tbuckley/cabot-search huggingface dataset:
Genomic analysis and personalized cancer therapy for metastatic colorectal cancer.
Authors: Rajan Paul Dang, Celina Ang, Randall F. Holcombe, Max W. Sung, Ross L. Cagan, Eric Schadt, Marshall R. Posner, Michael J. Donovan, Lewis A. Winder, Adnan Kahn, Nadia Camille, Claire R. Davis, Peter Smibert, Krzysztof Misiukiewicz
Journal: Journal of Clinical Oncology (2015)

568 Background: Standard approaches in cancer research identify new therapies based on observed benefit to average populations but without emphasis on individual patients whose responses can vary considerably. Also, targeted therapies rarely account for the genomic complexity of patient tumors; the result is poor efficacy and rapid resistance. We would identify drugs or drug cocktails that (1) target the details of an individual’s tumor and (2) account for its complexity. Models using the fruit fly Drosophila represent a potential new paradigm in cancer therapy. We have developed fly models that can include up to 10 of a patient’s tumor’s driver mutations; the result is an inexpensive drug-screening platform to identify drug cocktails through empirical screening. Methods: Patients with metastatic CRC who have progressed or become intolerant to fluoropyrimidines, oxaliplatin, irinotecan, avastin, and (if KRAS wild-type) EGFR inhibitor therapy. Mutations identified by deep DNA and RNA sequencing of individual tumors are screened for tumor drivers, which are then incorporated into the “personal” Drosophila model and tested against a library of FDA approved drugs. Fly mortality is used as a surrogate for toxicity; improvements in tumor mutation-linked eye and/or wing abnormalities serve to quantify efficacy. This allows rapid and parallel screening of up to 800 drugs and subsequent drug combinations. The most efficacious and least toxic combinations are presented to a multidisciplinary tumor board of experts, who will then select the best therapeutic option for the patient. Results: To demonstrate that the personalized Drosophila model approach is superior to the current standard, regorafenib, which performed best in CRC with a 10% response rate (RR) against placebo in a phase III trial. Using the 10% RR as a benchmark, we will apply a sequential Bayesian method for 50 MTC patients enrolled to receive personalized treatment to demonstrate that this approach has greater efficacy, or at minimum, substantially similar efficacy with reduced toxicity. Conclusions: To demonstrate that personalized cancer therapy is superior to the current standard and is an effective therapy worth exploring for other cancers too.
Predicting clinical benefit from EGFR TKIs: Not all EGFR mutations are equal
Authors: F. R. Hirsch, W. A. Franklin, J. McCoy, F. Cappuzzo, M. Varella-Garcia, S. E. Witta, P. Gumerlock, H. West, D. R. Gandara, P. A. Bunn
Journal: Journal of Clinical Oncology (2006)

7072 Background: EGFR mutations are associated with better response and in some studies (mainly Asian) also with prolonged survival after gefitinib therapy in patients with advanced NSCLC. Although a number of mutations have been reported, most frequent are exon 19 or exon 21 mutations of the EGFR tyrosine kinase domain.Whether clinical outcomes differ by subtype of EGFR mutation has not been previously reported. Methods: Mutation analysis (as previously described) was performed in 157 of 204 patients with advanced NSCLC treated with gefitinib (250 mg or 500 mg) in 2 study cohorts (Italian study of Iressa Expanded Access Program and SWOG 0126). Fifty nanograms of genomic DNA was isolated from pretreatment tumors, amplified for EGFR exons 19 and 21 by touchdown hemi-nested polymerase chain reaction and sequenced in both sense and antisense directions. Results: EGFR mutations were found in 43 pts (27%). Overall, patients with EGFR mutations had a response rate of 39% versus 7% for those without (p ≤ 0.001), disease control rate of 52% versus 37% (p = 0.14), time to progression of 3 months in both groups and median survival of 13 months versus 11 months (p = 0.14). Patients with exon 19 mutations exclusively (N = 11) had better outcome than those with exon 21 mutations exclusively (N = 31), with response rates of 67% versus 20% (p = 0.02), median time to progression of 15 months versus 2 months, and median survival of 26 months versus 10 months. There was a difference in time to progression (11 months versus 3 months) and overall survival (median 26 months versus 11 months) between patients with and without exon 19 mutations, while no difference was apparent in these outcome measures in patients with and without exon 21 mutations. Sample size provided insufficient power for significance tests of differences in survival outcomes. Conclusions: Not all EGFR mutations are created equal. Mutations in exon 19 are more predictive of response and survival after gefitinib than exon 21 mutations. [Table: see text]
Chronic traumatic encephalopathy is reported in 25 year old former American football player
Authors: Michael McCarthy
Journal: BMJ (2016)

A 25 year old man who was repeatedly concussed while playing American football as an amateur and subsequently developed learning and behavioral problems has been found at autopsy to have chronic traumatic encephalopathy, a neurodegenerative disorder associated with repetitive head injury. 

