tbuckley/cabot-search huggingface dataset:
The role of the physician in the prognostic accuracy of advanced cancer patients and their caregivers.
Authors: Rachel Jimenez, Paul K Maciejewski, Holly Gwen Prigerson
Journal: Journal of Clinical Oncology (2014)

9521 Background: Accurate understanding of prognosis among terminally ill patients and their informal caregivers is necessary for informed medical decision-making. We report on the relationship between physician prognostic discussions and prognostic accuracy of advanced cancer patients and their caregivers. Methods: Coping with Cancer is an NCI/NIMH-funded prospective, longitudinal study of advanced cancer patients and their informal caregivers. Baseline interviews conducted at seven outpatient oncology centers throughout the United States between September 2002 and August 2008, asked patients and caregivers if they had discussed prognosis with a physician and to estimate the patient’s life expectancy. Results: 240 patient-caregiver dyads were identified. Median survival was 3 months. 39% (94/240) of dyads offered a numeric estimate of prognosis; the remainder answered: “I don’t know.” 12% of patient and 29% of caregiver estimates were accurate (+/- 3 months of survival); 34% of patients and 31% of caregivers overestimated prognosis (+/- >3-12 months of survival); 52% of patients and 36% of caregivers grossly overestimated prognosis (>12 months from death). Only 2% of patients and 4% of caregivers underestimated prognosis. Caregivers reported more prognostic discussions with the patient’s physician (58.3% caregivers; 33.3% patients; χ2= 7.6; df=1; p=0.006) and were significantly more accurate in their life-expectancy estimates when reporting a conversation had taken place (OR 5.3, 95% CI 1.7-16.9; p = 0.002), but patients were not. Accurate life expectancy estimates were significantly associated with patient with completion of a DNR Order (OR 11.7; 95% CI 3.6-38.0; p < 0.001). Conclusions: Patients and caregivers overestimate life expectancy, but caregivers recall more prognostic discussions with physicians and are more accurate about the patient’s prognosis following such discussions than patients. However, patients with greater prognostic accuracy are more likely to complete a DNR order. Therefore, physicians should involve family caregivers in prognostic discussions whenever possible to promote a more accurate understanding of the patient’s life-expectancy and advance care planning.
Vorinostat, temozolomide, and bevacizumab for patients with recurrent glioblastoma: A phase I/II trial.
Authors: Katherine B. Peters, James J. Vredenburgh, Annick Desjardins, Henry S. Friedman, James Emmett Herndon, April D. Coan, Frances McSherry, Eric S Lipp, Alise Brickhouse, Woody C Massey, David A. Reardon
Journal: Journal of Clinical Oncology (2012)

2027 Background: Prognosis for recurrent glioblastoma (GBM) remains poor with median survival between 3 to 6 months. Use of anti-vascular endothelial growth factor inhibitor, bevacizumab (BEV), has advanced this area of research, but continued studies have focused on whether the addition of other chemotherapies can improve efficacy in recurrent GBM. Vorinostat, a small molecule inhibitor of histone deactylase (HDAC), has anti-tumor activity directly through HDAC inhibition and indirectly by promoting anti-angiogenesis. Its good oral bioavailability and favorable toxicity profile make it a promising additive agent to standard therapy. Thus, we evaluated the efficacy of vorinostat in combination with BEV and daily temozolomide (TMZ) in recurrent GBM. Methods: This was a phase I/II open-label, single arm study in recurrent GBM patients. Primary endpoint was 6-month progression free survival (PFS). Secondary endpoints were safety/tolerability, radiographic response, PFS, and overall survival of recurrent GBM patients treated with BEV plus daily TMZ and vorinostat. Chief eligibility criteria included age ≥ 18 years, KPS ≥ 70, time interval ≥ four weeks from previous treatment, and maximum of 2 prior progressions. Dosing regimen was as follows: BEV 10 mg/kg IV every two weeks, TMZ 50 mg/m 2 po daily, and vorinostat 400 mg po for 7 days on then 7 days off in a 28 day cycle. Results: 46 recurrent GBM patients were enrolled with 42 of those patients receiving a vorinostat dose of 400 mg. Most common grade 2 and above toxicities were leukopenia (36%), neutropenia (29%), fatigue (24%), and thrombocytopenia (19%). Serious toxicities included 4 grade 4 toxicities (grade 4 hyperglycemia, pulmonary embolism, bowel perforation and intracranial hematoma) and 1 patient expired on day of informed consent due to pulmonary embolism (grade 5). With a median follow-up of 11.3 months (95% CI: 10.1, 13.1 months), the 6-month PFS was 52.4% (95% CI: 36.4%, 66.1%). Best radiographic responses were 2 complete responses, 17 partial responses, 20 stable responses, and 1 radiographic progression. Conclusions: In summary, combination of BEV, daily TMZ, and vorinostat has promising efficacy on recurrent GBM with reasonable toxicity/safety.
