tbuckley/cabot-search huggingface dataset:
End-of-life care for glioblastoma multiforme patients at an academic institution.
Authors: Kamini Kuchinad, Roy E Strowd, Anne Evans, Louise Knight, W. Anthony Riley, Thomas J. Smith
Journal: Journal of Clinical Oncology (2016)

202 Background: End of life care for glioblastoma patients has not been studied in the United States. We studied 100 patients with GBM to examine use of advance directives (AD), symptom assessments, hospitalizations, chemotherapy use, and hospice use. Methods: A single center retrospective cohort study of adult patients actively treated for GBM at Johns Hopkins Hospital from 2009-2014. 100 patients were randomly chosen from the group of 317 GBM patients. Information included documentation of AD, code status, hospitalizations, chemotherapy use, code status and symptom assessments. A secondary analysis of all JHH GBM patients who received hospice care at Gilchrist Hospice during this time period was analyzed using the electronic medical record and hospice records to evaluate date of referral to hospice, length of stay in hospice and location of death. Results: Of 100 patients, 76 were referred to hospice. Only 40% of individuals had documentation of code status and only 17% had any documentation of ADs in the outpatient chart. Formal symptom, spiritual, or psychosocial assessments were seldom documented in the outpatient record. Only 17% used chemotherapy in their last month of life. 37% were hospitalized in the last month of life for an average of 9 days. Of the Gilchrist Hospice patients, the median length of stay in hospice was 21 days and 64% of these patients died in their residence with hospice services. Conclusions: More formalized palliative care utilization and structure could improve end of life care for GBM patients, especially in the use of ADs; formal symptom, spiritual, and psychosocial assessments; and earlier use of hospice to prevent end of life hospitalizations.
Effect of IKKϵ knock-down on prostate cancer xenograft growth.
Authors: B. Péant, Y. Huon, K. Leclerc-Desaulniers, N. Delvoye, M. Latour, A. Mes-Masson, F. Saad
Journal: Journal of Clinical Oncology (2010)

10541 Background: Inflammation is part of the host response to stress induced by internal or external environmental stimuli. When inflammation becomes recurrent or chronic, it may contribute to the development of human cancers. Inflammation is controlled by the release of various mediators of the immune response. Elevated inflammatory cytokine levels in serum, such as interleukin (IL)-6, have been associated with metastasis-related morbidity in prostate cancer (PCa) patients. We were the first to publish that high IKKϵ expression results in its nuclear translocation and an increase of IL-6 promoter stimulation. These novel observations suggest that IKKϵ nuclear translocation leads to the nuclear activation of several transcription factors that control inflammatory cytokine gene expression, particularly IL-6 which could act as a growth factor for PCa cells. Methods: We developed a sub-cutaneous xenograft PCa models able to control inducible IKKϵ expression. This model makes use of the doxycycline- (dox-) inducible PC-3-6TR-shIKKϵ cells, as well as shLacZ-inducible controls. The cells are mixed with matrigel prior to injection into the flank of SCID mice to limit their spread and to allow the formation of better defined tumors. Dox is delivered through dox-supplemented food (625 mg/kg) to minimize mouse stress. Mice were sacrificed when the tumor volume reached 2,500 mm3 according to the CIPA recommendations. Results: We performed a large- scale experiment (48 mice) to study the effect of IKKϵ depletion on PC-3-6TR-shIKKϵ cell proliferation in vivo. No dehydratation or weight loss was observed in control or IKKϵ-depleted mice fed with the dox-supplemented diet. We observed an important decrease of the PC-3-6TR- shIKKϵ xenograft proliferation in SCID mice fed with the dox-supplemented diet. Moreover, PC-3-6TR-shIKKe mice fed with normal diet and all PC-3- 6TR-shLacZ control mice reached the predefined tumor volume more than 20 days before PC-3-6TR-shIKKϵ mice fed with dox-diet. Conclusions: These results provide solid evidences for a role of IKKϵ in PCa cell proliferation and survival. We believe that a better understanding of IKKϵ involvement in PCa may advance our understanding of PCa progression and lead to novel therapeutics options. No significant financial relationships to disclose.
Trends in prostatectomy: Centralization, robotics, and access to care.
Authors: K. B. Stitzenberg, Y. Wong, M. E. Nielsen, R. Uzzo
Journal: Journal of Clinical Oncology (2010)

