tbuckley/cabot-search huggingface dataset:
Speeding up access to new drugs threatens evidence based medicine, says health economist
Authors: Nigel Hawkes
Journal: BMJ (2016)

Accelerating access to new drugs in the NHS will do more harm than good, asserts Karl Claxton, a health economist at the University of York. Expensive new drugs absorb money that, on his calculations, could achieve greater benefits to patients if spent elsewhere in the NHS.

Claxton was speaking at a Westminster Health Forum seminar in London and in the 10 minutes allocated to him issued a powerful challenge to the more conventional views being offered by other speakers. The government’s Accelerated Access Review, which seeks to speed new drugs from the laboratory into the clinic (https://www.gov.uk/government/organisations/accelerated-access-review), would “increase the rate of harm” already done by the Cancer Drugs Fund and the National Institute for Health and Care Excellence (NICE), he said.

Changes to the Cancer Drugs Fund would …
Phase II study of induction and adjuvant bevacizumab in patients with stage IB-IIIA non-small cell lung cancer (NSCLC) receiving induction docetaxel and cisplatin
Authors: K. Price, M. G. Kris, V. Rusch, D. J. Finley, C. G. Azzoli, R. J. Downey, M. S. Bains, V. A. Miller, N. Rizk, N. A. Rizvi
Journal: Journal of Clinical Oncology (2009)

7531 Background: VEGF supports growth of NSCLC and is blocked by bevacizumab. Bevacizumab with chemotherapy is an established treatment for advanced NSCLC. We conducted this study to assess the efficacy and toxicity of induction bevacizumab (Bev) with cisplatin (C) and docetaxel (D) in patients with resectable NSCLC. Methods: All patients (pts) had resectable Stage IB-IIIA NSCLC and received up to 4 cycles of D 75 mg/m 2 and C 75 mg/m 2 followed by surgery. Pts with non-squamous NSCLC also received 3 cycles of Bev 15 mg/kg along with induction DC (Bev-DC). Bev was not given in pre-operative cycle 4. Pts with squamous or central tumors or hemoptysis received 4 cycles of DC only (DC). All resected pts were eligible for adjuvant Bev 15 mg/kg q3 weeks for 1 year. The primary endpoint was rate of downstaging from pre-operative clinical stage to pathologic stage. Results: From Aug 2005 - Nov 2008, 47 pts were enrolled: 27 women; median age 62; Stage 1B -15%, Stage II-17%, Stage IIIA-68%. Of 36 pts given Bev-DC, 15/30 (50%) who have completed surgery were downstaged. Of 11 pts given DC, 3/11 (27%) were downstaged. In Bev-DC group, 22/33 (67%) completed all 4 cycles of DC without a dose reduction and 28/33 pts (85%) completed all 3 planned cycles of Bev. Pts received &lt;3 cycles due to: hemoptysis (n=3), consent withdrawal (n=1), hypertension (n=1), and sepsis (n=1). For DC, 6/11 pts (55%) completed all 4 cycles of DC without a dose reduction. 42/43 patients were resected. R0 resection rate: 29/31 for Bev-DC and 9/11 for DC. Grade 3/4 surgical complications were seen in 5/31 pts (16%) in Bev-DC and 1/11 (9%) in DC. Only 17/41 (41%) who completed surgery received adjuvant bev (median 6 cycles), and 7/41 (17%) completed all adjuvant Bev. Pts did not receive adjuvant Bev due to: POD prior to adjuvant Bev (n=9), POD during adjuvant Bev (n=6), toxicity (n=4), consent withdrawal (n=1), RT for unresectable disease (n=1), surgical complications (n=4), chemotherapy complications (n=4). No treatment related deaths. Conclusions: Induction chemotherapy with Bev-DC in NSCLC is feasible and is associated with an improved rate of downstaging compared with historical controls (33%). In patients treated with DC-Bev, grade 3/4 surgical complications were increased by 7%. [Table: see text]
India to track progress of 75 cities to improve sanitation
Authors: Sanjeet Bagcchi
Journal: BMJ (2016)

The Indian government is to rank 75 of the country’s major cities according to their sanitation and cleanliness as part of a survey to map the progress of a national campaign launched in 2014 to end open defecation.