Mechanism-based PKPD model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET- 743) treatment
Authors: G. J. Fetterly, J. S. Owen, K. Stuyckens, J. A. Passarell, P. Zannikos, A. S. Matos, M. A. Izquierdo, J. J. Perez-Ruixo
Journal: Journal of Clinical Oncology (2007)

2545 Background: Reversible transient elevations in transaminases have been observed after trabectedin (T) administration, despite no alteration in plasma PK. A PKPD model was developed to evaluate the time course of ALT elevation, tolerance development, and covariate effects following different dosing schedules in cancer subjects. Methods: T was administered to 711 subjects as monotherapy (dose range: 0.024 - 1.8 mg/m 2 ) as 1-, 3-, or 24-hr infusions every 21 days; 1- or 3-hr infusions on days 1, 8, and 15 every 28 days; or 1-hr infusions daily for 5 consecutive days every 21 days. Population PKPD modeling was performed with covariate evaluation [dexamethasone use (469/711 pt), ECOG PS scores (89.7% pts = 1), and BW (36–122 kg)] on PD parameters, followed by model validation. Simulations assessed the influence of dosing regimen and selected covariates on the time course of ALT and the effectiveness of the dose reduction strategy. Results: A precursor-dependent PKPD model described the temporal relationship between ALT elevation and T concentrations, where the transfer process of ALT from hepatocytes to plasma is stimulated by trabectedin plasma concentration. Overall, 66% of subjects had transaminitis. Mean predicted (%SEM) baseline ALT (ALT o ) and T 1/2 in plasma were 33 (5.5) U/L and 1.4 days, respectively. The magnitude of the T stimulation on the ALT transfer rate from hepatocytes to plasma was 11.2% per 100 pg/mL of trabectedin plasma concentration. Dexamethasone decreased the rate of T-induced ALT release from hepatocyte by 63% (p&lt;0.001). Model validation results showed good concordance with the observed incidence of grade 3/4 toxicity. Simulations showed that severity of ALT elevation was dose- and schedule-dependent. The dose reduction strategy decreased the incidence of grade =3 toxicity by 13% and 39% following 2 and 4 cycles of therapy, respectively. Conclusions: A PKPD model quantifying the hepatoprotective effect of dexamethasone on transient and reversible transaminitis after T treatment has been developed. The model predicts that co-administration of dexamethasone and the suggested dose reduction strategy will enhance the safe use of T in the clinic. No significant financial relationships to disclose.
Optimizing the therapy of desmoplastic small round cell tumor: Combined experience from the two major cancer centers.
