tbuckley/cabot-search huggingface dataset:
BIM deletion polymorphism and the clinical outcome of patients with advanced NSCLC who received first-line platinum-based chemotherapy: Preliminary results.
Authors: Jie Zhang, Di Zheng
Journal: Journal of Clinical Oncology (2013)

e22137 Background: The up-regulation of the proapoptotic polypeptide BIM was acquired during the cancer cell apoptosis induced either by cytotoxic agents or tyrosine kinase inhibitors (TKIs). Germline polymorphism of BIM deletion was associated with shorter progression free survival (PFS) in patients with EGFR-mutated lung cancer treated with EGFR-TKIs. The aim of this study is to investigate the correlation between the germline polymorphism of BIM deletion and the clinical outcome of patients with advanced NSCLC who received first-line platinum based chemotherapy. Methods: Since June of 2012, 140 consecutive chemo-naive advanced NSCLC patients who completed two cycles of first-line platinum based chemotherapy evaluable for response assessment were eligible for inclusion in Shanghai Pulmonary Hospital. Patients with stable disease were excluded in order to eliminate the indolent disease effect. Each patient’s genomic DNA was extracted from peripheral blood sample, then the genotype of the BIM deletion was performed using a single PCR reaction with the primers 5’-AATACCACAGAGGCCCACAG-3’ and 5’-GCCTGAAGGTGCTGAGAAAG-3’. Results: There are 49 patients who responded to chemotherapy (RE group) while 32 patients developed progressive disease (PD group). The clinical characteristics at baseline and chemotherapy regimens received were balanced between the two groups except for more stage IV patients noted in PD group (57 vs 58 years old of median age, 59% vs 62.5% of male, 63% vs 100% of stage IV in RE group and PD group respectively, and the predominant regimen with gemcitabine plus cisplatin in both groups). BIM deletion polymorphism were detected in 4 of RE group (4/49, 8.2%) and 8 of PD group (8/32, 25%) respectively, (odds ratio=0.267, 95% CI=0.073-0.977, P=0.046). Conclusions: The germline polymorphism of BIM deletion may contribute to the intrinsic resistance to the chemotherapy in advanced NSCLC.
Imaging biomarkers in Parkinson’s disease and Parkinsonian syndromes: current and emerging concepts
Authors: Usman Saeed, Jordana Compagnone, Richard I. Aviv, Antonio P. Strafella, Sandra E. Black, Anthony E. Lang, Mario Masellis
Journal: Translational Neurodegeneration (2017)

Two centuries ago in 1817, James Parkinson provided the first medical description of Parkinson's disease, later refined by Jean-Martin Charcot in the mid-to-late 19th century to include the atypical parkinsonian variants (also termed, Parkinson-plus syndromes). Today, Parkinson's disease represents the second most common neurodegenerative disorder with an estimated global prevalence of over 10 million. Conversely, atypical parkinsonian syndromes encompass a group of relatively heterogeneous disorders that may share some clinical features with Parkinson's disease, but are uncommon distinct clinicopathological diseases. Decades of scientific advancements have vastly improved our understanding of these disorders, including improvements in in vivo imaging for biomarker identification. Multimodal imaging for the visualization of structural and functional brain changes is especially important, as it allows a 'window' into the underlying pathophysiological abnormalities. In this article, we first present an overview of the cardinal clinical and neuropathological features of, 1) synucleinopathies: Parkinson's disease and other Lewy body spectrum disorders, as well as multiple system atrophy, and 2) tauopathies: progressive supranuclear palsy, and corticobasal degeneration. A comprehensive presentation of well-established and emerging imaging biomarkers for each disorder are then discussed. Biomarkers for the following imaging modalities are reviewed: 1) structural magnetic resonance imaging (MRI) using T1, T2, and susceptibility-weighted sequences for volumetric and voxel-based morphometric analyses, as well as MRI derived visual signatures, 2) diffusion tensor MRI for the assessment of white matter tract injury and microstructural integrity, 3) proton magnetic resonance spectroscopy for quantifying proton-containing brain metabolites, 4) single photon emission computed tomography for the evaluation of nigrostriatal integrity (as assessed by presynaptic dopamine transporters and postsynaptic dopamine D2 receptors), and cerebral perfusion, 5) positron emission tomography for gauging nigrostriatal functions, glucose metabolism, amyloid and tau molecular imaging, as well as neuroinflammation, 6) myocardial scintigraphy for dysautonomia, and 7) transcranial sonography for measuring substantia nigra and lentiform nucleus echogenicity. Imaging biomarkers, using the 'multimodal approach', may aid in making early, accurate and objective diagnostic decisions, highlight neuroanatomical and pathophysiological mechanisms, as well as assist in evaluating disease progression and therapeutic responses to drugs in clinical trials.
Tenosynovial giant cell tumor (TGCT)/pigmented villonodular synovitis (PVNS): Outcome of 313 patients before the era of kinase inhibitors.
Authors: Emanuela Palmerini, Stefano Pengo, Robert G. Maki, Eric L. Staals, Angela Cioffi, Marco Alberghini, Piero Picci, Pietro Ruggieri, Sergio Mapelli, Antonina Parafioriti, Carol Morris, Alessandro Gronchi, Paolo Giovanni Casali, Stefano Ferrari, Silvia Stacchiotti
Journal: Journal of Clinical Oncology (2012)