India’s Ministry of Urban Development has commissioned the survey to be carried out by the Quality Council of India.1 It will cover all the state capitals of India plus another 53 cities with populations of more than one million.

India’s campaign to promote sanitation and …
Utility of 11C-Methionine and 18F-FDG PET/CT in Patients With Functioning Pituitary Adenomas
Authors: Zize Feng, Dongsheng He, Zhigang Mao, Zongming Wang, Yonghong Zhu, Xiangsong Zhang, Haijun Wang
Journal: Clinical Nuclear Medicine (2015)

MRI is commonly used in the evaluation of pituitary adenomas (PAs). However, it has difficulty to locate the lesions sometimes, especially microadenomas and/or postoperative recurrent tumors. We aimed to evaluate the role of combined C-methionine (MET) and F-FDG PET/CT in patients with functioning PAs.This study included 43 patients: 15 had Cushing disease, 16 had acromegaly, and 12 had a prolactinoma. F-FDG PET/CT was performed on all of the patients; C-MET PET/CT was performed on 39 of the patients. The PET images and surgical findings were analyzed.On F-FDG PET/CT, 29 (67%) of 43 cases had positive results, all of which were true positives, including 2 cases with equivocal MRI results. On C-MET PET/CT, 37 (95%) of 39 cases had positive results, of which 2 were false positives. All patients underwent surgery, and the results of PET/CT scans were confirmed by surgery and pathological examination. All F-FDG PET/CT results were negative when C-MET PET/CT results were negative. However, 12 patients with positive C-MET PET/CT results had negative F-FDG PET/CT results. The positive rate of F-FDG PET/CT in patients with somatostatin analog treatment, radiosurgery, transsphenoidal surgery, and microadenoma was 63% (5/8), 50% (1/2), 33% (4/12), and 48%(10/21), respectively, while that of C-MET PET/CT was 86% (6/7), 50% (1/2), 100% (12/12), and 100% (21/21), respectively. In the 9 patients with a recurrent microadenoma, the positive rate of F-FDG PET/CT was as low as 22% while that of C-MET PET/CT was 100%. There was no significant difference in the positive rate of C-MET and F-FDG PET/CT between the 3 types of PA.PET/CT may be useful to detect tumors in patients with equivocal MRI results. C-MET PET/CT can provide valuable diagnostic information when F-FDG PET/CT yields negative results, especially in patients with recurrent microadenomas.
Charge to the Community: Some Early Effects of a State Hospital System's Change of Policy
Authors: EDWIN ROBBINS, LILLIAN ROBBINS
Journal: American Journal of Psychiatry (1974)

The current thrust toward community care in New York State has had a dramatic positive effect as local facilities have actively presented alternatives to long-term hospitalization. But there have also been negative effects, some anticipated and some unanticipated, as local facilities have found it difficult to meet the needs of many patients, particularly those unable to make the transition from custodial care to living on their own. The authors discuss these developments in the light of New York City's recent experiences with community psychiatry and offer some recommendations for similar transitions in other communities.
Epigenetic Repression of CCDC37 and MAP1B Links Chronic Obstructive Pulmonary Disease to Lung Cancer
Authors: Mathewos Tessema, Christin M. Yingling, Maria A. Picchi, Guodong Wu, Yushi Liu, Joel L. Weissfeld, Jill M. Siegfried, Yohannes Tesfaigzi, Steven A. Belinsky
Journal: Journal of Thoracic Oncology (2015)
Fat accumulation in enterocytes: a key to the diagnosis of abetalipoproteinemia or homozygous hypobetalipoproteinemia
Authors: Lobke Desomer, Martine De Vos, Danny De Looze
Journal: Endoscopy (2015)