The disorder, which currently can be diagnosed only on autopsy, has become a growing concern among young athletes and their families in the United States, owing to an increasing number of reports of it among older National Football League athletes and a heightened awareness of the frequency of concussions among young people playing contact and non-contact sports.

The report comes from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) study (www.bu.edu/alzresearch/ctecenter/cte-center-research/unite-study/), a project designed to develop consensus criteria for the pathological diagnosis of chronic traumatic encephalopathy, establish …
A New Pathway for Senescence Regulation
Authors: Xi Cao, Mo Li
Journal: Genomics Proteomics & Bioinformatics (2015)

Research concerning senescence has become a hotspot since the conception of 'cellular senescence' was put forward by Drs.Hayflick and Moorhead over five decades ago [1].Recently, a paper published in Science by Kang and colleagues, which this article aims to comment on, provides evidence of a new pathway involved in senescence [2].Senescence is a physiological and pathological process induced by numerous factors, during which cell growth ceases and gene expression alters.As can be imagined, such state protects against the development of cancer and plays an important role in tissue repair [3].On the other hand, senescence is involved in many other processes such as aging and neurodegenerative disease [4][5][6].Recent studies show that senescent cells produce senescence-associated secretory phenotype (SASP) factors including chemokines, proteases, pro-inflammatory cytokines, growth factors, macrophage inflammatory proteins (MIPs), and granulocyte-macrophage colony-stimulating factors (GM-CSFs) [7,8].It is known that SASP is mediated by the transcription factors NF-jB [9].But how SASP is initiated and maintained is not clear.There are up to 10 6 DNA damages happening in each cell per day.To respond to these threats, cells evolve the DNA damage response (DDR) system to sense and repair the damages if these damages are not so severe.However, if the damages are beyond the capability of the cell to repair, DDR will
Sunitinib in patients (pts) with unresectable primary renal cell carcinoma (RCC)
Authors: L. Wood, J. A. Garcia, P. Elson, R. N. Salas, B. R. Lane, E. Klein, A. Stephenson, R. Dreicer, S. C. Campbell, B. I. Rini
Journal: Journal of Clinical Oncology (2009)

5096 Background: Sunitinib inhibits VEGF and related receptors, with high tumor shrinkage rates in metastatic (met) RCC. Shrinkage of primary tumors has been observed, although prospective investigation is lacking. The ability of sunitinib to convert primary RCC tumors from unresectable to resectable is of high clinical interest. Methods: Pts with histologically-confirmed RCC with an unresectable primary tumor with or without met disease were enrolled on a single-arm phase II trial. Primary tumors were unresectable due to ≥ 1 of the following: large tumor size, bulky lymphadenopathy, encasement of renal vessels, IVC thrombosis or proximity to vital structures. Pts received 50 mg sunitinib continuous dosing in repeated 6-week cycles. Staging by CT scans or MRI was done at baseline and every 2 cycles. A Simon 2-stage design was employed to test the alternative hypothesis of a conversion to resectability rate of 20% versus the null hypothesis of 5%; β = 0.8, α = 0.05 (n = 31). Results: 18 pts have been enrolled; 1 excluded due to a non-RCC diagnosis. Pts were unresectable due to bulky lymphadenopathy (6), IVC thrombosis (4), proximity to vital structures (4) or tumor size (3), although most pts had multiple factors. Median age among 14 evaluable pts was 61 years (range, 37–80), 59% male, 76% ECOG PS 0; 79% had distant met disease. The 14 evaluable pts have received a median of 3 cycles of therapy (range, 1–10+). Three pts (21%) have undergone primary tumor resection; viable RCC was identified in all specimens with no unexpected surgical morbidity. Nine pts (53%) had primary tumor reduction (median 19%; range, -64% to -1%). Overall, median best % change in tumor burden was 4.9% reduction for primary tumors (range, -43.1% to +8.5%) and 10.7% reduction for met sites (range, -89.5% to +28.6%). Median PFS is 4.9 months. Eleven pts (79%) discontinued therapy; 8 for PD, 1 for adverse events and 2 following surgery which removed all visible disease. Eight pts (57%) experienced grade 3 toxicity including thrombocytopenia, fatigue, hypertension, anemia, hemoptysis, and hand-foot syndrome; 1 pt had grade 4 neutropenia. Conclusions: Sunitinib has activity in unresectable primary RCC tumors, permitting resection in some pts. Continued prospective investigation is required to optimize patient selection and timing of surgery. [Table: see text]
Exceptional extra pulmonary tuberculosis localizations: A 15 years series
Authors: Hajer Ben Abdelghaffar, Amani Ben Mansour, Ines Akrout, Leila Fekih, Hela Hassene, Hanene Smadhi, Ikbel Khalfallah, Dorra Greb, Dalinda Belhabib, Mohamed Lamine Megdiche
Journal: European Respiratory Journal (2014)

