tbuckley/cabot-search huggingface dataset:
A phase 2 study of defactinib (VS-6063), a cancer stem cell inhibitor that acts through inhibition of focal adhesion kinase (FAK), in patients with KRAS-mutant non-small cell lung cancer.
Authors: David E. Gerber, Suresh S. Ramalingam, Daniel Morgensztern, Ronan Joseph Kelly, Timothy Francis Burns, Ariel Lopez-Chavez, David R. Spigel, Ahmad Mouhamad Wehbe, Rachel Sorensen, David T. Weaver, Joanna Horobin, Mitchell Keegan, Pier P. Scaglioni, D. Ross Camidge
Journal: Journal of Clinical Oncology (2014)

TPS8126 Background: KRAS mutations have been associated with poor prognosis in NSCLC and resistance to epidermal growth factor (EGFR) tyrosine kinase inhibitors. FAK represents a therapeutic target in KRAS mutant NSCLC. The RHOA-FAK axis is a critical downstream mediator of RAS signal transduction and FAK inhibition results in growth suppression in KRAS mutant but not KRAS wild type (wt) cancers both in vitro and in vivo. Interestingly, loss of function of the tumor suppressors CDKN2A/INK4a/ARF (p16) and/or p53 appears requisite for efficacy of FAK inhibition in KRAS-driven cancers. Specifically, in vitro and in vivo studies in xenograft and transgenic KRAS mutant NSCLC adenocarcinoma models carrying INK4a/Arf and/or p53 mutant genotypes demonstrated susceptibility to FAK inhibition evidenced by tumor inhibition and prolonged survival. Furthermore, treatment with FAK inhibitors reduces the proportion of cancer stem cells (CSCs) compared to treatment with standard chemotherapy which enriches for CSCs. Defactinib is an oral inhibitor of FAK and proline-rich tyrosine-kinase-2 currently in clinical development in a number of indications including mesothelioma and ovarian cancer. Methods: Pts with KRAS mutant advanced NSCLC (> 1 prior platinum based doublet) are enrolled into 1 of 4 cohorts (A-D): wt INK4a/Arf, wt p53 (A); INK4a/Arf mutation, wt p53 (B); wt INK4a/Arf, p53 mutation (C), or INK4a/Arf mutation, p53 mutation (D). Defactinib is administered continuously at 400 mg PO BID in 21 day cycles until disease progression. The primary endpoint is the Progression Free Survival (PFS) rate at week 12. In the Simon 2 stage design, if ≥ 4 of 11 pts have PFS at week 12, enrollment in that cohort will be expanded to a total of 34 pts. PFS at 12 weeks of ≥ 50% will be deemed clinically important and ≤ 25% will be deemed not clinically valuable. Response rate (RR), PFS, overall survival (OS), and comparisons between Cohort A to B, C, and D will also be measured. Associations between pharmacodynamic biomarkers (including pFAK) and clinical outcomes (RR, PFS, OS) will be evaluated. The study is currently enrolling at 8 US centers. Clinical trial information: NCT 01951690.
A boy with fever and arthralgia
Authors: Federico Poropat, Serena Pastore, Valentina Gesuete, Egidio Barbi,
Journal: BMJ (2017)

An eight year old boy was admitted to the emergency department with a seven day history of medium grade fever with mild headache, sore throat, arthralgia in his wrists, and pain in the soles of his feet. He had been evaluated on the second day by his general practitioner, who had prescribed amoxicillin, but this treatment had been ineffective. Physical examination on admission showed the boy to be well, with body temperature 37.4°C, mild pharyngeal erythema with a moderate enlargement of cervical lymph nodes, heart rate 107 beats per minute without murmurs, clear breath sounds, no liver or spleen enlargement, no skin rash, and no arthritis.

Blood tests showed white blood cell count 8.66 ×109/L (reference range: 4-11 ×109/L) with 60% neutrophils, haemoglobin 12.5 g/dL (reference range: 12-16 g/dL), platelet count 374.  ×109/L (reference range: 15-40 ×109/L), erythrocyte sedimentation rate 85 mm/h (normal value <20 mm/h), C reactive protein 11.5 mg/dl (normal value <0.5 mg/dL), and anti-streptolysin titre 854 UI/ml (normal value <100 UI/mL).