A 20-year-old woman was referred by her ophthalmologist to investigate the reason for her hypovitaminosis A and secondary night blindness. She had no other symptoms of deficiencies in fat-soluble vitamins, no abdominal complaints, and no weight loss.
Risk of multiple sclerosis during tumour necrosis factor inhibitor treatment for arthritis: a population-based study from DANBIO and the Danish Multiple Sclerosis Registry
Authors: L Dreyer, M Magyari, B Laursen, R Cordtz, F Sellebjerg, H Locht
Journal: Annals of the Rheumatic Diseases (2015)

Multiple sclerosis (MS) is a chronic inflammatory neurological disease with multifactorial aetiology.1 Evidence of tumour necrosis factor (TNF)-α as an important factor in the pathogenesis of MS has emerged.2 However, attempts of treating MS with TNF-inhibitors (TNFi) have increased disease activity.3 Several case reports have indicated that demyelinating diseases could be a serious adverse event following TNFi treatment while data from the Spanish Registry of biological therapies in rheumatic diseases did not bring clarification.4 ,5 Some, but not all, studies have suggested a negative association between rheumatoid arthritis (RA) and MS.6 ,7 

We aimed to investigate whether TNFi treatment in patients with arthritis is associated with an increased risk of developing MS and whether RA is associated with a decreased risk compared with the general population.

The nationwide Danish DANBIO Registry started in 2000 and covers >90% of adults with rheumatological disease treated with TNFi in routine care.8 Since 2005, patients not treated with …
Triterpenoids from the tirucallic and boswellic acid families induce G0/G1 checkpoint arrest and apoptosis in prostate cancer cells
Authors: Tatiana Syrovets, Aydee C. Estrada, Berthold Büchele, Esther Weidlich, Jürgen Gschwend, Thomas Simmet
Journal: Cancer Research (2006)

1920  The gum resins from various Boswellia species contain a complex mixture of mono- and triterpenoids that possess biological activities, including antitumor properties. We have previously shown that systemic application of acetyl-11-keto-β-boswellic acid (AKβBA) inhibited tumor growth and triggered apoptosis in pre-established PC-3 xenografts in nude mice via inhibition of IκB kinase α. Here, we have analyzed the molecular mechanisms of the cytotoxic effects of 3-keto-tirucallic acid (KTA) and AKβBA in human prostate cancer cell lines in vitro. The triterpenoids were isolated from the gum resin of Boswellia Carterii, and purified by reversed phase HPLC to chemical homogeneity; their structures were confirmed by mass spectroscopy. AKβBA and KTA (1-100 μM) exerted concentration-dependent anti-proliferative and cytotoxic effects on the androgen-dependent LNCaP prostate cancer cell line as well as on the androgen-independent, chemoresistant PC-3 prostate cancer cell line as measured either by the XTT assay or by lactate dehydrogenase release. A rapid induction of apoptosis was confirmed by analysis of phosphatidyl serine expression on the cell surface and formation of DNA-laddering. Flow cytometric cell cycle analysis of LNCaP and PC-3 cells treated with KTA and AKβBA (10 μM) for 24 and 48 h demonstrated accumulation of the cells in the G0/G1 phase, whereas the amount of cells in the S-phase was drastically reduced. Accordingly, the cycle-dependent phosphorylation of the retinoblastoma protein was rapidly reduced. Cell division is under strict control of cyclin-dependent kinases (CDKs) and their heterodimeric cyclin partners. Western blot analysis of prostate cancer cells treated with the triterpenoids revealed downregulation of cyclin D1, a crucial cell cycle regulator, but not of cyclin E or Cdk4. Downregulation of cyclin D1 occurred at the transcriptional level. The cyclin D1 promoter is regulated by NF-κB and TCF transcriptional regulators. Accordingly, an early downregulation of the nuclear accumulation of β-catenin and p65 was observed in triterpenoid-treated prostate cancer cells. Overexpression of the NF-κB inhibitor IκBα-SR, inhibited the constitutively active NF-κB signaling in PC-3 cells and reduced the cell proliferation, but did not trigger apoptosis. These results indicate that a sole inhibition of the NF-κB activity is not sufficient to trigger apoptosis in prostate cancer cells. Thus, triterpenoids inducing a G0/G1 checkpoint arrest might provide a novel approach for the treatment of chemoresistant human prostate cancer. This work was supported by the Deutsche Krebshilfe
CD4 tumor-reactive T cells enhance intratumoral proliferation and effector function of CD8 cells and synergistically mediate tumor regression.
Authors: Li-Xin Wang, Suyu Shu, Gregory E. Plautz
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5567 