Authors: Vivek Subbiah, Aaron D Viny, Peter Meade Anderson, Andrea Anita Hayes-Jordan, Wei Qiao, Robert S. Benjamin, Robert G. Maki, Joseph A. Ludwig
Journal: Journal of Clinical Oncology (2012)

10021 Background: Desmoplastic small round cell tumor (DSRCT) is a rare translocation-positive (EWS-WT1)sarcoma subtype that often presents as diffuse peritoneal sarcomatosis in male adolescents and young adults. The objective of this study was to assess the survival of patients with DSRCT from the two major cancer centers. Methods: A multi-center retrospective review was performed of patients diagnosed with DSRCT treated at The University of Texas MD Anderson Cancer Center (MDACC) and Memorial Sloan-Kettering Cancer Center (MSKCC). Results: Of the 197 pts evaluated at both cancer centers (109 from MSKCC and 88 from MDACC) 87 % were male. The mean age was 25 ± 11 years; 139 (70.6%) underwent surgery; 38 ( 19.6%) had debulking surgery, 30 received radiation therapy, and 27 underwent hyperthermic chemotherapy after debulking (CHPP), 11 had a stem cell transplant. 112 patients were seen after 2003 in both the centers vs 85 before 2003. Neoadjuvant chemotherapy included Ewing’s-like chemotherapy with MSKCC’s P6 regimen (&lt;18 yrs of age) and VAI in adults. We further analyzed the MDACC cohort. In univariate analysis radiotherapy, surgery, CHPP, removal of primary mass + metastases, age &lt; 30 and patients treated after 2003 were associated with significantly improved overall survival. Multi-variate analysis showed that patients treated after 2003 had 59% lesser hazard (HR=0.41) than those treated earlier (p=0.04). Comparing 1990-2003 vs. 2004-2010 survival &gt;3 yr with DSRCT was &lt;25 % and is now &gt;50 %, a significant improvement. Conclusions: We present long-term outcomes for the largest series of patients diagnosed with DSRCT. A multidisciplinary approach to DSRCT treatment is required to prolong 3- and 5-yr overall survival. Our recent improved outcomes required not only aggressive chemotherapy but also regional local control measures. Best adjuvant therapy remains to be determined. A treatment algorithm will be proposed.
Comparison of incidence and patterns of recurrence in colon cancer (Cca) treated by sentinel lymph node (SLN) mapping (M) versus conventional surgery.
Authors: Mohammed Saifullah Shaik, Mohammed Nawaf Kanaan, Anteneh A. Tesfaye, Sunil Nagpal, Mohamed Elfakharany, Gregory Johnston, Madan L. Arora, T.Trevor Singh, David S. Eilender, Sukamal Saha
Journal: Journal of Clinical Oncology (2012)

3619 Background: Recurrence of Cca patients (pts) depends on the initial stage at diagnosis. SLNM upstages more pts than conventional surgery (Conv. Surg.) for nodal metastasis, this might have an impact on the incidence and pattern of recurrence. Hence comparative study was undertaken for recurrence in Cca pts undergoing SLNM Vs Conv.Surg. Methods: Group (Gp) A pts underwent SLNM with 1% Lymphazurin. The first 1-4 blue nodes were marked as SLNs followed by standard oncologic resection. Gp B pts underwent Conv. Surg. Data was collected for, TNM staging, Recurrence sites and follow up treatment. Minimum follow up of all pts was 12 month, with mean follow up period 44 months for both Gps. Results: There were 357 pts in GpA and 466 pts in GpB. For GpA pts, SLNM was successful in 99.6% of pts with average (Avg.) SLN was 2.8/pts. Avg. no. of LNs in GpA was 15.4/pts vs. 12.8/pt in GpB (p=0.001). For GpA pts, 46% was LN +ve vs 34% in GpB . Excluding T0, Tis and M1 pts at diagnosis, recurrence was calculated for 313 pts in GpA vs. 314 pts in GpB. An overall recurrence was 7.9% in GpA vs 22.2% (p=0.001) in GpB with distant mets being most common in both Gps. Recurrence of LN +ve and LN –ve pts also were significantly lower in GpA vs GpB (Table). The pattern of recurrence between the two Gps is shown in the Table. Conclusions: SLNM upstages significantly more pts in Cca than conv. surg. Even though pattern of recurrence was similar in both Gps, better staging may have resulted in better treatment, reducing the recurrence in SLNM Gp. Hence SLNM may be beneficial for Cca surgery. [Table: see text]