6023 Background: Robotic surgery has been widely adopted for urologic procedures, particularly prostatectomy. We hypothesize that this change is rapidly shifting procedures away from hospitals that do not offer robotics and consequently increasing patient travel distances. Methods: A population-based observational study of all prostatectomies in NY, NJ, and PA from 1998-2008 was performed using hospital discharge data. Annual hospital procedure volume was defined as the number of prostatectomies performed for cancer in a given year. Straight-line travel distance to treating hospital was calculated for each case. Hospitals with robots in 2008 were identified through communication with the vendor. Results: 96,188 prostatectomies were included. Over the study period, the total number of prostatectomies performed annually increased by >40% (Table). All of the increase occurred at the highest volume centers; both the total number and proportion of cases performed in all other volume categories declined over time. In 2008 the 37/286 (13%) highest volume hospitals performed 69% of the procedures. Procedure volume was associated with presence of a robot (p<0.01); the 30% (85/286) of hospitals with a robot in 2008 performed 83% of procedures in the study area. Median travel distance increased with hospital volume: 4.8 mi at lowest volume centers vs. 13.4 mi at highest volume centers. Population-wide median travel increased from 6.5 mi in 1998 to 10.3 mi in 2008. Conclusions: Over the past decade, prostatectomies have been centralized to high-volume centers. Few prostatectomies are now performed at hospitals that do not offer robotic surgery. Future work should examine the impact of robotics and of increasing travel burden on access to care and cancer outcomes. Distribution of prostatectomies among hospital volume categories* Hospital procedure volume 0-15/yr 16-29/yr 30-45/yr 46-77/yr ≥78/yr Total n % n % n % n % n % n 1998 1,285 20 1,312 20 1,276 20 1,337 21 1,254 19 6,464 2000 1,569 18 1,477 17 1,519 18 1,276 15 2,708 32 8,549 2002 1,452 16 1,430 16 1,307 15 1,251 14 3,411 39 8,851 2004 1,262 17 1,436 19 903 12 1,550 20 2,500 33 7,651 2006 1,244 13 1,076 11 504 5 1,235 13 5,587 58 9,646 2008 1,040 10 535 5 772 7 1,103 10 7,514 69 10,964 * Cutpoints are based on 1998 volume quintiles. (Odd years omitted for space.) No significant financial relationships to disclose.
Enhanced antitumor effect via combination of triptolide with 5-fluorouracil in pancreatic cancer cell lines.
Authors: Wei Wang
Journal: Journal of Clinical Oncology (2012)

352 Background: Pancreatic cancer is one of the most aggressive types of cancer, and lack of effective treatment results in a very low 6-month survival rate. This study aims to explore the enhancement of therapeutic effect on human pancreatic cancer cell lines (AsPC-1, MiaPaCa-2 and PANC-1) via combination of triptolide (TPL),derived from the herb Tripterygium wilfordii, and 5-fluorouracil (5-FU). Methods: Cell proliferation was measured by MTT, apoptotic cells were assessed by flow cytometry and western blot for cleaved caspase-8, 9, 3 and PARP. To explore the role of nuclear factor kappaB (NF-kB) activity in pancreatic cancer cell lines, AsPC-1/IkBaM and PANC-1/IkBaM cells (NF-kB activity of AsPC-1 and PANC-1 cells was silenced by IkB-a mutation) were treated with TPL plus 5-FU. NF-kB activity was determined by electrophoretic mobility shift assay. Results: TPL demonstrated toxicity on three pancreatic cancer cell lines with the IC50 of 25-40 nM. The combination of TPL (IC30 concentration) and 5-FU enhanced the cytotoxicity significantly compared to not only 5-FU alone but also Gemcitabine (the first line drug for advanced pancreatic cancer) alone. Combination index (CI) indicated the effect of TPL plus 5-FU was highly synergistic. Furthermore, pancreatic cancer cells treated with TPL plus 5-FU exhibited increased apoptosis, as evidenced by stronger Annexin V/ PI staining, higher levels of pro-apoptotic proteins including cleaved caspases and activated PARP compared to cells treated with TPL or 5-FU or Gemcitabine alone. In the mechanism study, AsPC-1/IkBaM and PANC-1/IkBaM cells showed more resistance to enhanced apoptosis induced by TPL plus 5-FU compared to wild-type cells. It indicated the enhanced effect of TPL was related with NF-kB activity. Conclusions: 1) TPL has a potent therapeutic effect on pancreatic cancer cell lines; 2) the combination of TPL with 5-FU enhances the therapeutic effect which is more powerful than Gemcitabine in vitro, low concentration of TPL showed high synergistic effect with 5-FU; 3) the inhibitory effect of TPL plus 5-FU on pancreatic cancer is mediated by the induction of apoptosis and TPL enhanced the apoptosis via inhibition of NF-kB activity.
Tolerability of carboplatin, paclitaxel and erlotinib as first-line treatment of ovarian cancer
Authors: S. V. Blank, J. P. Curtin, N. A. Goldman, E. Fusco, Z. Lesko, H. Hochster, C. D. Runowicz, S. Wadler, F. M. Muggia
Journal: Journal of Clinical Oncology (2005)

