pts) with histologically confirmed, invasive, TNBC (T2-T4 N0-2 or T1 N1-2) who are candidates for potentially curative surgery. No prior breast cancer treatment or sentinel lymph node biopsy is permitted. Pts will be stratified by BRCA status, lymph node stage (N0 versus N1-2), and schedule of AC administration (q2 weeks versus q3 weeks), and randomized in a 2:1:1 ratio to: (Arm A) P 80 mg/m2 weekly + Cb AUC 6 mg/mL/min q3weeks x 4 + V 50 mg PO BID for 12 weeks followed by AC (60 mg/m2/600 mg/m2 q2 or 3 weeks x 4); (Arm B) P + Cb + PO placebo followed by AC; (Arm C) P + IV placebo + PO placebo followed by AC. After completing study therapy, pts will undergo surgery with sentinel node sampling or axillary lymph node dissection. Post-op radiotherapy is at MD discretion. The primary objective of the study is to assess the incidence of pCR defined as absence of residual invasive cancer in resected breast tissue and lymph nodes (i.e., ypT0/is N0 per AJCC staging system). Assuming pCR rates in the V + Cb, Cb only and control arms are 60%, 45% and 40%, respectively, the study has > 80% power at 2-sided α level of 0.05 to detect a statistically significant treatment effect in pCR for the V + Cb arm compared to either of the other two arms using chi-square test. Secondary objective is the rate of eligibility for breast conservation after therapy. Other endpoints are residual cancer burden, EFS and OS. The study opened in Jan 2014. Clinical trial information: NCT02032277.
Use of inflammation-based prognostic score to predict survival in patients with advanced gastric cancer receiving biweekly docetaxel and S-1 combination chemotherapy.
Authors: Chikara Kunisaki, Masazumi Takahashi, Hidetaka Ono, Takashi Oshima, Shoichi Fujii, Takashi Kosaka, Hirochika Makino, Hirotoshi Akiyama, Itaru Endo
Journal: Journal of Clinical Oncology (2012)

e14624 Background: The Glasgow Prognostic Score (GPS), an inflammation-based prognostic score composed of C-reactive protein (CRP) and albumin measurements, has been reported to be a prognostic factor in patients with various cancers. This study was conducted to determine the prognostic value of GPS for patients with advanced cancer. Methods: The GPS was classified according to a previous study. A total of 83 advanced gastric cancer patients receiving bi-weekly docetaxel/S1 treatment (DS) were included. Correlation of clinicopathological factors and the GPS was assessed. To identify the impact of GPS as prognostic factors for disease-specific survival (DSS) and progression-free survival (PFS), univariate and multivariate analyses were performed. Results: Of these 83 patients, unresectable tumors were observed in 78 patients and recurrent tumors were detected in 5 patients. Of these, 13 patients underwent surgery and 12 patients underwent gastrectomy. There were significant correlations between the GPS and the neutrophil to lymphocyte ratio (NLR). Univariate analysis revealed that the GPS, ECOG-PS and gastrectomy after DS treatment significantly affected prognosis. The Cox proportional regression hazard model showed that the GPS, age and gastrectomy independently influenced DSS, and that the GPS and gastrectomy also influenced PFS. The Cox proportional regression hazard model restricted patients without gastrectomy showed that the GPS and age independently influenced DSS, and that the GPS influenced PFS. Conclusions: The GPS may be an useful prognostic factor for advanced gastric cancer patients receiving uniform first-line treatment (DS). The impact of the GPS should be confirmed in a well-designed prospective trial in many patients.
Impact of primary tumor sidedness on survival after resection of colorectal liver metastases (CRLM).
Authors: Richard M. Lee-Ying, Nicholas Bosma, Patricia A. Tang
Journal: Journal of Clinical Oncology (2017)