Detection of R337H, a germline mutation predisposing to multiple cancers, in asymptomatic women participating in a breast cancer screening programme in southern Brazil
Authors: E. I. Palmero, M. Caleffi, M. I. Waddington Achatz, G. Martel-Planche, V. Marcel, I. Petroni Ewald, R. Giugliani, L. Schüler-Faccini, P. Hainaut, P. Ashton-Prolla
Journal: Journal of Clinical Oncology (2007)

21029 Background: A specific germline mutation at codon 337 in TP53 (R337H) has been detected in a number of unrelated subjects with familial cancer risk in South Brazil, suggesting that this mutation may be relatively common in this population. Methods: To assess the TP53 R337H prevalence in a group of asymptomatic individuals unselected for family history of cancer, we studied 750 women aged 40–69 ys participating in a mammographic screening programme in Porto Alegre, Brazil`s southernmost capital. DNA was extracted from peripheral blood using standard procedures and PCR-amplified to generate a 238-base product encompassing TP53 exon 10, which was analyzed by RFLP using the restriction enzyme HhaI. The mutant, uncleaved allele was identified in agarose gels and positive RFLP findings were further confirmed by an independent PCR amplification and bi-directional, automated sequencing. Results and Discussion: The R337H mutant was detected in two of the 750 participants (0.15%), suggesting a much higher prevalence for this than for other TP53 germline mutations causing the LFS/LFL syndromes in the general population. Interestingly, these two subjects reported a familial history of cancer, and were found to be 2 nd degree relatives. Three additional family members were also positive: one woman affected with breast cancer at the age of 36 years and two asymptomatic 62- and 80-year-old women. The presence of four R337H-positive cancer- unaffected individuals in this family, two of them well above the age of 50, indicates that this is a low-penetrance allele. In addition, the pedigree does not fulfill any of the currently recognized clinical criteria for the diagnosis of LFS/LFLS syndrome. This is the first study to report detection of a germline TP53 mutation in a population-based screening programme. Conclusions: The TP53 R337H mutant appears to be relatively common and may occur in families that do not fulfill the known clinical criteria for LFS/LFLS, the family described here contains asymptomatic carriers suggesting partial penetrance. No significant financial relationships to disclose.
Erratum: Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer (J Natl Cancer Inst (1993) 85 (622-632))
Authors: S. A. Rosenberg, M. T. Lotze, J. C. Yang
Journal: JNCI Journal of the National Cancer Institute (1993)
A phase I study of temozolomide (TMZ) and RAD001 in patients (pts) with glioblastoma multiforme (GBM)
Authors: W. P. Mason, M. MacNeil, J. Easaw, L. McIntosh, Z. Lwin, E. Chen, E. E. Eisenhauer
Journal: Journal of Clinical Oncology (2009)

2036 Background: The mTOR protein kinase is a critical step in the PI3K/Akt/PKB signaling pathway. RAD001 exerts antiproliferative and antiangiogenic effects by mTOR inhibition. This phase I trial was designed to determine the maximum tolerated dose(s) (MTD) and recommended phase II dose(s) of RAD001 in combination with TMZ in patients with GBM. Patients receiving enzyme inducing anti-epileptic drugs (EIAEDs) and those not receiving EIAEDs (NEIAEDs) were studied separately. Methods: Enrollment was restricted to pts with proven GBM, either newly diagnosed following completion of radiotherapy with concurrent TMZ, or at first progression. TMZ was administered at a starting dose of 150 mg/m2/d for 5 days every 28 days, and RAD001 was administered