5052 Objectives: The aims were to determine whether erlotinib (erl; OSI774, Tarceva), an orally-active selective inhibitor of the EGFR tyrosine kinase, given with paclitaxel (T) and carboplatin (CBDCA) to patients (pts) with ovarian (OC), fallopian tube (FT) or primary peritoneal (PPC) cancers is tolerable, to evaluate response rates and to correlate molecular markers of response. This report addresses the degree and type of toxicity associated with this combined regimen. Methods: Since June 2003, pts with histologically-confirmed Stage III or IV OvC, FTC or PPC received T (175 mg/m2) and CBDCA (AUC 6) every 21 days, along with erl (150 mg) by mouth daily, continuously. Pts had adequate bone marrow, renal and liver function. Informed consent and IRB approval were obtained. Results: We report on 28 pts so far enrolled in this trial. Of these, 24 have completed or withdrawn from study, and four continue treatment. A total of 123 cycles with erl have been analyzed. 16 pts completed the full six cycles of chemotherapy with erl, and 13 have undergone reassessment surgery. Four did not continue on erl following 1, 3, 6 and 1 cycles due to dissatisfaction with the skin changes associated with treatment in three, and allergy in one; these pts did complete the total planned six cycles of chemotherapy. One pt showed disease progression after cycle three and expired. One pt came off study after two cycles due to underlying cardiac issues, and one was lost to follow up after three cycles. Another pt did not receive erl on cycle 1 by error, and was not continued on trial. Among the pts completing therapy, all experienced at least a g1 rash, and three experienced g2 or 3 rash. Severity of rash did not correlate with withdrawal from study, and did not increase with repeated cycles. Three pts had wound-related complications after their initial surgeries. Other side effects noted were not different from those experienced with standard T/CBDCA treatment, and dose modifications or dose delays have been infrequent. Conclusions: The addition of erl to T/CBDCA as a front line regimen for OC and related epithelial cancers is feasible and well-tolerated similar to standard chemotherapy, with the exception of skin rash. No significant financial relationships to disclose.
The impact of rhabdoid differentiation on prognosis in patients with grade 4 renal cell carcinoma.
Authors: Ben Yiming Zhang, John C. Cheville, Robert Houston Thompson, Stephen A. Boorjian, Christine M. Lohse, Bradley C. Leibovich, Brian Addis Costello
Journal: Journal of Clinical Oncology (2015)

494 Background: Renal cell carcinoma (RCC) with rhabdoid differentiation is thought to portend a poor prognosis, similar to RCC with sarcomatoid differentiation. Both rhabdoid and sarcomatoid differentiation are classified as grade 4 RCC based on the most recent International Society of Urological Pathology (ISUP) grading system. We sought to determine the prognostic value of rhabdoid differentiation in comparison to RCC with sarcomatoid differentiation, grade 4 RCC without rhabdoid or sarcomatoid differentiation, and grade 3 RCC. Methods: Using the Mayo Clinic Nephrectomy Registry, we identified 406 patients with ISUP grade 4 RCC and 1,758 patients with grade 3 RCC. A urologic pathologist reviewed all specimens to determine the presence of both rhabdoid and sarcomatoid differentiation. Associations of clinical and pathologic features with death from RCC were evaluated using Cox models. Results: Among the 406 grade 4 RCC tumors, 111 (27%) had rhabdoid differentiation and 189 (47%) had sarcomatoid differentiation, although only 28 (7%) demonstrated both rhabdoid and sarcomatoid differentiation. In multivariable analysis of grade 4 RCC tumors, the presence of rhabdoid differentiation was not associated with death from RCC (HR 0.95, p=0.75); in contrast, sarcomatoid differentiation was significantly associated with death from RCC (HR 1.63, p&lt;0.001). Patients with RCC with rhabdoid differentiation were significantly more likely to die of RCC than patients with grade 3 RCC (HR 2.45, p&lt;0.001) and grade 3 RCC with necrosis (HR 1.62; p&lt;0.001). Conclusions: This study confirms that RCC with rhabdoid differentiation is appropriately classified as grade 4. However, unlike sarcomatoid differentiation, the presence of rhabdoid differentiation in grade 4 RCC is not associated with an increased risk of death from RCC. Therefore, rhabdoid and sarcomatoid differentiation should not be grouped together when assessing risk in a patient with grade 4 RCC.
Meta-analysis of efficacy and safety of single-agent and doublet chemotherapy with or without platinum in advanced non-small cell lung cancer in the elderly.
Authors: G. Des Guetz, B. Uzzan, P. Nicolas, K. Chouahnia, G. Sebbane, J. F. Morere
Journal: Journal of Clinical Oncology (2011)