A two dimensional echocardiogram (fig 1, fig 2⇓) showed a regurgitant jet, which was minimal, inconsistent, and visible only in a single projection. The regurgitation is a not uncommon finding in the paediatric population.12



Fig 1  Apical view with colour Doppler echocardiography of the four chambers of the heart showing minimal regurgitation, which is commonly seen in the paediatric population. LA=left atrium, LV=left ventricle, RA=right atrium, RV=right ventricle





Fig 2  Colour Doppler echocardiography on long axis projection with no pathological findings on the aortic valve. LA=left atrium, LV=left ventricle, …
Radiotherapy (RT) potentiation with weekly (q1w) or standard every 3 weeks (q3w) cisplatin chemotherapy (CT) for locally advanced head and neck squamous cell carcinoma (HNSCC).
Authors: Yann Molin, Emilie Lavergne, Pascal Pommier, Severine Racadot, Xavier Montbarbon, Marc Poupart, Philippe Zrounba, Philippe Ceruse, Jerome Fayette
Journal: Journal of Clinical Oncology (2013)

6056 Background: Q3w CT is standard RT potentiation for HNSCC but its toxicity requires to look for new treatment’s modalities. The aim was to explore if q1w CT could be a safe and effective alternative. Methods: Patients (pts) treated by chemoradiation (CT-RT) for a HNSCC were retrospectively included. Study population was first described. Then overall (OS) and progression-free survival since the RT onset were performed. Survival distributions were estimated by Kaplan-Meier method and compared between CT groups using the Log-Rank test. Prognostic effect of CT group was explored using Cox model. Results: 266 pts treated between January 2004 and December 2008 were included: 170 and 96 pts respectively received q1w and q3w CT. At diagnosis, 46% had oropharynx lesions, 20% larynx, 17% hypopharynx and 14% oral cavity. 70% pts experienced surgery, 39% CT induction and a median dose of radiation of 64 Gy without any significant difference between CT groups. However, median age at diagnosis was significantly different between q1w and q3w CT (58 vs 54, p&lt;0.001) as well as alcohol consumption (79% vs 68, p=0.047), stage at diagnosis (30%-60% stage III-IV vs 13% -80%, p=0.003), IMRT use (4% vs 13%, p=0.011) and median weight before RT (66 kg vs71kg, p=0.014). Q3w CT was more toxic than q1w in terms of weight loss (87% vs 75%, p=0.012), renal failure (50% vs 35%, p=0.022), worse CT plan completion (42% vs 66%, p&lt;0.001). Moreover, grade 3/4 toxicities, such as mucositis (34% vs 13%, p&lt;0.001) and dermatitis (7% vs 1%, p=0.012), were more frequent. More pts needed parenteral nutrition (10% vs 2%, p=0.008), analgesics (91% vs 70%, p&lt;0.001), secondary hospitalization (31% vs 8%, p&lt;0.001), RT interruption &gt;= 3 days (8% vs 2%, p=0.037) and had long-term toxicities (24% vs 12%, p=0.014). With a median follow-up of 42 months 95% CI [36.8-48.8], a trend in favour of q3w CT was found:2-years OS of 83% (95% CI [73-90]) vs 74% (95% CI [66-80]), p=0.089. However, after adjustment on prognostic factors CT group was not significantly associated with OS nor with PFS. Conclusions: Q1w RT-CT is safer than q3w and may be as efficient. Follow-up data will be updated to reinforce efficacy results.
Neoadjuvant trastuzumab and sequential chemotherapy with cisplatin, vinorelbine, and docetaxel for stage II-III breast cancer patients: Final results of a single institution phase II study.
Authors: Guido Carillio, Rosa Anna Aiello, Maurizio Chiarenza, Marco Alì, Antonella Mazzola, Rosanna Di Marco, Eleonora Taibi, Giuseppina Fallica, Tiziana Casella, Alessandra Zacchia, Gaetano Castiglione, Francesco Caruso, Michele Caruso
Journal: Journal of Clinical Oncology (2013)