694 Background: The impact of primary tumour sidedness has recently been demonstrated in patients with metastatic colorectal cancer (mCRC). Differences in right (R) versus left (L) sided mCRC may be due to differences in consensus molecular subtyping. Clinically predictive mutations in ras, ( kras, nras and braf) may also help drive some of the differences in outcome. However, patients with mCRC who undergo surgical resection of CRLM often have a good prognosis. The aim of this study was to assess the impact of tumour sidedness on OS after resection of CRLM. Methods: Patients who underwent resection of CRLM in the province of Alberta, Canada were identified from 2004-2016. Tumour sidedness was determined by chart review, with R from the cecum to transverse and L from splenic flexure to sigmoid. Where available, ras mutational status was collected. OS was measured from the time of CRLM resection to death or last follow-up using the Kaplan-meier method. R and L were compared using the log-rank test and a Cox regression model. Results: 471 patients were identified who underwent resection of CRLM for mCRC, including 204 R and 267 L. Median age was 65, 63% male, with 54% synchronous metastatic disease, and 67% with a Charleson comorbidity index of 0. All ras wildtype was present in 22% of cases, any ras mutation was detected in 21% and 57% were unknown at the time of analysis. The median OS of R was 45 months, compared to 72 months for L, log-rank p = 0.01. After adjusting for potential confounders with a Cox-proportional hazard model, R compared to L remained significant, with a HR of 1.4 (95% CI 1.0-1.9, p = 0.02). ras mutational status was also significant for ras mutant, HR 2.4 (95% CI 1.7-3.3) and ras unknown HR 2.2 (95% CI 1.5-3.1) compared to ras wildtype p &lt; 0.01. Conclusions: Primary tumour sidedness continues to have an impact on OS in mCRC, even when disease is managed surgically with resection of CRLM. Though limited by numbers, the impact remained significant even after controlling for potential confounders, including ras mutational status. Additional ras testing is underway. Further molecular classification may provide a biologic rationale for the observed differences.
Safety and efficacy of eribulin as second-line treatment for HER2-negative metastatic breast cancer.
Authors: Vasiliki Michalaki, John Psychogios, John Contis, Agathi Kondi, Constantine Gennatas, Christos A. Papadimitriou, John Vasiliou
Journal: Journal of Clinical Oncology (2015)

e11583 Background: Backgroud:The treatment of metastatic breast cancer (MBC) has become increasingly challenging as the primary goals of therapy include prolonging life without added toxicity. Eribulin mesylate, a novel non-taxane microtubule nhibitor, is approved for treatment of metastatic breast cancer (MBC) in patients who have previously received at least 2 chemotherapeutic regimens for MBC that should have included an anthracycline and a taxane in the adjuvant or metastatic setting. This phase 2 study evaluated efficacy and safety of eribulin as second-line therapy for human epidermal growth factor receptor 2-negative (HER2-negative) MBC. Methods: Patients with measurable HER2-negative, MBC with ≥ 12 months since prior adjuvant chemotherapy received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 3-week cycle. Endpoints included objective response rate (ORR) per RECIST v1.1 (primary), safety, progression-free survival (PFS) and clinical benefit rate (ORR + stable disease ≥ 6 months; CBR. Results: Thirty four patients were enrolled and received eribulin; all had prior adjuvant therapy, including 31(91%) who had anthracycline and/or taxane-containing chemotherapy; 25 (73 %) had estrogen receptor-positive disease, and 9 (24 %) had estrogen receptor-negative, progesterone receptor-negative, and HER2-negative (triple-negative) disease. Patients received a median of 8 cycles (range 2–24); 5 (14 %) received treatment for ≥ 12 months. ORR was 36 % (95 % CI 13.2–36.1), CBR was 55 %, and median PFS was 7.4 months. Sixteen patients (47%) had grade 3/4 treatment-related adverse events; most common were fatigue (45%), neutropenia (35%), leukopenia (18%), and peripheral neuropathy (7%). Conclusions: These results demonstrate that eribulin has substantial antitumor activity early in the course of metastatic breast cancer, specifically as second -line treatment for HER2-negative MBC with acceptable safety profile Methods: Results: Conclusions:
Mechanisms of resistance to low-dose metronomic cyclophosphamide
Authors: U. Emmenegger, L. Chen, Y. Shaked, G. Francia, A. Kouri, A. J. Mutsaers, J. M. Ebos, S. Man, R. S. Kerbel
Journal: Journal of Clinical Oncology (2006)