Tumor antigen-primed T cells are highly enriched in the CD62Llow subset derived from lymph nodes draining progressing tumors and in vitro activation with anti-CD3 mAb and cytokines promotes acquisition of potent tumoricidal function in vivo following adoptive transfer. At the effector phase CD8 T cells can directly kill MHC class I+/class II− tumors, however, CD4 T cells function through cross-presentation by intratumoral APCs. We have demonstrated that CD4 as well as CD8 T cells each have stand-alone curative potential against advanced MCA205 fibrosarcomas in lung, brain, and subcutaneous sites. Here, we tested whether CD4 effectors augment the function of CD8 T cells. MCA205 draining lymph nodes were depleted of CD62Lhigh cells then CD4 cells were purified by positive MACS selection and activated with anti-CD3/IL-7/IL-23, whereas the purified CD8 subset was activated with anti-CD3/IL-2/IL-7. Adoptive transfer of CD4 combined with CD8 effector T cells (2.5 × 106 each) completely eradicated 10-day pulmonary metastases whereas 5 × 106 of either CD4 or CD8 subset alone was sub-therapeutic (p<0.05). A similar synergistic effect was observed in 3-day subcutaneous tumors. In vitro, the percentage of CD8 cells that produced IFN-γ upon exposure to MCA205 tumor digest was augmented by the addition of CD4 cells (3.6±0.6% v.s 12.7±1.7%)). Intratumoral proliferation of transferred CFSE-labeled CD8 effector cells was minimal in the absence of CD4 cells but was markedly augmented by co-transfer of either viable or immediately post-irradiated CD4 effector cells. CD4 effector cells underwent vigorous intratumoral proliferation and released large amounts of IL-2 (6 hr, 442±107 pg/ml; 24 hr, 17.3±1.9 pg/ml; 48 hr, 3.4±1.0 pg/ml) and IFN-γ (6 hr, 595±177 pg/ml; 24 hr, 3108±478 pg/ml; 48 hr, 305±26 pg/ml). Interestingly, treatment of mice with 10-day pulmonary metastases using 107 highly activated CD4 cells that had undergone repetitive in vitro stimulation induced a delayed (5 days later) release of large amounts of TNF-α (day 1, 45.6±4.9 pg/ml; day 5, 38.5±6.4 pg/ml) simultaneous with tumor regression that was associated with lethal pulmonary congestion in the MCA205 tumor but not in the antigenically distinct MCA207 fibrosarcoma. These data demonstrate that T cell mediated tumor regression is more complex than simple CTL killing of targets and that tumor antigen-specific CD4 cells synergistically augment CD8 function and can initiate tumor-regression even in the absence of CD8 cells. This provides a strong rationale to define class II tumor antigens and indicates a need to optimize CD4 preservation in adoptive immunotherapy strategies.
Significance of sentinel lymph node micrometastases on treatment of breast cancer
Authors: M. Sandera, D. Hadlock
Journal: Journal of Clinical Oncology (2008)