continuously at a starting dose of 2.5 mg orally on a daily schedule starting on day 2 of cycle 1 in 28-day cycles (maximum 10 mg daily unless PK interaction shown). Response was evaluated every 2 cycles. Pharmacokinetics (PK) of TMZ and RAD001 were determined during cycle 1. Results: To date, 16 NEIAEDs and 9 EIAEDs pts have been enrolled and received 79 and 58 cycles respectively. The majority of pts (20/23) were newly diagnosed. In the NEIAEDs group at dose level 2 (RAD001 2.5 mg, TMZ 200 mg/m2) 3 of 4 pts had cycle 2 delays and dose reduction of TMZ because of myelosuppression (neutropenia 2 pts, neutropenia and thrombocytopenia, 1 pt), so further escalation of only RAD001 was undertaken, while fixing TMZ at 150 mg/m2. RAD001 at 10 mg daily with TMZ 150 mg/m2/day has been well tolerated in the NEIAEDs cohort without DLTs; RAD001 PK at this dose level have been comparable to historical single agent RAD001 PK (AUC at steady state is 602 ng*hr/mL in our study vs. 536 ng*hr/mL historical data), so no further escalation is planned. Enrollment in the EIAEDs cohort has been accelerated to 10 mg RAD001 with TMZ 150 mg/m2 because no additional DLTs have been observed in the EIAEDs cohort. Escalation beyond this dose will only take place if supported by evidence of reduced exposure of RAD001 or TMZ when PK results are available. Conclusions: RAD001 at a daily dose of 10mg can safely be combined with TMZ at 150 mg/m2/d and is the recommended dose for GBM pts receiving NEIAEDs. EIAED pts are being enrolled at this dose level; further escalation in this group will depend on PK data. [Table: see text]
Comparison of deep sequencing miRNA expression analysis in primary colorectal cancer and paired metastases.
Authors: Tineke E Buffart, Maarten Neerincx, Daud LS Sie, Mark A van de Wiel, Nicole C.T. van Grieken, Jan Dirk Burggraaf, Henk Dekker, Paul P Eijk, Bauke Ylstra, Cornelis Verhoef, Gerrit A. Meijer, Henk M.W. Verheul
Journal: Journal of Clinical Oncology (2015)

e14682 Background: MicroRNAs (miRs) have been recognized as promising biomarkers because of their role in cancer biology while being protected from degradation in tissue and blood samples. It is unknown to what extent tumor derived miRs are differentially expressed between primary colorectal cancers (CRCs) and metastatic lesions and between tumor and the surrounding normal tissue. We analyzed and compared miR expression profiles of novel and known miRs in primary CRC tissue and metastases as well as their surrounding normal tissue. Methods: Total RNA was isolated from 125 snap-frozen resection specimens including 40 primary CRC, 45 metastases, 23 normal colorectal en 17 normal extracolonic tissues corresponding to paired primary tumor samples and metastases from 38 patients. MiR expression profiles were obtained by next generation sequencing (NGS) using the Illumina Highseq 2000 platform. Sequence data were aligned to miRBase (release 19). Prediction of novel candidate miRs was based on specific folding characteristics of the precursor sequences using miRdeep2. Cluster analysis and differential expression for known miR sequences was performed using the R statistical software package in a paired manner. Results: 1714 different miRs were identified of which only 8 (0.5%) were differentially expressed between metastases and primary tumors (BFDR < 0.1), including five known and three novel candidate miRs. 212 miRs were significantly different expressed between CRC and normal colorectal tissue samples (BFDR < 0.05). Unsupervised clustering did not separate primary tumor tissue from their paired metastases, while tumor tissues and normal colorectal mucosae were completely separated. Conclusions: MiR expression profiles of primary or secondary origin of CRC tissues may be of similar value for their potential prognostic or predictive value.
Characterization of the number and site of APC mutations in sporadic colorectal cancer.
