tbuckley/cabot-search huggingface dataset:
Antitumor activity of zoledronic acid in primary breast cancer cells determined by the ATP tumor chemosensitivity assay.
Authors: T. N. Fehm, H. Seeger, M. Zwirner, D. Wallwiener, H. Neubauer
Journal: Journal of Clinical Oncology (2011)

e11112 Background: The NeoAzure study has demonstrated that the use of the bisphosphonate zole-dronate in the neoadjuvant setting increases the rate of complete response in primary breast cancer and therefore indicates direct antitumor activity (Coleman et al. 2010). The purpose of this study was to compare the antitumor effect of zolendronic acid with standard chemotherapy in primary breast cancer cells using ATP-tumor chemosensitivity assay (ATP-TCA). Methods: Breast cancer tissues were obtained from patients with breast cancer who underwent primary breast cancer surgery at the Dept of OB/Gyn, Tübingen, Germany, between 2006 through 2009. Antitumor effects of zoledronic acid (Zol), TAC (docetaxel, doxorubucin hydrochloride, cyclophosphamide) and FEC (5-fluorouracil, epirubicin, cyclophosphamide) were tested in 116 fresh human primary breast cancer specimens using ATP-TCA. ATP-TCA results were analyzed with different cut-off levels for the half maximal inhibitory concentration (IC50) and for IC90 and for the sensitivity index (IndexSUM). Each single agent or combination was tested at six doubling dilutions from 6.25, 12.5, 25, 50, 100, and 200% of test drug concentrations (TDC) derived from the plasma peak concentrations determined by pharmacokinetic data. The assay was carried out in duplicate wells with positive and negative controls. Results: The median IndexSUM value was lower for Zol (170) than for the combined regimen FEC (296) and TAC (195), respectively, indicating increased direct antitumor activity of Zol in primary breast cancer cells. The difference regarding IndexSUM between Zol and FEC was significant (p< 0.05). The median IC50 value for Zol (8.03% TDC) was significantly lower than the IC50 values for FEC (33.5% TDC) and TAC (19.3% TDC) treatment (p< 0.05). However, the median IC90 value for Zol (152.5% TDC) was significantly higher than the IC90 value obtained with TAC (49.5% TDC; p< 0.05), but similar to the IC90 value for FEC (180.9% TDC). Conclusions: Zol has a direct strong antitumor effect on primary breast cancer cells in vitro which is comparable to the antitumor effect of commonly used chemotherapeutic regimens in breast cancer. The clinical consequences have to be discussed.
Association of body mass index (BMI) with progression-free survival (PFS) in patients with advanced renal cell cancer (RCC) treated with targeted therapies.
Authors: J. Dhaliwal, H. S. Gill, B. I. Chung, L. C. Harshman, K. Rajan, S. Srinivas
Journal: Journal of Clinical Oncology (2011)

e15103 Background: Obesity is strongly associated with an increased risk of RCC. Patients with higher BMI have improved outcomes with nephrectomy. No data exists evaluating the impact of BMI on (PFS) after targeted therapy (TT) for advanced RCC. The majority of targeted drugs are administered in a uniform dose as the initial pharmacokinetics studies did not observe differences based on weight. We investigated whether BMI is associated with (PFS) in advanced RCC. Methods: Using our existing RCC database, we retrospectively identified 141 patients from Jan 2004 to December 2010 who were treated with sorafenib, sunitinib, pazopanib, bevacizumab, temsirolimus or everolimus. This equated to 261 TT courses.Of these, 46 data sets were excluded either for lack of followup or BMI data. BMI was calculated at the start of each therapy and classified into three groups- less than 25 kg/m2, 25 to 30 kg/m2 and greater than 30 kg/m2. PFS was defined as the number of days from treatment initiation to the date of relapse on a treatment. A Cox proportional hazards regression model for multiple events per patient was used to study the increase in hazard ratio between the BMI groups after adjusting for age, gender and treatment regimens Results: In all, 120 patients who received 215 treatment courses were evaluated. The majority was male (79%). The median age was 59 yrs (18-85). The mean KPS was 80. The mean BMI was 27.8 (12.4-52.6); 75 cases had a BMI <25; 79 had a BMI of 25-30, and 60 cases had a BMI >30. Holding age and gender constant, patients who had a BMI of 25-30 had a reduced hazard of progression by 0.58 (p<.0001), which was 42% lower than patients with BMIs <25. Similarly, patients with a BMI >30 had a reduced hazard of progression by 0.39 (p<.0001), which is 61% lower than patients with a BMI <25. Conclusions: Increased BMI was associated with a lower hazard of relapse among patients independent of age, gender and treatment received. To our knowledge this is the first report to show the association of increased BMI with prolonged PFS after targeted therapy in RCC. These findings require validation in larger datasets.