12020 Background: The use of sentinel lymph node biopsy (SLNB) is a well established and accurate method for identifying involvement of axillary lymph nodes in early stage breast cancer. SLNB can be used as an initial evaluation of the axilla in patients with clinically negative axillary nodes. Lymph node metastases are the most significant prognostic indicator for breast cancer. Micrometastases in the SLN are defined as metastases between 0.2mm and 2.0mm in size, based on the 6th ed AJCC staging criteria, and their clinical significance remains unknown. This study was designed to determine if patients with micrometastatic disease in the SLN were treated differently than patients with true N1 or greater disease. Methods: A retrospective chart review was conducted of patients in the Scott & White electronic medical record. Inclusion criteria were breast cancer patients treated at our Clinic between 2003–2006 with biopsy results consistent with breast carcinoma and positive SLNB. All patients had been treated surgically with mastectomy or breast conservation surgery. Results: Between 1/2003 and 12/2006, 280 breast cancer patients with positive SLN were reviewed. Of the 280 patients, 15.7% patients had micrometastases (Group I) and 3.92% patients had metastases <0.2mm in the SLN (Group II). The rest (80.3%) of the patients had N1 disease or greater, with tumor deposits >2mm (Group III). In Group I, 40.9% patients were treated with chemotherapy followed by hormonal therapy if ER/PR positive and 45.4% patients were treated with hormonal therapy alone. The remaining patients received no treatment. In Group II, 63.6% patients received chemotherapy ± hormonal therapy and 36.3% patients received hormonal therapy alone. Patients in Group III were treated with chemotherapy ± hormonal therapy (68.9%), hormonal therapy alone (24.5%), or no treatment (6.3%). Radiation was incorporated into therapy if applicable for all study patients. Conclusions: At our institution, micrometastatic disease in the SLN did not preclude offering aggressive and standard therapy to breast cancer patients. These patients are treated similarly to patients with N1 disease and are offered appropriate systemic chemotherapy or hormonal therapy. No significant financial relationships to disclose.
Human endogenous retrovirus-K contributes to motor neuron disease
Authors: Wenxue Li, Myoung-Hwa Lee, Lisa Henderson, Richa Tyagi, Muzna Bachani, Joseph Steiner, Emilie Campanac, Dax A. Hoffman, Gloria von Geldern, Kory Johnson, Dragan Maric, H. Douglas Morris, Margaret Lentz, Katherine Pak, Andrew Mammen, Lyle Ostrow, Jeffrey Rothstein, Avindra Nath
Journal: Science Translational Medicine (2015)

Human endogenous retrovirus-K is activated in the cortical neurons of patients with amyotrophic lateral sclerosis, and expression of the viral envelope protein in mouse brain reproduces the clinical and pathological phenotype of this disease.
Survival advantage by neoadjuvant radiochemotherapy in locally advanced noninflammatory breast cancer
Authors: S. L. Roth
Journal: Journal of Clinical Oncology (2009)

