tbuckley/cabot-search huggingface dataset:
Chemotherapy at the end of life: Appropriateness and economic impact
Authors: A. Jirillo, A. Bortolami, G. Iadicicco, E. Di Lenardo, G. L. de Salvo, S. Monfardini, P. Berto§
Journal: Journal of Clinical Oncology (2005)

8213 Background: Antiblastic chemotherapy in preterminal patients is a common and well known prescription, often identified as ‘therapeutic obstinacy’, but which is very difficult to quantify. Aim of this work was to understand which factors mostly influence the decision to continue chemotherapy in the last months of life in cancer patients and to estimate the economic effect of this decision. Methods: A retrospective review of all patients firstly visited at the Medical Oncology Unit of the Padova University Hospital during 1999 was performed. Patients were included if they were diagnosed with cancer in 1999, were treated with chemotherapy at any time afterwards and died of cancer (as primary cause of death) in the following 5 years. For each patient, date of death, age, sex, weight, height, bodily surface, tumor type (lung cancer n°120 pts, breast cancer n°37, GI n°90, ovarian n°27, melanoma n°22, head and neck n°20, pancreas n°20, NHD n°15 and others n°55) performance status, chemotherapy dose and administration schedule, were recorded. Patients were stratified by not being treated with chemotherapy in the last 1–3 months before death (NO-THER), being treated in the last 3 months (3-THER) or being treated in the last month (1-THER). Statistical analysis was performed on the correlation between demographics, clinical variables and the average/patient chemotherapy cost (in Euro). Results: 406 patients satisfied study entry criteria, of which 52% were reported as NO-THER, 20% as 3-THER, and 28% as 1-THER. No differences were found in the use of chemotherapy by sex and age. The average/patient cost of antiblastic drugs was Euro 306 (2,3–2.984)and Euro 493 (7,0–3.397) for the 1-THER and 3-THER group, respectively. Our results confirm that therapeutic obstinacy leads to remarkable costs, not adding overall benefits and possibly at increased risk of side effects. No significant financial relationships to disclose.
The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer
Authors: Victoria M. Youngblood, Laura C. Kim, Deanna N. Edwards, Yoonha Hwang, Pranav R. Santapuram, Steven M. Stirdivant, Pengcheng Lu, Fei Ye, Dana M. Brantley-Sieders, Jin Chen
Journal: Cancer Research (2016)

Abstract Dysregulation of receptor tyrosine kinases (RTK) contributes to cellular transformation and cancer progression by disrupting key metabolic signaling pathways. The EPHA2 RTK is overexpressed in aggressive forms of breast cancer, including the HER2+ subtype, and correlates with poor prognosis. However, the role of EPHA2 in tumor metabolism remains unexplored. In this study, we used in vivo and in vitro models of HER2-overexpressing breast cancer to investigate the mechanisms by which EPHA2 ligand–independent signaling promotes tumorigenesis in the absence of its prototypic ligand, ephrin-A1. We demonstrate that ephrin-A1 loss leads to upregulated glutamine metabolism and lipid accumulation that enhanced tumor growth. Global metabolic profiling of ephrin-A1–null, HER2-overexpressing mammary tumors revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis. Pharmacologic inhibition of glutaminase activity reduced tumor growth in both ephrin-A1–depleted and EPHA2-overexpressing tumor allografts in vivo. Mechanistically, we show that the enhanced proliferation and glutaminolysis in the absence of ephrin-A1 were attributed to increased RhoA-dependent glutaminase activity. EPHA2 depletion or pharmacologic inhibition of Rho, glutaminase, or fatty acid synthase abrogated the increased lipid content and proliferative effects of ephrin-A1 knockdown. Together, these findings highlight a novel, unsuspected connection between the EPHA2/ephrin-A1 signaling axis and tumor metabolism, and suggest potential new therapeutic targets in cancer subtypes exhibiting glutamine dependency. Cancer Res; 76(7); 1825–36. ©2016 AACR.
The use of computed tomography of the spine to identify patients at high risk for epidural metastases.
Authors: D E Weissman, M Gilbert, H Wang, S A Grossman
Journal: Journal of Clinical Oncology (1985)