13079 Background: It has been postulated that antiangiogenic therapies are less susceptible to acquired resistance compared to conventional treatment strategies, which target genetically unstable tumor cells. However, resistance is commonly seen (pre)clinically. A better understanding of the underlying mechanisms is clearly needed to improve such therapies. Methods: We studied mechanisms of acquired resistance to low-dose metronomic (LDM) cyclophosphamide (CTX), the continuous or frequent administration of comparatively low doses of CTX with no extended breaks resulting primarily in antiangiogenic effects, by using LDM CTX relapsed/resistant variants obtained during prolonged in vivo therapy from the human prostate cancer cell line PC-3, which initially is highly responsive. The variants were analyzed for their growth characteristics, angiogenic “phenotype” and impact on circulating endothelial cells (CEC)/endothelial cell progenitors (CEP). Furthermore, we obtained microvessel density (MVD) counts of corresponding xenografts and analyzed in vitro resistance to 4-hydroxycyclophosphamide (4-OH-CTX), hypoxia, acidosis, and glucose as well as serum deprivation. Results: The resistant variants did not show consistent changes in their angiogenic “phenotype”. The decrease in MVD upon LDM CTX treatment was comparable to that obtained in xenografts from parental PC-3, which was reflected by similar changes in the number of CEC and CEP. Despite in vivo resistance to LDM CTX, there was no evidence of in vitro resistance of the variants to 4-OH-CTX. However, they exhibited increased tolerance to microenvironmental stress resulting from sustained antiangiogenic activity. Conclusions: In this model, resistance to LDM CTX develops despite sustained antiangiogenic activity. This provides further evidence that reduced vascular dependence of the tumor cell population may be a basis for the observed resistance. The administration of CTX in a LDM manner does not result in tumor cell CTX resistance, supporting the notion that LDM protocols target primarily the tumor vasculature. If confirmed in ongoing clinical metronomic chemotherapy trials, our results will have major implications for the management of patients that progress under such treatment. No significant financial relationships to disclose.
Comment on Inzucchi et al. Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease. Diabetes Care 2016;39:1684–1692
Authors: Niki Katsiki, Dimitri P. Mikhailidis
Journal: Diabetes Care (2017)

We read with interest the results of the Insulin Resistance Intervention after Stroke (IRIS) trial prespecified secondary analysis for type 2 diabetes mellitus (T2DM) prevention, in which Inzucchi et al. (1) reported that pioglitazone almost halved the risk of T2DM development in insulin-resistant patients with cerebrovascular disease. This effect was driven by a larger impact in participants who at baseline had HbA1c >5.7% (39 mmol/mol), impaired fasting plasma glucose …
Phase Ib trial of trastuzumab emtansine (TE) in combination with lapatinib (L) plus nab-paclitaxel in metastatic HER2-neu overexpressed breast cancer patients: STELA trial.
Authors: Tejal Amar Patel, Jaime Alberto Mejia, Angel Augusto Rodriguez, Jenny Chee Ning Chang
Journal: Journal of Clinical Oncology (2014)

TPS669 Background: Therapies directed at HER2 establish a successful treatment paradigm, but de novo and acquired resistance exist. Multiple large randomized clinical trials have demonstrated that dual HER2 targeted therapies are synergistic and result in improved efficacy. We hypothesize that dual targeted therapy with trastuzumab-emtansine and lapatinib will affect both PI3K and ERK1,2 MAPK pathways. This trial was designed to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of trastuzumab-emtansine (TE) and lapatinib (L), together with Nab paclitaxel (A). Methods: Eligible patients have stage IV HER2 positive breast cancer, normal LVEF, and Peripheral neuropathy < grade 2. Phase IB planned for up to 9 patients in a standard 3+3 dose de-escalation design. Starting dose level of TE 3.6mg/kg, Lapatinib 750mg and Abraxane(A) 80 mg/m2. DLTs were defined as ≥ grade 3 non hematological toxicity attributed to the study drugs. Currently, our lead cohort has three patients with manageable toxicities and we will start expansion cohort soon. The secondary endpoint includes the description of DLT and other toxicities, document anti-tumor activity as assessed by RECIST 1:1 criteria as well as plasma pharmacokinetics and pharmacodynamics of TE in combination of L and A as well as potential biomarkers of response including HER2 expression levels, PTEN, PI3K and others.
The outcome of ALK positive and ALK negative anaplastic large cell lymphoma (ALCL) following DA-EPOCH.
Authors: Catherine Lai, Stefania Pittaluga, Margaret Shovlin, Seth M. Steinberg, Mark J. Roschewski, Elaine S. Jaffe, Wyndham Hopkins Wilson, Kieron Dunleavy
Journal: Journal of Clinical Oncology (2015)