7547 Background: Chemotherapy (CT) of elderly patients with advanced non small cell lung cancer (NSCLC) is still a matter of debate. Methods: PubMed query, using keywords simultaneously: NSCLC, aged, antineoplastic combined CT, randomized controlled trial. Articles were also obtained by cross-checking references; abstracts from ASCO and ESMO, WCLC proceedings. The efficacy outcomes were dichotomous: Overall Response Rate (ORR) and 1-year overall survival (OS). We assessed all grade and grade ¾ toxicities. Hazard ratios (HRs) were calculated from the recorded events. We used EasyMA software and fixed-effect model, due to absence of statistical heterogeneity between studies. HRs < 1 meant increased survival among doublets compared with single-agents. Results: Twelve eligible studies included 2,530 patients (mean age 74; 1,911 men and 545 women; 591 stage IIIB and 1,600 stage IV; 796 squamous cell carcinomas, 860 adenocarcinomas). One-year OS significantly improved with doublets, compared with single-agents (HR 0.92; 95% CI: 0.87-0.99). HR for ORR was 1.40 (95 % CI: 1.21-1.63; p= 0.004). Doublets including platinum significantly improved OS (HR 0.82; 95 % CI 0.73-0.93), but not those without platinum. HRs for nausea/vomiting, neutropenia, thrombocytopenia and anaemia were significantly higher for doublets than for single-agents (1.28, CI 1.14-1.45; 1.30, CI 1.18-1.42; 1.66, CI 1.32-2.09; 1.32, CI 1.18-1.48 respectively; p=0.001). Concerning grade 3/4 toxicity, only HRs for the biological side-effects were significantly higher for doublets: neutropenia (1.79; 1.51-2.13), thrombocytopenia (2.54; 1.69-3.81) and anaemia (1.68; 1.15-2.45). Conclusions: Compared with single-agents, doublet CT significantly improved ORR and OS, specifically when including platinum, but haematological side-effects were more frequent. The benefit-to-risk ratio of platinum based doublets in advanced NSCLC appears favourable in the elderly.
Continuity of care: A program for multidisciplinary post-treatment surveillance after definitive treatment for head and neck cancer.
Authors: Beth Michelle Beadle, Laura Burke, Amy Clark Hessel
Journal: Journal of Clinical Oncology (2014)

82 Background: Patients with head and neck cancers (HNC) are treated with a combination of radiation therapy, chemotherapy, and surgery. With the epidemic of HPV-related oropharynx cancers, patients are younger and healthier; they will require routine surveillance and management of long-term toxicity for many years. There is little data on optimal follow-up and significant duplication of efforts with multiple appointments. Our goal was to create a multidisciplinary post-treatment surveillance program for patients with HNC treated with organ preservation to standardize their evaluation, decompress clinics, reduce duplication of testing, and improve patient satisfaction. Methods: A consensus schema to standardize follow-up was created, consistent with the institutional practice and NCCN guidelines. All services agreed to standardized testing with a rotation between the treating physicians for each follow-up. For the first year, testing occurred at 8 weeks and then every 3 months; for the second year, it occurred every 4 months. Deemed the Continuity of Care (COC) program, patients were identified at the time of tumor board, labeled as eligible at treatment initiation, and followed per its rules on completion. Results: A total of 360 new patients were identified that were eligible for follow-up on COC. In total, 237 (65%) of them had been treated at MD Anderson and reached or surpassed their 3 month follow-up visit. Of these, 209 patients (88%) were following the pathway. Overall, compliance with the pathway has been stable, and follow-up clinics have been streamlined for patients and providers. A 28% reduction in appointment duplications within 3 months of the past appointment has been measured. Conclusions: A model program for surveillance after treatment for HNC was designed and implemented. Patients enrolled had standardized testing and streamlined follow-up appointments during the first two years of surveillance, resulting in a significant decrease in appointment duplication. In addition, significant data was collected in this cohort, allowing for future studies of the optimal utilization of imaging, outcomes, and best practices for this growing group of patients.
Preliminary results of centralized HER2 testing in DCIS of the breast: NSABP B-43.
Authors: K. P. Siziopikou, M. A. Cobleigh, S. J. Anderson, T. B. Julian, D. W. Arthur, P. Zheng, E. P. Mamounas, E. R. Pajon, R. J. Behrens, L. Chu, N. C. Leasure, J. N. Atkins, J. Polikoff, T. E. Seay, W. J. McCaskill-Stevens, R. Rabinovitch, N. Wolmark
Journal: Journal of Clinical Oncology (2011)