e11527 Background: Several studies demonstrated the efficacy of neoadjuvant trastuzumab in breast cancer patients. However, cardiotoxicity intrinsic and increased by combining anthracyclines or chest wall radiotherapy remains a ticklish issue, mainly when is durable and occurs in potentially healable young patients. Methods: A phase II study of neoadjuvant trastuzumab and sequential chemotherapy was started in the late 2007 at Humanitas CCO and enrolled 42 patients with stage II-III HER2-positive breast cancer. Treatment consisted of 18 administrations of weekly trastuzumab combined with a sequential regimen including 3 courses of cisplatin 80 mg/m 2 d1 + vinorelbine 25 mg/m 2 d1 and d8 q3w followed by 3 courses of docetaxel 100 mg/m 2 d1 q3w. Peg-filgrastim was given in each course. Postoperative trastuzumab q3w was administered for one year. Radiant and endocrine therapy were delivered according to standard practice. Primary objective was the rate of pathologic complete response (pCR), now defined as no evidence of residual invasive cancer, both in breast and lymph nodes. A first report of the study was presented as poster at ASCO 2010. Results: With regard to real patient characteristics observed in the daily clinical practice, no restrictive sample selection was established and the eligible patients were accrued consecutively. Median age was 48 (range 23-71). Twenty-three patients (55%) had stage III tumors and 7 of them stage IIIB, including 4 cases of tumor spreading to skin (T4b) and 3 cases of inflammatory carcinoma (T4d). Seventeen patients (40%) had tumor with no expression of hormone receptors and 36 (86%) with ki67≥14%. The rate of pCR was 26% (11/42). Among 29 women initially candidate to radical mastectomy, 13 of them (45%) finally received breast-conserving surgery and 8 skin-sparing mastectomy. Treatment was well tolerated and produced only moderate alopecia and no case of significant LVEF decrease. Conclusions: Neoadjuvant trastuzumab combined with the above non-anthracycline-containing sequential chemotherapy may be considered a safe and effective regimen in HER2-positive breast cancer patients. Clinical trial information: 2006 000392 15.
Breast cancer in low-income countries: India as a model.
Authors: Mahasweta Gooptu, Dinesh Doval, Kapil Kumar, Ajay Dewan, Anurag Mehta, Ullas Batra, Kumardeep Dutta, Tiffany P. Avery, Rebecca J. Jaslow, Edith P. Mitchell, Afzal Naiyer, John Manavalan, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2014)

e17517 Background: Developing countries contribute substantially to breast cancer mortality worldwide, as early-stage diagnosis and effective adjuvant therapies have decreased breast cancer-specific mortality in developed countries. Unfortunately, the costs of breast cancer screening programs and treatments limit translation of these results to developing nations. Methods: We retrospectively analyzed the tumor characteristics and modalities of management in 454 patients with Stage I-III invasive breast cancer in a single tertiary cancer center (Rajiv Gandhi Cancer Institute & Research Center) in New Delhi, India treated in 2010. Results: The median age at diagnosis was 52 (range 25-88). Stage II tumors predominated, with tumors ≤ 5 cm in size in 93% of patients. 84% of patients underwent modified radical mastectomy, while 14% underwent breast-conservation therapy (BCT). Overall, 79% of patients received adjuvant or neo-adjuvant chemotherapy and 49% received radiotherapy. Receptor characterization revealed: ER+/PR+/Her2-, 52.9%; ER+/PR+/Her2+, 10.2%; ER-/PR-/Her2+, 13.8%; and triple-negative, 23%. Of the ER+/PR+ patients, 58% were node-positive, 79% received chemotherapy and 100% were advised hormonal therapy. Of the Her-2 positive patients, 23% received trastuzumab. Conclusions: Breast cancer management strategies vary in Indian and US populations. Indian patients are younger with tumor sizes amenable to BCT followed by locoregional radiotherapy. Despite this, only a minority of patients opted for BCT. In the hormone-positive population, majority of patients received chemotherapy in addition to hormone therapy due to high incidence of node positivity, tumor size>2 cm and unaffordability of genomic assays. In the Her2+ population, trastuzumab use was limited, reportedly due to cost. Overall, management is adapted to limited resources and follow-up is inconsistent. It may be beneficial to set up Indian national breast cancer guidelines to promote multidisciplinary management, describe the molecular features of disease in this population, and evaluate the cost-effectiveness of expensive diagnostic and therapeutic interventions. This will encourage rational policies and help to create a comprehensive cancer treatment network.
Longitudinal Changes in LV Structure and Diastolic Function in Relation to Arterial Properties in General Population
Authors: Nicholas Cauwenberghs, Judita Knez, Jan D’hooge, Lutgarde Thijs, Wen-Yi Yang, Fang-Fei Wei, Zhen-Yu Zhang, Jan A. Staessen, Tatiana Kuznetsova
Journal: JACC. Cardiovascular imaging (2017)
A novel biomarker to predict sensitivity to enzalutamide (ENZA) in TNBC.
Authors: Joel S. Parker, Amy C. Peterson, Iulia Cristina Tudor, Jennifer Hoffman, Hirdesh Uppal
Journal: Journal of Clinical Oncology (2015)