Prevalence of metabolic syndrome in older (50 years and older) vs younger (less than 50 years) patients with colorectal cancer diagnosed in a safety net hospital system.
Authors: Ashish Sharma, Johanna Chan, Tony Trang, Milena Gould Suarez
Journal: Journal of Clinical Oncology (2016)

512 Background: Colorectal cancer (CRC) incidence has declined overall with screening, though incidence in patients younger than 50 years has increased. Younger patients present with more aggressive and advanced stage CRC. Potential mechanisms are sporadic, genetics, and environmental (alcohol, smoking, metabolic syndrome). Metabolic syndrome (MetS) is an established risk factor for CRC. We examined the prevalence of MetS in younger patients ( &lt; 50 yrs) compared with older patients ( ≥ 50 yrs) with CRC in a safety net hospital population. Methods: IRB-approved retrospective chart review of all patients diagnosed with CRC in the Harris County Hospital District cancer registry from Jan 2008 to Dec 2013. Data was collected for patient characteristics and metabolic syndrome to compare 2 patient groups: &lt; 50 yr (younger) and ≥ 50 yr (older). MetS was defined using 2005 AHA/NHLBI criteria as ≥ 3 of the following components: abdominal obesity (waist circumference &gt; 102 cm in men, &gt; 88 cm in women), serum triglycerides (TG) ( &gt; 150 mg/dL), serum HDL ( &lt; 40 mg/dL in men and &lt; 50 mg/dL in women), BP &gt; 130/85 mmHg, fasting glucose/diabetes ( ≥ 100 mg/dL). Per WHO criteria, BMI &gt; 30 was used as surrogate for waist circumference. Descriptive statistics were performed using t-test for continuous variables and Chi-square / Fisher’s exact test for categorical variables. Results: 625 cases of CRC diagnosed showed median age of 56.5 years and 54.7% female patients. The majority (77.76%) of cases occurred in the older group. Overall, 208/625 patients (33.28%) had MetS. Average BMI overall was 27.33. Prevalence of MetS was 38.27% vs 23% (older vs younger; p = 0.0001). In older compared with younger patients, average BMI 26.13 vs 25.05 (p = 0.02), obesity 25.92% vs 35.87% (p = 0.05), BP &gt; 130/85 mmHg 56.3% vs 31.6% (p = 0.001), low HDL 41.7% vs 31.9% (p = 0.02), TG &gt; 150 34.7 % vs 22.3 % (p = 0.02) and diabetes 36.2% vs 11.5% (p = 0.001). Conclusions: Overall prevalence of MetS in our patient cohort was similar to that of general population (which approximates 34%). Prevalence of MetS was higher in older patients with CRC than in younger patients, though this may reflect the natural history of MetS.
Impact of margin status and lymphadenectomy on clinical outcomes in resected pancreatic cancer: Implications for adjuvant radiotherapy.