10022 Background: Tenosynovial giant cell tumor (TGCT) is a rare, usually benign neoplasm of synovium and tendon sheath. TGCT is classified as localized or diffuse according to the extent of synovial involvement. Surgery is the primary treatment, but the recurrence rate is high, with possible multiple recurrences, joint function deterioration and decline in quality of life. Recent data suggest a role for TKIs in advanced disease. In order to identify prognostic factors for recurrence, a retrospective pooled analysis was carried out in three institutions (Istituto Ortopedico Rizzoli, Bologna, Italy; Istituto Nazionale Tumori, Milano, Italy; Memorial Sloan Kettering Cancer Center, New York, USA). Methods: Clinical charts and pathology reports of patients (pts) treated in the period 1998-2008 were examined. Results: The study included 313 pts, 177 F and 136 M; median age: 36 years (range: 11-89 years). Most (64%) pts had tumors in the knee (15% ankle, 11% hip, 10% other). Tumor size was: &lt;2 cm in 24% of pts, 2-5 cm in 44%, &gt;5 cm in 32%. A diffuse pattern was reported in 69% of pts. The resection status was available in 289 pts: 51% had R0 surgery, 28% R1 and 21% R2. No metastases were documented. Local recurrence was reported in 76 pts (median time to recurrence: 15.7 months). With a median follow-up of 4.2 years, 5-year local recurrence-free survival (LRFS) was 66% (95% CI: 59 - 73). Size (&lt; 2 cm 80% vs. 2-5 cm 67% vs. &gt;5 cm 62%, p=0.04), gender (F 73% vs. M 56%, p=0.02), type (localized 78% vs. diffuse 61%, p=0.02), and resection status (R0 76% vs. R1 55%, vs. R2 57%, p=0.002) influenced 5-year LRFS, whereas age, tumor location and bone involvement did not. The 5-year 2 nd LRFS was 43% (95% CI: 28 - 59). Multiple (2 to 5) local recurrences were observed in 39% of relapsed patients. Conclusions: The study confirms TGCT propensity to multiple local recurrences. Diffuse type, suboptimal surgery, male gender and larger tumors increase the recurrence risk. In order to improve the probability of local control, studies addressing the role of TKIs could be considered in subsets of patients.
Inequality trends in proximal and distal colon cancers.
Authors: Daniel David Bodek, Pavan Patel
Journal: Journal of Clinical Oncology (2017)