1083 Background: TNBC is a heterogeneous disease with multiple subtypes and drivers. ENZA, a potent inhibitor of AR signaling, is being tested in patients (pts) whose TNBC expresses AR (> 0%) by IHC (NCT01889238). However, AR expression may not confer ENZA sensitivity. Gene profiling was therefore explored to determine whether this could be superior to IHC in predicting benefit from ENZA. Methods: Consent and tissue for AR testing was collected from 404 pts. Next-Gen RNA-sequencing analysis was performed on 175 tissue samples: 122 samples came from pts treated with ENZA (118 unique pts) (ITT); 55 were from untreated pts. A Training Set (TrS, n = 122); and a Validation Set (VS; n = 55) were created. TrS consisted of 80 samples from ENZA treated pts (77 unique pts) + 42 from untreated pts (29 AR = 0%; 13 AR > 0 %). VS consisted of 42 samples from ENZA treated pts (41 unique pts) + 13 from untreated pts (10 AR = 0%; 3 AR > 0 %). A gene expression model of biological subtype (GES) was built directly from the response data in the TrS. Model development utilized the elastic-net algorithm in the context of 500 rounds of Monte-Carlo cross-validation. Tuned parameters were used to validate the gene-expression model in the VS, outcomes were blinded during model validation. Results: The selected GES achieved 80% sensitivity and 65% specificity in prediction of 16 week clinical benefit (CBR16). Utilization of this model to define Diagnostic positive (Dx+) and Dx- populations showed the following results in pts treated with ENZA are shown in the Table. Highest accuracy was demonstrated in pts receiving ENZA as their 1st or 2nd line of therapy. Conclusions: A genomic signature, associated with androgen biology, has been identified that demonstrates the potential to predict clinical response to ENZA in pts with TNBC. Nearly half of the pts enrolled in the phase 2 were classified as Dx+, suggesting a reasonable prevalence of pts who may benefit from this hormonal therapy. This assay may be useful to select TNBC pts for future studies evaluating ENZA. Clinical trial information: NCT01889238. Training Set Validation Set ITT (both sets) Dx+ (n=39) Dx- (n=38) Dx+ (n=17) Dx- (n=24) Dx+ (n=56) Dx- (n=62) CBR16 (% pts; 95% CI) 44 (29-60) 13 (5-27) 29 (12-54) 8 (2-26) 39 (27-53) 11 (5-21) CBR24 (% pts; 95% CI) 39 (24-55) 10 (4-24) 29 (12-54) 0 (0-13) 36 (24-49) 6 (2-16)
Exploring the association between diabetes and breast cancer outcomes among Latinas.
Authors: Kimlin Tan Ashing, Raynald Samoa, Lily L. Lai, Arti Hurria, Mayra Serrano, Eva Meyers
Journal: Journal of Clinical Oncology (2017)

221 Background: In cancer patients, diabetes increases the risk for poor overall health and cancer-specific outcomes even death. Moreover, both breast cancer (BC) and diabetes are amongst the most common illnesses in Latinas, who have documented poorer outcomes for both diseases. This study examined the impact of co-occurring diabetes on patient outcomes in a sample of Latina breast cancer survivors (BCS). Methods: 137 Latina BCS were recruited from the California Cancer Registry, hospital cancer registries, and community agencies. BCS completed a self-report questionnaire consisting of items related to demographic and medical characteristics, including diagnoses of cancer and diabetes, and physical and functional outcomes. Results: Thirty nine (28%) BCS reported a co-occurring diagnosis of diabetes; this is over twice the rate in the general population. Diabetes was most prevalent among BCS 65 years and older with 43% reporting co-occuring diabetes. BCS with diabetes, controlling for age, were more likely to report advanced BC staging at diagnosis ( p= 0.036) and more severe lymphedema symptoms than BCS without diabetes ( p= 0.038). BCS with diabetes also endorsed lower general health and greater social functioning limitations and physical role limitations than BCS without diabetes ( p= 0.048). Conclusions: This investigation sheds new light on emerging evidence documenting the negative associations of co-occurring chronic conditions, such as diabetes, on cancer patients’ outcomes. Our findings highlight the urgent need for additional inquiry examining multiple chronic conditions, particularly in the face of cancer. Early integrative and coordinated care that attends to multiple chronic conditions, especially among elderly and ethnic minority patients, may serve as a critical target for addressing disparate cancer risk and outcomes to improve quality, patient-centered care and patients’ outcomes. Clinical trial information: NCT00932997.
Population pharmacokinetics of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced solid tumors
Authors: H. Wu, R. K. Ramanathan, S. Srychor, B. A. Zamboni, S. Ramalingam, R. P. Edwards, D. M. Friedland, R. G. Stoller, C. P. Belani, W. C. Zamboni
Journal: Journal of Clinical Oncology (2009)