Authors: Arsen Osipov, Jason Naziri, Andrew Eugene Hendifar, Deepti Dhall, Joanne K Rutgers, Shefali Chopra, Quanlin Li, Alagappan Annamalai, Mourad Tighiouart, Nicholas N. Nissen, Richard Tuli
Journal: Journal of Clinical Oncology (2015)

429 Background: Adjuvant chemoradiotherapy (CRT) in the treatment of pancreatic ductal adenocarcinoma (PDA) is controversial. Minimal data exists regarding the clinical significance of margin clearance distance and lymph node (LN) parameters, such as extent of dissection and LN ratio. We assess the impact of these variables on clinical outcomes to identify the subset of patients who may benefit from adjuvant CRT. Methods: We identified 106 patients with resected stage 1-3 PDA from 2007-13. Resection margins were categorized as positive (tumor at ink), ≤ 1 mm, or &gt; 1 mm. LN evaluation included total number examined (NE), number of positive nodes (NP), ratio of NP to NE (NR), and presence of periportal adenopathy. The impact of these variables was assessed on disease-free survival (DFS) and overall survival (OS) using multivariate cox proportional hazards modeling. Actuarial estimates for DFS and OS were calculated using Kaplan-Meier methods. Results: Margin status was highly correlated with NP (p=0.012). Margin status adjusted for NP was a significant predictor of DFS in patients receiving adjuvant chemotherapy (CT) alone with greater margin clearance leading to improved DFS for all 3 groups (p=0.0412, HR = 0.51). Range of NE was 4-37, with a mean of 19. NE was not associated with DFS or OS, yet absolute NP of 5 or more was associated with a significantly worse DFS (p=0.005). A median NR of 0.11 was associated with inferior DFS (p=0.0043; HR=4.04), but was not associated with OS. Whereas periportal lymphadenectomy did not result in improved DFS or OS, patients with positive periportal LN had worse clinical outcomes (DFS, p=0.0052; OS, p=0.023). The use of adjuvant CRT was associated with improved OS (p=0.049; HR=0.29). Conclusions: In patients receiving adjuvant CT alone, there was a clinically significant benefit in clearing the surgical margin beyond tumor at ink. Higher NR, having 5 or more NP and presence of periportal adenopathy clearly led to worse clinical outcomes. A more comprehensive evaluation of margins and LN parameters may identify an increasing number of patients at risk for locoregional failure who may benefit from adjuvant CRT.
Toxicities of new targeted therapies in renal carcinoma.
Authors: M. N. Cortes, E. Richardet, M. E. Richardet
Journal: Journal of Clinical Oncology (2011)

e15107 Background: Renal-cell carcinoma is the most common cancer of the kidney. Up to 30% of patients present with advanced disease. Sunitinib, an inhibitor of tyrosine kinases, and temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) kinase, showed clinical activity in patients with metastatic disease.Our objective is to evaluate the most frequent toxicities in patients receiving first line treatment with targeted therapies. Methods: We retrospectively analized the medical records of patients with advanced Renal-cell Carcinoma assisted at the Instituto Oncológico de Córdoba, from 2006 to 2010. We used the Memorial Sloan-Kettering Cancer Center (MSKCC) model for risk stratification. 33 patients were included, 7 women and 26 men, with a median age of 60.7 years (26-88). Histollogical types were Clear Cell Carcinoma 94 % (31) and Papilar Carcinoma 6 % (2). Adverse events were asessed with Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0. Results: 69.69% (23) received sunitinib and 30.30 % (10) temsirolimus; 57.58 (19) were nephrectomized and 42.42 % (14) were not. The adverse reactions observed are shown in the Table. All patients that received temsirolimus were high risk. There were no dose suspension nor dose reduction due to toxicity in those patients. In the sunitinib arm (50 mg QD 4 weeks on/2 weeks off) 30.43% (7) of patients were low risk, 47.82% (11) intermediate and 21.73% (5) high risk. Most common toxicities were grade 1 and 2; for grade 3-4 toxicities, 30,43% (7) had dose reductions that allowed them to continue treatment. There were no permanent discontinuation of treatment due to toxicity. Conclusions: We observed a high percentage of grade 1 and 2 toxicities, but they had no effect on treatment adherence. Grade 3 and 4 toxicities were, in general, well manageable with dose reductions or supportive medication. Toxicities Sunitinib Temsirolimus Sunitinib Temsirolimus Grade 1-2 1-2 3-4 3-4 Asthenia 21% 13% Diarreah 30% 4% Dysgeusia 30% Dyslipemia 40% 10% Hyperuricemia 13% 20% 10% Hypothyroidism 13% HBP 30% 4% Mucosititis 30% 4% Neutropenia 9% Petechiae 13% Pruritus 40% Rash 20% Reflux gastritis 9% Hand-foot syndrome 13% 4% Dermis vasculitis 13% 9% Xerostomia 10%
First results from a phase I trial of AZD8055, a dual mTORC1 and mTORC2 inhibitor.