Extra-pulmonary tuberculosis remains an important health problem despite the overall decline in the incidence of tuberculosis.

The aim of this study was to determinate particularities and to identify the influences of individual life styles and medical history on the risk of developing rare extra-pulmonary tuberculous location.

We underlying through its pathogenic patterns, diagnosis and therapeutic difficulties

We report 28 cases of atypical tuberculosis localization hospitalized in our unit during a period of 15 years.

We have 15 men and 12 wemen with a mean age of 43 years (21-70).

No previous history of tuberculosis was noted and no patient was immunocompromised.

Thoracic wall tuberculosis was found in 7 cases. 8 cases of Haematopoietic organ tuberculosis associated with pulmonary or lymph nodes tuberculosis and Other more exceptional localizations are reported in our series: Cavum (1 case), larynx (4 cases), skin (1 case), ovary (1 case), cerebral tuberculoma (1 case), peritoneum (1 case), pericardium (1 case), tonsil (1 case), breast (1 case) and bone (1 case). Revealing symptoms were dysphonia, cephalalgia, abdominalgia, thoracic or bone algia, breast and cutaneous tumefaction, right cervical adenopathy. The confirmation of diagnosis was posed by anatomopathologic specimen or culture of mycobacterium tuberculosis. Through early detection and treatment for a suitable period are mandatory to improve the prognosis of this potentially curable infectious disease. Surgical treatment is not systematically indicated. Prognosis remains favourable, although diagnosis delay can cause complications.
Preoperative chemoradiotherapy (QRTP) and total mesorectal excision (TME) by laparoscopy (LPS) in rectal cancer (RC): Long-term outcomes.
Authors: E. Pineda, X. Garcia-Albeniz, S. Delgado, C. Conill, A. Gines, J. Ayuso, R. Gallego, M. Cuatrecasas, A. Lacy, J. Maurel
Journal: Journal of Clinical Oncology (2010)

3634 Background: QRTP and subsequent TME is the standard treatment in patients with stage II-III RC. Laparoscopic surgery in RC is not a standard treatment. We present long-term outcomes in patients with RC treated with QRTP and TME by LPS. An interval < 8 vs. ≥ 8 weeks between treatment completion and surgery as a predictive factor of pathological complete remission (pCR) was also analyzed (Kalady, Ann Surg 2009). Methods: We analyzed all patients with rectal cancer treated with QRTP and TME by LPS at the Hospital Clinic of Barcelona between 2000 and 2008. Tumor staging was performed with endorectal ultrasonography, abdominal helical CT and chest radiography. Neoadjuvant treatment consisted of 45 Gy delivered in fractions of 1.8 cGy/day concomitant with 5-fluorouracil given in a 120-hour continuous infusion at a dose of 225 mg/m2/d for 5 weeks. Results: Of 423 patients operated by LPS, 164 received QRTP achieving radical surgery in 156. Median follow-up 43.8 months. 17.9% of patients achieved a pCR. Subgroup of patients with good pathological response (n = 70, ypT0-2 N0) obtained better oncological results at 5 years than patients with poor pathological response (n = 86, ypT3-4NX, ypTxN1-2) in local recurrence (0% vs. 10.4% p = 0.004), relapse-free survival (92% vs. 54.8% p < 0.001) and overall survival (90.1% vs. 60.7% p < 0.001). On multivariate analysis, pathological response ypT0-2N0 was the only predictive factor for overall survival (HR 6.02 IC95% 2.08-17.45). An interval ≥ 8 weeks between treatment and surgery was not associated with a higher rate of pCR (HR 1.47 p = 0.365). Conclusions: Patients with rectal cancer treated with QRTP and TME by LPS have long-term outcomes comparable to open surgery. An extended interval between treatment and surgery is not a predictive factor of pCR in our analysis. No significant financial relationships to disclose.
Characteristics and outcomes of patients admitted to the acute palliative care unit (APUC) from the emergency center (EC) versus inpatient transfers (IP).
Authors: SeongHoon Shin, Eduardo Bruera, David Hui, Jung Hye Kwon, Gary B. Chisholm, Maria Teresa San-Miguel, Julio Allo, Sriram Yennurajalingam, Susan Frisbee-Hume
Journal: Journal of Clinical Oncology (2013)