8564 Background: Systemic anaplastic large cell lymphoma (ALCL) is a clinically and molecularly heterogeneous type of peripheral T-cell lymphoma (PTCL). It may be sub-divided into cases with or without translocation of the anaplastic lymphoma kinase gene (ALK), leading to overexpression of ALK. While the outcome for patients with ALK positive ALCL - particularly in pediatric patients - has been very favorable following doxorubicin-based therapy, ALK negative cases have fared more poorly. Approaches such as autologous transplantation have been studied in this group in an attempt to improve outcome (d’Amore et al. J Clin Oncol. 2012). Methods: 23 patients with newly diagnosed ALK positive (15) and ALK negative (8) ALCL underwent treatment with 6 to 8 cycles of dose-adjusted infusional etoposide, vincristine and doxorubicin with prednisone and cyclophosphamide (DA-EPOCH). Both groups had similar IPI characteristics (shown below). Results: 19/23 (83%) patients achieved CR or CRu; 3/23 (13%) a PR and 1 patients had PD. At the median potential follow-up time of 13 years, event free survival (EFS) in ALK positive and ALK negative ALCL was 72% and 62.5% (p = 0.50) and overall survival was 76% and 87.5% (p = 0.82), respectively. Toxicity was assessed on all 135 cycles. Neutropenic fever and thrombocytopenia < 25,000/mm3 occurred on 10% of cycles, respectively. Absolute neutrophil count (ANC) less than 500 cells/mm3 occurred on 35% of cycles. Conclusions: Following DA-EPOCH, the outcome of ALK negative ALCL is equivalent to ALK positive ALCL. The incorporation of etoposide, infusional scheduling and dose adjustment may play important roles in ALCL therapeutics. DA-EPOCH should be considered a reasonable front-line regimen in ALCL and especially in older patients where approaches such as transplantation may not be feasible. Clinical trial information: NCT00001337. Characteristics All Patients (N = 23) ALK + ALCL (N = 15) ALK – ALCL (N = 8) Median age (range) 38 (19-68) 36 (19-68) 43 (27-60) Male sex 16 (70%) 9 (60%) 7 (87%) Stage III or IV 17 (74%) 12 (80%) 5 (62%) Elevated LDH 12 (52%) 8 (53%) 4 (50%) Extranodal sites Bone/Bone marrow Lung Bowel 12 (52%) 5 (22%) 5 (22%) 3 (13%) 8 (53%) 3 (20%) 3 (20%) 2 (13%) 4 (50%) 2 (25%) 2 (25%) 1 (12%) IPI ≥ 2 14 (61%) 10 (67%) 4 (50%)
MicroRNA-137 and microRNA-29a expression in non-small cell lung cancer diagnosis and prognostic.
Authors: Zhao Ming
Journal: Journal of Clinical Oncology (2012)

e17501 Background: Current staging methods are inadequate for predicting the outcome of treatment of non–small-cell lung cancer (NSCLC). We investigated whether microRNA expression proﬁles can predict clinical outcome of NSCLC patients. Methods: We studied frozen specimens of lung-cancer tissue from 76 randomly selected patients who underwent surgical resection of NSCLC. Using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis, we chosed U6 as the internal control for real-time RT-PCR because it is invariant in clinical cancer specimens. We obtained microRNA137 and 29a expressions level in 76 NSCLC patients and evaluated diagnoisis value and the association between the level of expression and survival. Results: This microRNA137 is with diagnosis value, microRNA29a expression level signature is an independent predictor of the cancer relapse and survival of NSCLC patients. Conclusions: Our microRNA signature is closely associated with relapse-free and overall survival among patients with NSCLC.
Bruising and abnormal leucocytes on a blood film—a haematological emergency
Authors: Selina J Chavda, Sophie Lindsay, Fenella Willis, Mickey Koh
Journal: BMJ (2017)