Authors: U. Banerji, C. Aghajanian, E. Raymond, R. Kurzrock, M. Blanco-Codesido, E. Oelmann, L. Grinsted, W. Burke, S. B. Kaye, A. Naing
Journal: Journal of Clinical Oncology (2011)

3096 Background: AZD8055 is a dual mTORC1/mTORC2 inhibitor with properties that prevent the feedback activation of AKT seen with rapalogues. This is the first-in-man study of AZD8055 to determine the safety, PK and preliminary efficacy of two oral formulations in patients with advanced solid tumours (NCT00731263). Another dual mTORC1/mTORC2 inhibitor, AZD2014, is currently being tested in the clinic. Methods: In an open-label, ascending dose study, cohorts of 3 or 6 patients received a single dose of AZD8055 followed 1 week later by continuous, twice-daily dosing. Starting at 10 mg, each subsequent cohort received an increased dose until a non-tolerated dose was reached. The formulation was switched from oral solution to tablet when the tablet became available. Safety and PK data were collected in addition to FDG-PET and RECIST. Modulation of AKT phosphorylation on serine 473 and of 4EBP1 phosphorylation on threonine 37/46 was measured in peripheral tissue after single administration of AZD8055 to confirm proof-of-mechanism. Results: 49 patients (42 evaluable) were dosed in seven cohorts: oral solution; 10, 20, 40 mg BD, tablet; 40, 60, 90, 120 mg BD. Non-tolerated dose was 120 mg BD and so maximum tolerated dose (MTD) was 90 mg BD. Dose limiting toxicities of CTC grade 3 transaminases were reported with 40 mg BD solution (n=1), 90 mg BD tablet (n=1), 120 mg BD tablet (n=3). No cases of Hys law were observed. Onset of increased transaminases was typically between day 35 and 45 but there was no clear relationship with plasma concentration of AZD8055. AZD8055 was rapidly absorbed with median tmax of 0.5 h for both single dose (n=49) and steady state (n=36). Elimination was rapid with mean t1/2 of 2.4 h for single dose (SD=1.1, n=49) and 2.7 h for steady state (SD=0.79, n=36). AZD8055 showed a large apparent volume of distribution and high apparent clearance: mean Vss/F 2400L (SD=2062; 90 mg dose, n=11), mean Cl/F 950 L/h (SD=889; 90 mg dose, n=11). Pharmacodynamic changes in peripheral blood mononuclear cells were observed and results will be presented. Conclusions: The MTD for AZD8055 is 90 mg BD. Toxicities frequently associated with administration of rapalogues such as rash and mucositis were not dose limiting. Updated data will be presented.
Clinical T1 urothelial bladder cancer: USC experience.
Authors: Mehrdad Alemozaffar, Hooman Djaladat, Jie Cai, Gus Miranda, Anne Schuckman, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2014)

327 Background: Patients with clinical T1 (cT1) urothelial bladder cancer (UBC) present a dilemma regarding the decision to proceed with radical cystectomy (RC) or conservative therapy. We review outcomes of patients with cT1 UBC who underwent RC. Methods: Retrospective review of 1,964 patients undergoing RC for UBC at our institution from 1971-2008 revealed 442 patients with cT1 disease on last TURBT (excluding patients with any TURBT with &gt;cT1 or receiving neoadjuvant therapy) of whom 97 had muscle present on last TURBT. Results: Of 442 patients with cT1 UBC, 260 (58.8%) remained &lt;pT1, 124 (28.1%) were upstaged to &gt;pT2, and 58 (13.1%) had positive lymph node (LN+) at RC; therefore, 182 (41.2%) had more extensive disease pathologically than clinically. LN+ patients were more likely than &lt;pT1 or &gt;pT2 to have LVI on TURBT (24.1% vs 11.5% vs 11.3%, p=0.029) and RC (67.2% vs 5.8% vs 36.3%, p&lt;0.001). No clinical variables were associated with upstaging to &gt;pT1 or LN+ disease on multivariate analysis (MVA). 5-yr recurrence-free survival (RFS) was 75.4% with MVA associating worse RFS with &gt;pT2 (HR=1.819, p=0.02), LN+ (HR=8.202, p&lt;0.001), pathologic LVI (HR=2.022, p=0.002), multifocal disease (HR=1.306, p&lt;0.001), and increasing TURBTs (HR=1.306, p&lt;0.001). 