The usefulness of spinal computed tomography (CT) in predicting the presence of epidural tumor was evaluated in cancer patients undergoing CT myelography for suspected epidural tumor. Two hundred ninety two vertebral levels were evaluated in 30 patients. Spinal CT demonstrated cortical disruption surrounding the epidural space from metastatic cancer in 109 vertebrae. Eighty-five (78%) of these vertebral levels had tumor extension into the adjacent epidural space. The incidence of epidural tumor adjacent to vertebrae which had normal spinal CT or metastatic tumor without cortical disruption was 11%. Eighty-six percent of the epidural tumor adjacent to these vertebrae were a result of craniocaudal tumor extension in the epidural space from adjacent vertebral levels with cortical disruption. Twenty-one of 23 patients (91%) with cortical disruption at more than one vertebral level on spinal CT had epidural tumor. Synchronous noncontiguous epidural lesions were observed in 38% of patients with epidural tumor. Spinal CT is an important diagnostic test in determining which patients are at high risk for epidural tumor. Myelography should be performed in all patients with suspected epidural tumor to accurately define the full extent of tumor.
Impact of <i>EGFR</i> and <i>KRAS</i> mutations on survival in 1,000 patients with resected lung adenocarcinoma.
Authors: S. P. D'Angelo, Y. Y. Janjigian, M. G. Kris, W. Pao, G. J. Riely, J. Marks, C. Sima, J. Dycoco, B. J. Park, C. G. Azzoli
Journal: Journal of Clinical Oncology (2010)

7011 Background: Previous studies have reported trends toward improved overall survival in patients with resected adenocarcinoma of the lung and EGFR mutation compared to patients without detectable mutation (Marks, et al, 2008). Some studies demonstrated no difference in survival, but did not classify patients by KRAS mutation status. Reports on the prognostic significance of KRAS mutations have been inconsistent. In this study, we evaluated the prognostic significance of EGFR and KRAS mutations in 1,000 patients. Methods: Clinical information was prospectively collected on patients with completely-resected stage I-III lung adenocarcinoma at Memorial Sloan-Kettering Cancer Center who had surgery between Jan 2002–Oct 2009. EGFR mutation (exon 19 deletion or L858R) was determined by PCR, KRAS mutation was determined by sequencing. Overall survival from the date of surgery was analyzed using Kaplan-Meier and Cox regression analyses. Patients who received an EGFR tyrosine kinase inhibitor (TKI) during their treatment were excluded (N=131). Results: 1,000 patients (618 women) with stage I (732), stage II (121), and stage III (147) were evaluated. Median follow-up was 16 months. After adjustment for stage, there was a trend towards better survival in EGFR mutation-positive patients (N=145) compared to wildtype (N=588), HR 0.76 95% CI 0.45 to 1.30, p=0.3. There was a trend towards worse survival in patients with KRAS mutation (N=267) compared to wildtype, HR 1.20 95% CI 0.83 to 1.70, p=0.4. Three year survival proportions for each group were: EGFR mutation 80% (95% CI 0.67 to 0.89), KRAS mutation 73% (95% CI 0.63 to 0.81), wildtype 73% (95% CI 0.69 to 0.78). Conclusions: This is the largest cohort of patients with resected lung adenocarcinoma reported for these mutations (N=1,000). Despite excluding patients who received perioperative EGFR TKI, the trend for patients with EGFR mutation is towards better survival compared to wildtype. A trend for survival decrement in patients with KRAS mutations was less apparent. Longer follow-up is required to determine whether these trends are statistically significant. Future analyses will include assessments of the impact of perioperative EGFR TKI and EGFR TKI at recurrence. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Boehringer Ingelheim, Molecular MD
The Convergent Cancer Evolution toward a Single Cellular Destination
Authors: Han Chen, Xionglei He
Journal: Molecular Biology and Evolution (2015)

The essence of Darwin's theory is that evolution is driven by purposeless mutations that are subsequently selected by natural environments, so there is often no predefined destination in organismal evolution. Using gene expressions of 107 cell types, we built a functional space of human cells to trace the evolutionary trajectory of 18 types of solid tumor cancers. We detected a dominant evolving trend toward the functional status of embryonic stem cells (ESC) for approximately 3,000 tumors growing in distinct tissue environments. This pattern remained the same after excluding known cancer/ESC signature genes (∼3,000 genes) or excluding all oncogenic gene sets (∼12,000 genes) annotated in MSigDB, suggesting a convergent evolution of the overall functional status in cancers. In support of this, the functional distance to ESC served as a common prognostic indicator for cancers of various types, with shorter distance corresponding to poor prognosis, which was true even when randomly selected gene sets were considered. Thus, regardless of the external environments, cancer evolution is a directional process toward a defined cellular destination, a finding reconciling development and evolution, the two seemingly incompatible philosophies both adopted by the cancer research community, and also raising new questions to evolutionary biology.
EGFR, Cox-2, and EGF polymorphisms associated with progression-free survival of EGFR-expressing metastatic colorectal cancer patients treated with single-agent cetuximab (IMCL-0144)
Authors: F. Nagashima, W. Zhang, M. Gordon, H. M. Chang, G. Lurje, E. Borucka, D. Yang, R. Ladner, E. Rowinsky, H. J. Lenz
Journal: Journal of Clinical Oncology (2007)