588 Background: NSABP-B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER-2-positive DCIS. It compares whole breast irradiation (WBI) alone (Group [G] 1) with WBI given concurrently with trastuzumab (Group [G] 2) in women with HER-2 positive DCIS treated by lumpectomy. The primary aim is to determine trastuzumab’s value in preventing ipsilateral breast cancer recurrence. Historically, the rate of HER-2 positive DCIS has been estimated as >50%; it is seen primarily in ER-negative, comedo-type DCIS of high nuclear grade. In that population HER-2 positivity was thought to be >70%, based mainly on single-institution studies with relatively few DCIS patients. There has been no documented centralized multi-institutional HER-2 analysis of DCIS. B-43 provides a unique opportunity to evaluate this question in a large cohort of DCIS patients. Methods: Patients who have undergone lumpectomy for DCIS without evidence of an invasive component are eligible to participate. A central review of each patient’s pure DCIS lesion is first carried out by IHC analysis. If the lesion is 1+ or 2+, FISH analysis is performed. Patients who are HER-2 3+ or FISH positive can then be entered into the trial and randomly assigned to receive 2 doses of trastuzumab during WBI or WBI alone. Results: NSABP B-43 opened 11/9/08. As of 12/31/10, 1816 patients’ specimens have been received centrally; 613 (33.8%) were HER-2 positive. The average time on study as of 12/31/10 for the 452 patients who were randomly assigned was 10.8 months. No grade 4 or 5 toxicity has been observed. Lower toxicity grades were equally balanced between groups. Nuclear grade for G 1 and G 2 were: low (0.4 vs 0.9%), intermediate (17.8 vs 14.9%), and high (81.8 vs 84.2 %), respectively. Negative ER status for G 1 and G 2 were 41.3% vs 41.9%, respectively. Conclusions: In B-43 the HER2-positive rate for pure DCIS is 33.8%, lower than previously reported. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust, as demonstrated by an average specimen submission rate of about 70/month. Funded by NCI PHS grants U10-CA-37377, U10-CA-69974, U10-CA-12027, and U10-CA-69651, with additional support from Genentech.
Genomic features of primary and recurrent anal squamous cell carcinoma.
Authors: Jonathan W Pike, Kent William Mouw, Lior Zvi Braunstein, Neil E. Martin, Harvey J. Mamon, Jason L. Hornick, Eliezer Mendel Van Allen, Alan D. D'Andrea
Journal: Journal of Clinical Oncology (2016)

556 Background: Approximately 7000 cases of anal squamous cell carcinoma (ASCC) are diagnosed annually in the US, and the incidence is increasing. Combination chemoradiotherapy (CRT) is the standard of care for locally-advanced ASCC, and the 5-year survival rate is approximately 70%. Unlike many other tumor types, no large-scale genomic studies have been reported for anal cancer. In order to characterize the mutational landscape of ASCC and identify potential therapeutic targets, we perform comprehensive genomic analysis of a pilot cohort of ASCC cases. Methods: We performed whole exome sequencing of tumor and matched germline DNA from a pilot cohort of twelve patients with locally advanced (Stage II-IVA) ASCC cases treated at Dana-Farber Cancer Institute. All patients received concurrent chemoradiotherapy (CRT): seven ‘responders’ had complete response and no evidence of recurrence with a minimum of one year follow-up, while five ‘non-responders’ had residual or recurrent disease following CRT. For non-responders, both primary and residual/recurrent tumors were analyzed. Results: The overall mutation rate was 3.7 mutations per megabase (Mb). Recurrent mutations in several known cancer genes were observed. Five of twelve cases had a hotspot mutation in FBXW7, including 3 of the 5 non-responders. Known oncogenic mutations were also observed in PIK3CA (3 tumors) and NFE2L2/KEAP1 (3 tumors). Analysis of paired primary and recurrent samples revealed surprising examples of distinct driver mutations in clonally-related tumors. Copy number analysis revealed focal amplifications of chromosome 3q. Conclusions: This study represents one of the first genome-scale analyses in ASCC. The overall mutation rate was similar to other HPV-associated squamous cell carcinomas, and recurrent mutations in several known cancer genes were observed. Analysis of paired primary and residual/recurrent tumors revealed surprising heterogeneity. To extend our findings, we are currently performing a similar analysis in a larger extension cohort of ASCC tumors.