5-yr overall survival (OS) was 68.4% with MVA associating worse OS with increasing age (HR=2.234, p&lt;0.001), &gt;pT2 (HR=1.557, p=0.0055), LN+ (HR=4.391, p&lt;0.001), pathologic LVI (HR=1.641, p=0.002), and increasing TURBTs (HR=1.116, p=0.005). When limited to patients with muscle present on last TURBT (N=97), following RC there were 65 (67%) remaining &lt;pT1, 23 (23.7%) were upstaged to &gt;pT2, and 9 (9.3%) were LN+; therefore, 31 (33%) had more extensive pathologic disease than thought clinically. Their 5-yr RFS was 81.4% with MVA associating worse RFS with LN+ (HR=9.111, p=0.007) and increasing TURBTs (HR=1.408, p=0.028). Their 5-yr OS was 73.5% with MVA associating worse OS with LN+ (HR=7.976, p=0.004). Conclusions: Patients with cT1 UBC have a significant rate of upstaging to &gt;pT1 or LN+ disease at cystectomy, even with muscle present at last TURBT. Although LVI may be associated with more extensive disease favoring cystectomy over conservative management, there are no reliable clinical predictors to determine upstaging.
Response to imatinib mesylate in patients with the FIP1L1-PDGFR-alpha positive hypereosinophilic syndrome: Update of a multicenter prospective study and guidelines for eosinophilia diagnosis
Authors: S. Merante, M. Rondoni, E. Otaviani, S. Paolini, D. Cilloni, F. Messa, E. Iannitto, F. Pane, G. Saglio, G. Martinelli, M. Baccarani
Journal: Journal of Clinical Oncology (2008)

7034 Background: The hypereosinophilic syndrome (HES) may be associated with the fusion of the PDGFRα gene with the FIP1L1 gene in chromosome 4 coding for a constitutively activated tyrosine kinase. This condition understand a clonal chronic myeloproliferative disorder and it is usually referred to as chronic eosinophilic leukemia (CEL). These cases of FIP1L1-PDGFRα rearranged CEL have been reported to be very sensitive to the TK inhibitor Imatinib mesylate (IM). Methods: A prospective multicenter study of the HES was established in 2001. 72 patients were treated with IM 100 to 400 mg daily. The observation period ranges between 12 and 68 months (median 28 months). 33 patients (46%) were found to carry the FIP1L1-PDGFRα rearrangement, while 39 (54%) were negative. The main difference between rearranged and non-rearranged patients was gender, that was male in all but one rearranged patients vs 26 of 39 in negative cases. Other minor differences concerned the age, with a median of 50 years in positive patients vs 60 in negative ones; the total eosinophil count (median 4.9 x 109/L in positive patients vs 3.4 in negative patients); skin involvement, recorded only in 6 negative patients, and splenomegaly, reported in 7 rearranged patients and only one negative. Results: 32 male patients and only one female patient carried the FIP1L1-PDGFRα rearrangement. All 33 achieved a complete hematologic remission (CHR) and became RT-PCR negative for the fusion transcripts. With a median follow-up of 25 months (15–60 months) All 33 patients remain in CHR and RT-PCR negative, and continue the treatment at a dose of 100 to 400 mg daily. In four patients IM treatment was discontinued for few months, the fusion transcript became rapidly detectable, and was again undetectable upon treatment resumption. 39 patients did not carry the rearrangement. 5/39 (13%) achieved a CHR, that was lost in all cases after 1 to 15 months. Conclusions: All patients fitting the criteria for the HES should be screened for the FIP1L1-PDGFRα rearrangement and for rearranged patients, chronic IM treatment ensures complete and durable responses. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis Bristol-Myers Squibb, Novartis, Roche
Patients' and family caregivers' (FC) quality of life (QOL) and mood during hospitalization for hematopoietic stem cell transplantation (HCT).