4129 Background: A phase II study of cetuximab (IMCL-0144) has shown response rate of 12 % in patients with EGFR expressing metastatic colorectal cancer (mCRC). Recently, we reported that polymorphisms in the EGFR pathway may be useful molecular markers to predict clinical outcome. In this larger study, we tested whether polymorphisms in genes involved in the EGFR and angiogenesis pathway will be associated with clinical outcome. Methods: We analyzed 136 tissue samples from 346 mCRC pts enrolled in the phase II study of cetuximab (IMCL-0144), 133 cases were informative. The response rate in these 133 pts was 10% with a median progression-free survival (PFS) of 1.3 months (95% CI, 1.2 to 1.5) and an overall survival time (OS) of 5.5 months (95% CI, 4.1 to 7.5). Gr3–4 toxicity was observed in 56%. Gene polymorphisms of EGFR, Cox-2, EGF, cyclin D1, fragment c γ receptor 2A (FCGR2A), FCGR3A, VEGF, IL-8 were assessed from gDNA extracted from tissue samples by using PCR-based RFLP technique. Univariate analysis (Fisher’s exact test for response; log-rank test for PFS and OS) was performed to examine associations between polymorphisms and clinical outcome. A classification and regression tree (CART) analysis was used to identify subgroups of patients who were more likely to benefit from cetuximab. Results: Pts with EGFR G497C GA, Cox-2 G-765C CC, EGF A61G GG genotype showed better PFS (p=0.02, 1.8mo. vs. 1.2mo.; p=0.03, 6.9mo. vs. 1.3mo.; p=0.04, 1.4mo. vs. 1.2mo.), respectively. We found trends in associations between Cox-2 and tumor response (p=0.09), between EGF and Gr3–4 toxixity (p=0.06). CART analyses indicated that germline polymorphisms in EGFR, EGF, Cox-2, Cyclin D1, IL-8, FCGR2A and FCGR3A genes could be used to identify patients who benefit most likely of cetuximab therapy. Conclusions: Our data suggest that the polymorphisms of EGFR, Cox-2, and EGF may be useful molecular markers to predict clinical outcome in mCRC pts treated with single-agent cetuximab. And prospective studies will need to be done to confirm these preliminary findings. [Table: see text]
Maximizing metastatic breast cancer therapy selection: Physician practice patterns and competence assessment.
Authors: Tina Boyd Stacy, Maureen E. Haas, Alison A. Heintz
Journal: Journal of Clinical Oncology (2012)

127 Background: Due to the volume and pace of scientific advances within oncology, peer discussion and professional reflection regarding appropriate therapeutic decision making is necessary to provide the highest quality patient care. Increasing awareness in the breast cancer community of similarities and differences amongst practice management strategies helps to identify and benchmark individual practice patterns against one’s professional peers, ultimately leading to increased competence in therapy selection. Methods: During 2011 and 2012, educational outcomes assessments were gathered during 85 independent continuing medical education (CME) activities held within community practices and institutions across the USA. Participants were asked a series of case-based questions via an audience response system to assess baseline knowledge, competence, and identify practice patterns. Assessments were repeated post a 1-hour CME certified activity, with an additional 6-week electronic follow-up. Results: To date, over 330 physicians have participated in the program. Number of years in practice ranged from &lt; 10 to &gt; 30. The number of breast cancer patients seen per month ranged from ≤ 10 to &gt; 40. Provider competency and preferences in applying guideline based therapy was assessed. Results of participant preferences including single-agent, combination, first-line, and second-line therapy preferences as well as toxicity management for select patient case scenarios in advanced breast cancer will be presented. Self-rated competence for the physician audience improved by approximately 50% as a result of participation. Conclusions: The results highlight the diversity of clinical opinion in selecting therapy for advanced breast cancer and need for continued dialogue and scientific advancement. Education and peer discussion of how to optimize translation of new scientific information into patient care contributes to maximizing physician competence in therapy selection for metastatic breast cancer.
Bortezomib (BTZ) prior to and as maintenance therapy after autologous stem cell transplant (ASCT) in multiple myeloma (MM): Long-term follow-up of a phase II study
Authors: S. D. Goyal, G. Uy, J. F. DiPersio, R. Vij
Journal: Journal of Clinical Oncology (2007)