A 20 year old man was referred to the emergency department by his general practitioner with a one week history of easy bruising, gum bleeding, and lethargy. He had no medical history and took no regular medications. He did not smoke or drink alcohol and had no travel history. On examination, he appeared unwell and had widespread petechiae with evidence of gum bleeding. The rest of the clinical examination, including funduscopy, was normal.

His observations were: heart rate 110 beats per minute, blood pressure 100/80 mm Hg, temperature 38.5°C, respiratory rate 20 breaths/minute, and oxygen saturations 100% on room air.

Blood results showed: haemoglobin 77 g/L (133-167 g/L), white blood cell count 6×109 cells/L (3.5-11×109 cells/L), neutrophils 1.1×109 cells/L (2.0-7.0×109 cells/L), platelets 45×109/L (150-410×109/L), and C reactive protein level 160 nmol/L (0.76 −28.5 nmol/L). A coagulation screen showed INR 1.9 (0.8-1.1), APTT ratio 1.07 (0.85-1.15), fibrinogen 0.8 g/L (2-4 g/L), and D-dimer 3334 ng/ml (<250 ng/ml). Urea, creatinine, and liver function tests including bilirubin were normal.

His blood film at×40 magnification (fig 1⇓) showed large promyelocyte blast cells with bilobed nuclei with azurophilic granules and Auer rods within the cytoplasm. His bone marrow aspirate showed a hypercellular marrow packed with large promyelocyte blast cells containing Auer rods.



Fig 1  Peripheral blood sample×40 magnification



Flow cytometry from peripheral blood showed a clonal population of cells that were HLADR–, CD34– CD13+, CD33+and CD117+. Cytogenetic testing confirmed the presence of t(15;17) abnormality in these cells.



### 1. What is the diagnosis?

#### Short answer

The blood film and bone marrow show large promyelocyte blast cells consistent with acute promyelocytic leukaemia. This is confirmed by …
Functional polymorphism in the microRNA-367 binding site as a prognostic factor for colonic cancer.
Authors: Yee Soo Chae, Soo Jung Lee, Jong Gwang Kim, Byung Woog Kang, Yoo Jin Lee, Ho Yong Park, Gyu Seog Choi, JUN Seok PARK
Journal: Journal of Clinical Oncology (2013)

e14549 Background: As microRNAs play important roles in cancer development and progression by regulating the expressions of oncogenes and tumor suppressor genes though interacting with the 3′ untranslated region (UTR) of target genes, we aimed to evaluate the association between genetic variants of miRNAs and their binding sites and prognosis in patients with colorectal cancer (CRC). Methods: Three miRNA variants and four variants in the miRNA binding sites were selected based on allelic frequencies and potential impact described in previous studies. DNA was extracted from fresh-frozen tissues of 344 patients with CRC who underwent curative surgery and genotyping analyses were performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Results: Among seven target variants, rs1044129 at the miR-367 binding site of calcium channel ryanodine receptor gene 3 (RYR3) was associated with relapse-free survival (RFS) for colon cancer patients as a recessive model in a univariate analysis. Moreover, a multivariate analysis revealed that patients carrying the GG genotype had poor RFS compared to those with the AA or AG genotype (hazard ratio, HR=2.864; p=0.005), yet there was only a marginal trend for disease-specific survival (HR=2.226; p=0.087) regardless of the patient and tumor characteristics. Conclusions: The current study suggests that the functional variant (rs1044129) in the miR-367 binding site of RYR3 may be a potential marker for prognosis in patients after curative surgery for CRC.