Authors: Areej El-Jawahri, Lara Traeger, Justin Eusebio, Kailyn Kuzmuk, Harry Vandusen, Jennifer Shin, Joseph A. Greer, William F. Pirl, Karen K. Ballen, Thomas R. Spitzer, Timothy A. Graubert, Steven L. McAfee, Bimalangshu Dey, Vicki A. Jackson, Yi-Bin Albert Chen, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2014)

160 Background: While the long-term outcomes of HCT survivors have been described, the acute impact of hospitalization for HCT on patients’ and FC QOL and mood has received little attention. Methods: We conducted a longitudinal study of patients (and FC) hospitalized for HCT. At baseline (6 days pre-HCT), day+1, and day+8 of HCT, we assessed QOL (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation FACT-BMT), fatigue (FACT-Fatigue), and mood (Hospital Anxiety and Depression Scale HADS). We used the SF-36 to examine FC QOL [physical component scale (PCS), and mental component scale (MCS)]. Using multivariable linear mixed models, we examined predictors of QOL changes during hospitalization. Results: We enrolled 97% of consecutively eligible patients undergoing autologous (n=30), myeloablative (n=30) or reduced intensity (n=30) allogeneic HCT. Patients’ QOL markedly declined and fatigue increased throughout hospitalization (Table). The proportion of patients meeting criteria for depression (HADS-D &gt; 7) more than doubled from baseline to day+8 (15.6% to 37.8%, P &lt; 0.0001) whereas the proportion of patients with anxiety remained stable (22.2%, P = 0.8). Depression (β= -2.24, F=42.2, p &lt; 0.0001) and anxiety (β= -0.63, F=4.4, p = 0.03) at baseline independently predict worse QOL throughout hospitalization. The FC QOL declined during patient’s hospitalization (PCS: 83.1 to 79.6, P= 0.03, MCS: 71.6 to 67.4, P = 0.04). Conclusions: Patients undergoing HCT reported a rapid and steep deterioration in QOL along with substantially worse fatigue and depression during hospitalization. Greater decrements in QOL were predicted by depression and anxiety highlighting the importance of assessing pre-HCT psychiatric morbidity. [Table: see text]
Comparison of sizes of sentinel and non-sentinel lymph nodes in colorectal cancers (CRCa).
Authors: Sukamal Saha, Ujwala Koduru, Jacob Burke, Alpesh K. Korant, Supriya Kumar Saha, Vikrom K. Dhar, Gregory Johnston, David Wiese, Madan L. Arora, Trevor Singh
Journal: Journal of Clinical Oncology (2014)

557 Background: Sentinel lymph node (SLN) mapping (M) in CRCa with ultrastaging of SLNs find more nodes per patient (Pt) and more metastasis in the SLNs than non-SLNs (NSLNs) compared to conventional methods. We hypothesized that SLNs may represent a subset of nodes smaller than those detected by routine pathological exam, and hence missed by conventional methods. Hence, we compared the sizes of SLNs and NSLNs in CRCa pts undergoing SLNM. Methods: 365 pts underwent subserosal peritumoral injections of blue dye for SLNM. Blue stained nodes were tagged as SLNs. SLNs were sectioned at 5 levels, 4 stained with H &amp; E, one with cytokeratin (CK-IHC). The non-SLNs were sectioned at one level and stained with H &amp; E. Greatest diameter of nodes for sizes were measured on glass slides or from gross examination. Results: Of the total of 5,601 LNs (Average 15.3/pt) included, 912 were SLNs and 4689 non-SLNs. Of the total lymph nodes removed, 78% were 5mm or less; 69% of positive LNs and 97% of negative LNs were less than 9mm (Table). On average, the size of SLN was bigger (5.7mm) than NSLN (4.0mm). Both positive and negative SLNs were also bigger than positive and negative NSLNs (Table). Conclusions: Our study confirms that on average, SLNs are bigger than NSLNs whether positive or negative or as a whole. This also highlights diligent efforts needed by the pathologists, as 77% of all lymph nodes were less than 5mm. [Table: see text]