638 Background: The impact of timing of radiochemotherapy (RCT) relative to surgery has been assessed in terms of ten year survival rate for locally advanced or surgically in terms of breast conserving surgery or simple mastectomy unfavourable, noninflammatory breast cancers (LABC). Methods: A total of 644 women were included in the retrospective study from 1991–1998. Chemotherapy was applied in 166 as neoadjuvant, in 236 simultaneously and in 113 as adjuvant. 119 patients received no chemotherapy. 40% of the patients received four courses of epirubicin/ cyclophosphamide, 26% concurrent mitoxantrone, 5% three cycles of CMF, 3% six cycles of CMF and 15% had no chemotherapy. 315 patients with locally advanced breast cancer (LABC) received neoadjuvant and 329 adjuvant RCT. Preoperative radiotherapy consisted of 50 Gy to the breast and the supra/infraclavicular lymph nodes with a 10 Gy electron or interstitial boost. The mean time interval between the end of radiotherapy and the surgery was 27 weeks (6–89 weeks). Results: Breast conservation was possible in 48% in the preoperative arm and in 52% in the postoperative arm. The rate of pT0 after neoadjuvant RCT was 38% (120/315) and the pCR in breast and axilla 30% (95/315). The ten year survival in the neoadjuvant group (n = 315) compared favourably 68.6% vs. 65% in case of the adjuvant group (n = 329; p = 0.21) in spite of more advanced disease. Patients with cT1- (n = 3) and cT2- (n = 97) categories had a significantly 13.6% better ten year survival rate after neoadjuvant RCT (85.76% vs. 72.19%) compared to cT1- (n = 1) and cT2- (n = 180) after adjuvant RCT (p = 0.0026). Conclusions: This study compares, retrospectively, neoadjuvant RCT vs. adjuvant RCT in LABC. Preoperative RCT achieved a pT0-rate of 38% and a prolonged ten year survival to a degree of 13.6% statistically significant in patients with cT2- category breast cancer compared to adjuvant RCT. No significant financial relationships to disclose.
Received Dose and Dose-Intensity of Chemotherapy and Outcome in Nonmetastatic Extremity Osteosarcoma
Authors: Ian J. Lewis, Simon Weeden, David Machin, Dan Stark, Alan W. Craft
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To examine the relationship between received dose, received dose-intensity (RDI), and survival in patients with osteosarcoma. PATIENTS AND METHODS: Between 1983 and 1993, the European Osteosarcoma Intergroup (EOI) conducted two randomized trials involving patients with high-grade, nonmetastatic, biopsy-proven osteosarcoma of the extremity. These trials shared a common treatment arm of doxorubicin (DOX) 75 mg/m 2 and cisplatin (CDDP) 100 mg/m 2 planned for six cycles at 3-week intervals. Definitive surgery was scheduled at week 9, after three cycles. Survival time was calculated from 122 days, the scheduled end of chemotherapy. RESULTS: A total of 287 patients randomized to DOX/CDDP received at least one cycle of chemotherapy, and 232 (81%) received all six cycles. On average, 79% of the intended dose of DOX and 80% of the intended dose of CDDP was given. Mean time to completion of chemotherapy was 1.27 times that specified by the protocol. Mean RDI was 0.64 for DOX (SD = 0.19) and 0.65 for CDDP (SD = 0.18). Progression-free survival was lower for those who received one to five cycles compared with those who completed all six cycles (hazards ratio, 1.69; 95% confidence interval, 1.03 to 2.78). Survival and progression-free survival were lowest for patients with RDI less than 0.6, although these differences were not statistically significant at the 5% level. There was no clear evidence of preoperative dose or dose-intensity influencing histologic response. CONCLUSION: This analysis did not establish a clear survival benefit for increasing received dose or dose-intensity in the context of this two-drug regimen. The hypothesis that increasing dose-intensity may improve survival in osteosarcoma requires prospective evaluation.
Abstract 16798: Notch Ligand Delta-Like 4 Promotes Vein Graft Disease: A Novel Mechanism
Authors: Jun-ichiro Koga, Jose-Luiz Figueiredo, Tomiharu Niida, Peng Yu, Charles K Ozaki, Masanori Aikawa
Journal: Circulation (2012)

Background: Vein graft failure occurs frequently, and leads to loss of limb/life. Despite its serious clinical burden, no effective medical therapy is available. Macrophage accumulation contributes...
A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group Study.
Authors: G A Omura, J A Blessing, F Major, S Lifshitz, C E Ehrlich, C Mangan, J Beecham, R Park, S Silverberg
Journal: Journal of Clinical Oncology (1985)

After hysterectomy, 156 evaluable patients with stage I (limited to the corpus) or stage II (limited to the corpus and cervix) uterine sarcomas were randomly assigned to adjuvant chemotherapy with Adriamycin (Adria Laboratories, Columbus, Ohio) for six months or to no further treatment. Pelvic irradiation (external or intracavitary) was optional before randomization. Of 75 patients receiving Adriamycin, 31 have suffered recurrences compared with 43 of 81 receiving no adjuvant chemotherapy. This difference is not statistically significant. Moreover, there is no difference in progression-free interval or survival. The optional radiotherapy did not influence the outcome although there was a suggestion that vaginal recurrence was decreased by pelvic radiotherapy. The recurrence rates in specific cell types (leiomyosarcoma, homologous mixed mesodermal sarcoma, or heterologous mixed mesodermal sarcoma) were not significantly different although the pattern of recurrence differed, with pulmonary metastases being more common in leiomyosarcoma and extrapulmonary recurrence being more common in mixed mesodermal sarcoma. The outcome with respect to chemotherapy was not altered even after adjusting for maldistribution of cases. Thus, we could not show a benefit for this dose schedule of Adriamycin as adjuvant treatment for uterine sarcomas.