8044 Background: BTZ and immunomodulatory drugs have emerged as active therapeutic options for MM. However, the optimal method of incorporating these agents in the ASCT paradigm remains unclear. Data is available on thalidomide induction and post ASCT maintenance therapy. However, there are no published data on BTZ used in this manner. Methods: Following induction therapy, BTZ 1.3 mg/m 2 was administered on d 1, 4, 8, and 11 q21d × 2 cycles. ASCT with melphalan 200mg/m 2 was performed using G-CSF mobilized PBSC. Maintenance BTZ 1.3 mg/m 2 /d was administered weekly for 4 of 5 weeks × 6 cycles starting 90–120 days post-transplant. Results: 39 patients completed pre-transplant BTZ: 23M/16F, median age 56 years (range 38–69), IgG (28), IgA (10), light chain only (1), Durie-Salmon stage I (1) II (12) III (26), induction anthracycline/thalidomide-based regimen (37). 37 patients underwent ASCT. Pre-transplant treatment with BTZ did not adversely affect stem cell yield or engraftment (Uy et al, Blood, 2005;106(11): abstr 2926). The ORR /CR+VGPR were 92%/53% at d90–120 post-transplant. With a median follow up of 897 days, the median PFS was 806 days and Kaplan-Meier estimate of 3-year PFS is 41% (95% CI, 31–63%). Median OS has not been reached with 3-year OS estimate of 79% (95%CI, 63–94%). 14/39 (36%) patients experienced varicella zoster virus (VZV) reactivation at a median of 200 days post-enrollment. 12/39 patients had grade (Gr) 1 neuropathy at enrollment. Gr 3/4 neuropathy emerged in 2 patients preventing initiation of maintenance BTZ. Gr 3/4 neuropathy emerged in 3 patients during maintenance BTZ requiring drug discontinuation in two and dose reduction in one patient. No grade 3/4 hematologic toxicity was observed during maintenance BTZ. Conclusions: This is the first trial reporting on sequential administration of BTZ prior to and as maintenance therapy post ASCT in MM. Impressive CR/VGPR, PFS and OS were observed and a high rate of VZV reactivation was seen. No significant financial relationships to disclose.
A Phase I/Ii Trial of Weekly Nab-Paclitaxel(Nab-P)+ Gemcitabine(G) with Metastatic Pancreatic Cancer(Mpc)
Authors: Masafumi Ikeda, Hideki Ueno, Makoto Ueno, Nobumasa Mizuno, Tatsuya Ioka, Yasushi Omuro, Takako Nakajima, Junji Furuse
Journal: Annals of Oncology (2014)
Erlotinib has activity in androgen-independent prostate cancer (AIPC) patients who are chemotherapy-naive: A phase II trial
Authors: C. Nabhan, K. Tolzien, S. Newman, S. Kelby, T. Lestingi, A. Galvez, J. D. Bitran
Journal: Journal of Clinical Oncology (2007)

15606 Background: Mechanisms of hormone resistance for AIPC are variable. One proposed mechanism is the over expression of the epidermal growth factor receptor (EGFR) which in turn stimulates proliferation through its pathway. We aimed to determine the efficacy of an oral anti-EGFR inhibitor (erlotinib) in this patient population that was chemotherapy-naive. The primary end point was to evaluate the overall clinical benefit defined as the sum of complete response (CR), partial response (PR), and stable disease (SD). Methods: Between January and December 2006, sixteen patients were enrolled onto this phase II study. Median age was 78 years (66–85). Median PSA was 61.9 (9.2–800.2). Median time from initial diagnosis until starting Erlotinib was 7.8 years. Erlotinib was given daily at 150 mg until disease progression. Patients were evaluated every 2 weeks for toxicity. Response assessment took place every 2 cycles (each cycle was 4 weeks). Evaluations included computed tomography of measurable disease areas, bone scans, and serum PSAs. Patients who progressed radiographically but maintained a PSA response or those who progressed biochemically but maintained a radiographic response were considered stable and were allowed to continue on study. Results: Sixteen patients were enrolled with 14 being evaluable at this time (2 patients are early in their course). Median cycles received is 2 (range 1.5–12). One patient achieved a PR and continues on Erlotinib after one year of enrollment. Three patients demonstrated stable disease but two of them later progressed. One patient withdrew after 9 days of starting therapy due to fatigue and poor taste. All other patients developed disease progression after two cycles of therapy. The calculated overall clinical benefit was 28% (4 responses out of 14 patients). One patient died from pneumonia and seizures unrelated to Erlotinib as confirmed by an autopsy that showed progression in the central nervous system. Erlotinib was well-tolerated with skin rash and diarrhea being the most common toxicities. Conclusions: Erlotinib has clinical activity as a single agent in AIPC. Updated results of this ongoing study will be presented at the meeting. Further studies with this agent alone or in combination are warranted. No significant financial relationships to disclose.
Results of trastuzumab targeted therapy in metastatic breast cancer (MBC): The Sultanate of Oman experience 2002–2006
Authors: A. Khalifa, M. Faris, B. Al-Bahrani
Journal: Journal of Clinical Oncology (2007)