e20581 Background: Most patients admitted to APCU are transferred from inpatient oncology units. We hypothesized that EC admissions have different symptom burden and outcomes compared to IP patients. In this retrospective cohort study, we compared the symptom burden and survival between the EC and IP groups. Methods: Among all 2,568 patients admitted to our APCU between September 1, 2003 and August 31, 2008, 312 (12%) were EC patients. We randomly selected 298 IP patients as controls. We retrieved the patient demographics, cancer diagnosis, Edmonton Symptom Assessment Scale (ESAS), discharge outcomes, and overall survival from time of admission. Results: EC patients were more like to be black (22% v 11%, p=0.0006) and less likely to have hematologic cancer (5% v 14%, p=0.0003). EC patients had higher pain (5.4 v 4.6, p=0.0004), fatigue (6.7 v 6.1, p=0.0049), nausea (2.7 v 1.6, p&lt;0.0001), insomnia (4.8 v 4.2, p=0.03) and were less likely to be delirious (41% v 55%, p=0.001). EC patients had more public insurance (44% v 38%, p=0.0142), more home discharge (29% v 11%, p=0.0001), longer admission (8 v 7 days, p=0.0002), and were 2.3x as likely to be discharged alive as compared to IP patients (p&lt;0.0001, Wald Chi-square test). Kaplan-Meier plots and log-rank test for survival from admission of APCU for EC and IP groups were not statistically significant (Median survival after admission were 34 v 31 days, p=0.08). In multivariate analysis, EC admission (OR= 1.9, 1.2-3.0), wellbeing (OR=1.12, 1.02-1.23), dyspnea (OR=0.85, 0.79-0.92) and delirium (OR=0.39, 0.24-0.64) were independently significant for being discharge alive. The c-statistic value was 0.71. Conclusions: EC patients have higher acute symptom burden, but more likely to be discharged alive as compared to IP transfer patients. The APCU is successful at managing symptoms and facilitating discharge to the community for EC patients. [Table: see text]
Providing end-of-life care to patients seeking hope for cure: Improving Mayo Clinic palliative care utilization
Authors: K. Swetz, T. Moynihan, S. Ruegg, A. Tan, P. J. Atherton, J. Sloan
Journal: Journal of Clinical Oncology (2006)

18552 Background: We reviewed Palliative Care Consultation Service (PCCS) referrals to attempt to promote earlier referrals, and to improve overall patient care. Methods: Eligibility for PCCS referral is life expectancy of one year or less. Data was collected prospectively on the first 461 referrals (452 individual patients) over the initial 30-month period (January 1, 2003 to July 1, 2005). Additional factors were retrospectively abstracted from documentation. Kaplan-Meier survival analysis was then performed. Results: 452 patients were seen (mean age 71.9 years), and 387 (86%) have died. Median length of inpatient stay was 8 days, with PCCS consultation requested 3 days prior to discharge. 107 patients (24%) died prior to hospital discharge. 345 patients survived to discharge, 236 (68%) died within 3 months, and 262 (76%) died within 6 months. Median survival from consultation to death was 12 days and after hospital discharge was 6 days. Secondary analysis determined that patients with malignancy had longer median survival from discharge to death than those with other diagnoses (11 days versus 3 days, p = 0.025). Median survival was longer with referrals from general surgery and surgical specialties (37 days and 8 days, respectively), compared to hematology-oncology and critical care (2 days and 0 days, respectively). Conclusions: The primary goal of the PCCS is to provide symptom control and maximize quality of life at the end of life. These data suggest palliative care services are unnecessarily delayed until too late. Education is necessary to facilitate earlier PCCS intervention. Survival analysis suggests providers are more likely to consider PCCS involvement in patients with malignancy compared with other diseases. Critical care and hematology-oncology, showed the lowest median survivals. Education efforts must be focused on these areas. Programs are underway to identify eligible patients earlier in their disease process, and educate providers about key end-of-life services provided to patients and families. No significant financial relationships to disclose.
A phase 1 study of dinaciclib (SCH 727965) in combination with epirubicinin patients with metastatic triple-negative breast cancer.
Authors: Zahi Mitri, Kansu Karakas, Nuhad K. Ibrahim, Ricardo H. Alvarez, James L. Murray, Brian Briones, Holly Simmons, Khandan Keyomarsi, Stacy L. Moulder
Journal: Journal of Clinical Oncology (2014)