2545 Background: CKD-602, a semi-synthetic analogue of campothecin, is a potent topoisomerase I inhibitor. S-CKD602, a PEGylated long-circulating liposomal formulation of CKD-602, was developed to achieve a longer intra-tumoral exposure of CKD602 and a higher therapeutic index. Age and body composition were reported to affect the pharmacokinetics (PK) of S- CKD602 (Zamboni, ASCO'07). A population PK model for encapsulated and released CKD-602 following administration of S- CKD602 was developed to assess factors that may influence S-CKD602 PK. Methods: Plasma samples from 45 patients (pts) with solid tumors were collected in a phase I study. S-CKD602 was administered as a 1 h IV infusion with doses ranging from 0.1 to 2.5 mg/m 2 . Plasma concentrations of encapsulated (n=292) and released (n=268) CKD-602 were measured by LC-MS/MS, and population PK modeling was performed using NONMEM. Results: Pts were classified as linear and nonlinear pts according to the clearance (CL) of encapsulated CKD-602 using a classic two stage PK modeling approach. Mean ± SD ratio of total body weight to ideal body weight of pts with linear and nonlinear CL of encapsulated CKD-602 was 1.13 ± 0.16 and 1.53 ± 0.29, respectively (P = 0.003). PK of encapsulated CKD-602 was described by 1-compartment model with nonlinear CL (Michaelis-Menten kinetics). PK of released CKD-602 was described by a 2- compartment model with linear CL for all pts. The presence of primary or metastatic tumor(s) located in the liver decreased the inter- individual variability (IIV) in the CL of encapsulated CKD-602 by 13%. Typical values of Vmax of encapsulated CKD-602 in pts with and without hepatic tumor(s) were 156 and 103 μg/h, respectively (P &lt; 0.001). The inclusion of age decreased IIV in the release of CKD-602 from S-CKD602 by 22%. Typical values of release of CKD-602 from S-CKD602 in pts &lt; 60 years old (yo) and pts ≥ 60 yo were 0.21 and 0.10 L/h, respectively (P &lt; 0.001). Conclusions: These data suggest that older patients (pts ≥ 60 yo) have a reduced release of CKD-602 from S-CKD602. In addition, pts with tumors in the liver may have an increased clearance of S-CKD602. These observations have potential implications in the optimal dosing of liposomal agents. [Table: see text]
Use of flow cytometry in acute promyelocytic leukemia.
Authors: Tarik H. Hadid, Entezam A. Sahovic, John Lister
Journal: Journal of Clinical Oncology (2013)

7075 Background: Acute promyelocytic leukemia (APL) is a highly curable disease, with the majority of failures related to hemorrhagic complications. Hence, rapid diagnosis and early initiation of therapy can drastically prevent these complications and reduce mortality. The current diagnostic strategy utilizing fluorescent in situ hybridization (FISH) is often time-consuming and not readily available in some institutions. This is a review of our institutional experience with the use flow cytometry for diagnosis of APL. Methods: All cases with t(15;17) by FISH and karyotype between 2006 and 2012 were identified. A second group of consecutive cases of non-M3 acute myeloid leukemia (AML) and negative FISH and karyotype for t(15;17) was used for comparison. A total of 21 APL and 42 non-M3 AML cases were analyzed. Results: Both groups were comparable in regard to age, gender, white blood cell count, hemoglobin, blast count and lactate dehydrogenase level. The APL group had significantly higher prevalence of thrombocytopenia, disseminated intravascular coagulation and clinical bleeding at time of admission. Expression of CD11c was lacking in 92.3% (12/13) of APL and 14.6% (6/41) of non-M3 AML cases (p&lt;0.0001). CD34 expression was lacking in 68.4% (13/19) of APL and 42.9% (18/42) of non-M3 AML cases (p=0.06). HLA-DR expression was lacking in 88.9% (16/18) of APL and 9.5% (4/42) of non-M3 AML cases (p&lt;0.0001). Given that APL prevalence is 5% among all AML cases, lack of expression of CD11c, CD34 and HLA-DR have negative predictive values (NPVs) of 99.5%, 97.1% and 9933%, respectively. Among various immunophenotypic profiles, lack of expression of CD11c had the highest NPV (99.5%, p&lt;0.0001) and simultaneous lack of expression of CD11c and HLA-DR had the highest specificity (95.1%, p&lt;0.0001). Conclusions: Expression of CD11c reliably excludes the diagnosis of APL in the majority of AML cases. Flow cytometry has the potential of replacing FISH as the initial test to prompt initiating therapy in APL patients.