Authors: Ranjit Joseph, Paul Little, David N. Hayes, Michael Sangmin Lee
Journal: Journal of Clinical Oncology (2017)

630 Background: Truncating mutations in the adenomatous polyposis coli ( APC) gene are well-described events in the carcinogenesis of colorectal carcinomas (CRC) and may impact one or both APC alleles. These aberrations often fall within the mutation cluster region (MCR) of the APC gene to preserve a “just right” number of beta-catenin binding sites in the resulting mutant APC protein. Further clinical and genotypic characterization of CRCs based on number and site of mutations in APC determined using modern next generation sequencing methods is needed. Methods: Next generation sequencing of 70 CRC tumors was performed at a single institution via UNCseq to determine mutations in a panel of 247 oncogenes and tumor suppressors, including APC. RNASeq, DNA sequencing, and clinical characteristics from 224 colon and rectal cancer samples in The Cancer Genome Atlas (TCGA) project were also obtained. Results: In the UNCseq cohort, 58 patients (83%) had at least one inactivating APC mutation, and 33 (47%) had two mutations. Of those with at least one mutation, 81% had a mutation in the MCR (residues 1281-1556), but only 5/33 (15%) with two mutations had both in the MCR. In the TCGA cohort, 162 (72%) had at least one inactivating APC mutation, and 52 (23%) had two mutations. Of those with at least one mutation, 59% had a mutation in the MCR, but only 3/52 (6%) with two mutations had both in the MCR. Gene expression of APC was higher in those with no APC mutations vs. 1-2 mutations (p = 0.015), but was not significantly different between those with one vs. two mutations (p = 0.29). The absence of APC mutations was associated with microsatellite instability (p &lt; 0.001) and with right-sided primary tumors (p = 0.001 by chi-square). Conclusions: CRCs have high frequency of biallelic APC mutations, and the majority of tumors with APC mutations had a single mutation within the MCR region of the APC gene. These genotypic factors may impact tumor biology and clinical features.
Mammographic, MRI, and ultrasound characteristics of <i>BRCA1</i>, <i>BRCA2</i>, and other genetically high-risk women enrolled in a prospective multi-institution breast cancer screening trial
Authors: C. Isaacs, S. J. Skates, C. Lehman, K. Marcom, D. J. Bowen, S. Domchek, G. Tomlinson, D. K. Armstrong, M. Schnall
Journal: Journal of Clinical Oncology (2004)

9588 Background: Small retrospective studies suggest that BRCA1 carriers with breast cancer have higher breast density than women with sporadic breast cancer. Studies are examining the role of mammography, MRI and ultrasound (US) in genetically high risk women, however little data exist on the appearance of the breast by these imaging modalities in this population. Methods: We conducted a multi-institution prospective study of mammography, MRI and US in women ≥ 25 yrs old who were high risk defined as BRCA1 or BRCA2 carriers, or close relative (1st or 2nd degree) of a carrier, or multiple close relatives in same lineage with breast or ovarian cancer. Women were eligible if they were unaffected with cancer or had localized breast cancer but had completed adjuvant chemotherapy and radiation therapy at least 6 months prior to study entry and had a normal breast exam. All 3 imaging modalities were performed within 90 days of each other. Results: A total of 195 women were enrolled in this study over a 6 month period of which 190 were eligible. 171 completed all study exams. This included 41 BRCA1 and 39 BRCA2 carriers. The imaging characteristics are summarized in the table below. The only significant difference noted was in breast density. After controlling for menopausal status, BRCA1 and BRCA2 carriers had fewer women with extremely dense breasts than other high risk women (p=0.03). Conclusion: Our prospective study is the first to report results of the characteristics of multiple imaging modalities in BRCA1 and BRCA2 carriers and other genetically high risk women. Our findings suggest that fewer BRCA1/2 carriers have extremely dense breasts than other genetically high risk women. No other significant differences in imaging characteristics were noted. (Supported by NCI U24 CA78146–01 and UO1 CA74680) No significant financial relationships to disclose.