163 Background: Low molecular weight cyclin E (LMW-E) isoforms are overexpressed in a majority (~70%) of triple-negative breast cancers (TNBC). LMW-E isoforms have a role in tumorigenesis, likely mediated through binding and activation of CDK2. The combination of CDK1/CDK2 inhibitors, such as dinaciclib, with an anthracycline was found to be synergistic in decreasing viability of TNBC cell lines. Based on this data, we conducted a phase 1 study aimed to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC. Methods: Cohorts of at least 2 patients were treated with escalating doses of dinaciclib (20-50 mg/m 2 ) given on day 1 followed by standard dose of epirubicin (75 mg/m 2 ) given on day 2 of a 21 day cycle. All patients received pegfilagrastim 24-48 hours after chemotherapy. No intra-patient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30%. Results: Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. Patient characteristics are included in the Table. One patient was taken off treatment after 1 cycle due to toxicity. DLTs included febrile neutropenia (grade 3, n=2), syncope (grade 3, n=2) and vomiting (grade 3, n=1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was found to be too toxic. Eight patients had disease progression, median number of cycles was 1 (range 1-4), and median time to progression was 1 month (range 1-3). No treatment responses were noted and it was decided to stop accrual rather than explore lower dose levels. Associated with significant toxicities. Conclusions: The combination of dinaciclib and epirubicin does not appear to be an effective treatment option for TNBC, and is associated with significant toxicities. Clinical trial information: NCT01624441. [Table: see text]
Plasma 2 '-deoxyuridine (dUrd) as a surrogate marker of thymidylate synthase (TS) inhibition in patients in phase I clinical trials of the TS inhibitor ZD9331
Authors: F Mitchell, S Lynn, C Rees, I Judson, AH Calvert, M Ratain, S Diab, E Rowinsky, K Mayne, AL Jackman
Journal: Annals of Oncology (1998)
Hypogammaglobulinemia in pts receiving rituximab immunotherapy and the impact of rituximab maintenance.
Authors: C. Casulo, J. Maragulia, A. D. Zelenetz
Journal: Journal of Clinical Oncology (2010)

8088 Background: Several randomized studies demonstrated that rituximab maintenance (RM) prolongs PFS but not OS following induction with rituximab immunotherapy (I) alone or chemoimmunotherapy (CI) in patients (pts) with indolent lymphoma. The long-term impact of rituximab (R) on immune reconstitution has not been well studied; however R has been associated with hypogammaglobulinemia (hypogam) with recurrent infections. This retrospective study sought to evaluate the relationship between R, hypogam, and treatment with intravenous immune globulin (IVIG). Methods: We identified 215 pts treated with R for lymphoma between 12/1998 and 4/2009 and also had quantitative serum immunoglobulin levels (sIg) evaluated prior to and after treatment with R. Data on the use of IVIG was collected. Frequencies were compared using Pearson χ2. Results: Histologies included: DLBCL, N=68; FL, N=42; CLL/SLL, N=38; MZL, N=26; MCL, N=22; other subtypes, N=19. Pts received a median of 6 doses of R (range:2–50). Prior to treatment with R, 85% (183/215) of pts had normal sIg levels and 15% (32/215) had low levels. Histologies among 32 pts with baseline hypogam were well distributed: DLBCL, N=10; CLL/SLL, N=5; FL, N=5; MZL, N=4; MCL, N=2; other, N=6. Of 183 pts with normal sIg levels prior to R, 26.7% (49) received RM while 73.2% (134) received R as I or CI alone. Hypogam was documented in 39% (71/183) of pts with baseline normal sIg levels following R. RM was associated with a higher risk of developing hypogam, 55% (27/49) compared to 33% (44/134) receiving I or CI alone, p=0.006. IVIG was administered to 13% (23/183) of pts with normal baseline sIg. Among patients who received RM, 20% (10/49) received IVIG compared to 10% (13/134) among patients treated with I or CI alone, p=0.05. IVIG for treatment of symptomatic hypogam was administered to 10% (18/183) of pts with normal sIg prior to R therapy. Conclusions: R was associated with developing hypogam in 39% of pts with normal baseline sIg. Pts receiving RM had a significantly higher risk of developing hypogam and requiring IVIG. The risk of symptomatic hypogam should be considered in the use of R maintenance. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, GlaxoSmithKline, sanofi-aventis Physicians' Education Resource Amgen, Biogen Idec, Genentech, GlaxoSmithKline, Roche