11518 Background: The first random study of incidence of Her-2 over expression among Omani breast cancer patients was carried out by the Medical Oncology Department, the Royal Hospital in 2001. The incidence was reported as 40% (higher than international published figures). The Herceptest was routinely performed on all new patients for a whole year (2004) and the incidence was found to be 36%. Trastuzumab was approved for use in the Sultanate of Oman in 2002, since then a total of 26 patients with metastatic breast cancer received Trastuzumab, the results are presented. Methods: Prospective, single arm, single centre experience. Patients with confirmed metastatic breast cancer (at presentation or after adjuvant treatment), HER-2 positive (+++ by Herceptest, or FISH positive), age &gt; 18, ECOG PS ≤ 2, LVEF = 50% and adequate renal &amp; liver function, were included. Treatment consisted of trastuzumab as single agent or in combination with chemotherapy as indicated. A loading dose of 8mg/kg was followed by 6mg/kg q3 weeks. The endpoints were response rate (RR) progression free survival (PFS) and survival (OS). Results: a total of 26 patients were included between October 2002-October 2006, median age was 45.5years (27–60), 12 patients presented with metastasis at first presentation and 14 had metastatic disease 6 months or more after finishing adjuvant chemotherapy. The median number of received cycles was 10 (range 4–30), the overall response rate was 77% (54% CR and 23% PR), the median survival 15 months (range 4–36m), median Time to Progression 9m (range 4–33m). Six patients (23%) developed brain metastasis while on herceptin. There were 8 events (disease related deaths) during the study period. Conclusions: The incidence of Her-2 +ve breast cancer in Omani patients is slightly higher than the reported figures in international studies. The response to trastuzumab in metastatic disease is comparable to other similar studies. No significant financial relationships to disclose.
Molecular analysis of δ-aminolevulinate dehydratase deficiency in a patient with an unusual late-onset porphyria
Authors: Reiko Akagi, Chiaki Nishitani, Hideo Harigae, Yutaka Horie, Luba Garbaczewski, A. Hassoun, R. Mercelis, L. Verstraeten, Shigeru Sassa
Journal: Blood (2000)
Functional exercise capacity, respiratory and peripheral muscle strength, pulmonary functions and dyspnea in allogeneic hematopoietic stem cell transplantation candidates
Authors: Gulsah Bargi, Meral Bosnak Guclu, Zeynep Aribas, Elif Sakizli, Burcu Camcioglu, Muserrefe Nur Karadalli, Zeynep Arzu Yegin, Sahika Zeynep Aki, Gulsan Turkoz Sucak
Journal: European Respiratory Journal (2014)

Background: Although respiratory and skeletal muscle strength and submaximal exercise capacity are known to be reduced in a significant percentage of patients prior to hematopoietic stem cell transplantation (HSCT). Comparison of pre-allogeneic HSCT recipients' functional exercise capacity, muscle strength, pulmonary functions and dyspnea with healthy subjects have not been investigated previously.

Aim: To comparatively investigate the functional exercise capacity, pulmonary functions, muscle strength, and dyspnea in pre-allogeneic HSCT recipients.

Methods: A prospective, cross sectional study. Twenty seven HSCT candidates (42.04±12.64) and 31 healthy subjects (46.13±10.06) were included. Functional exercise capacity was evaluated using 6 minute walk test (6MWT), pulmonary functions using a spirometry, respiratory muscle strength (MIP, MEP) using a mouth pressure device, peripheral muscle strength using dynamometer, dyspnea using Modified Medical Research Council Dyspnea scale (MMRC) and Modified Borg scale.

Results: HSCT candidates' 6MWT distance, MIP, MEP were significantly lower, exertional dyspnea, dyspnea in activities of daily living were higher compared to healthy subjects (p 0.05).

Conclusions: Functional exercise capacity and respiratory muscle strength are impaired, dyspnea is worsened and pulmonary functions and peripheral muscle strength are preserved in patients prior to allogeneic HSCT. Possible mechanisms and the effects of aerobic exercises and inspiratory muscle training should be investigated prior to allo-HSCT.