565 Background: Recently, the USPHTF released new colon cancer screening guidelines. No priority was given to any screening method. Given studies showing that Blacks had a greater proportion of proximal cancers, we sought to better highlight the inequalities in outcomes in order to consider the appropriateness of sigmoidoscopies versus colonoscopies. Methods: The SEER database was utilized to pull incidence and 5 year relative survival data (1992-2013). Patients aged 50-84 were divided by race and percentage of a county’s population below the poverty line ( &lt; or &gt; 15%). Adenocarcinomas were divided between distal cancer in the sigmoid, rectum, and anus versus cancer in the remainder of the colon. This data was analyzed using HDCalc, modelling rate difference, rate ratio, and the Index of Disparity. The Joinpoint regression program was then used to model Average Annual Percent Change (AAPC). Results: The AAPC in distal cancer incidence among Whites (-3.2%, [95% CI = -3.5%, -2.8%], p &lt; 0.05) was greater than in Hispanics (-1.6%, [95% Cl = -2.1%, -1.1%], p &lt; 0.05), or Blacks (-2.3%, [95% CI = -2.9%, -1.8%], p &lt; 0.05). This resulted in a decline in the Index of Disparity (AAPC: -6.6, [95% Cl: -9.1, -4.0], p &lt; 0.05) largely due to Whites' greater gains relative to Hispanics (Rate Ratio AAPC: -1.6%, [95% Cl: -1.9%, -1.3%], p &lt; 0.05). Less impressive were AAPC trends in proximal cancers, which were significant in Whites (-1.8%, [95% CI: -2.2%, -1.5%], p &lt; 0.05) and Blacks (-1.3%, [95% Cl: -1.8%, -0.8%], p &lt; 0.05). Additionally, the AAPC for proximal cancer’s Index of Disparity was also lower (-3.1%, [95% Cl: -3.8%, -2.4%], p &lt; 0.05). In terms of survival, only distal cancer’s AAPC for its Index of Disparity was significant (-3%, (95% Cl: -5%, -1.1%), p &lt; 0.05). Poorer counties performed worse in incidence reduction across races but similarly in survival improvements. Conclusions: While it is encouraging to see improvements in distal colon cancer outcomes, it is troubling to see that measures in proximal cancers are lagging behind. The slower improvements among the Black population and higher baseline mortality and incidence of such cancers would seem to indicate a need to further study the comparative value of more aggressive screening, particularly in this group.
Abstract 11467: Rosvastatin Ameliorates Lung Ischemic-Reperfusion Injury via eNOS Upregulation and Inhibition of Macrophage Recruitment in Pulmonary Hypertensive Rat
Authors: Satoshi Matsuo, Yuriko Saiki, Koki Ito, Yukihiro Hayatsu, Yusuke Suzuki, Shinichi Fukushige, Shunsuke Kawamoto, Akira Horii, Yoshikatsu Saiki
Journal: Circulation (2013)

Introduction: Lung ischemic-reperfusion (IR) injury during cardiac surgery with cardiopulmonary bypass is associated with postoperative morbidity and mortality, especially in patients with pulmonary hypertension (PH). Statin, an inhibitor of HMG-CoA reductase has been demonstrated as an anti-inflammatory mediator via endothelial NO synthase (eNOS) for IR injury in normotensive lung. A role of statin on lung IR injury in PH with impaired endothelial function has not been defined yet. The aims of this study are to investigate whether statin can exert a protective effect on the IR injury in PH and to elucidate some mechanisms of statin’s action to mediate lung IR injury in PH.

Methods: Male Sprague-Dawley monocrotaline-treated rats were divided into 4 groups (n=8-9): Sham, IR-saline (control), IR-Rosvastatin (IR+R), and IR-Rosvastatin + Mevalonate. Lung ischemia was induced by occlusion of the left pulmonary artery for an hour, followed by reperfusion for 4 hours. Rosvastatin (2mg/kg) was injected intraperitoneally 18 hours before ischemia. Mevalonate (1mg/kg) was injected intraperitoneally just before reperfusion. Arterial blood was collected at the end of reperfusion to evaluate P/F ratio. Left lung tissue was submitted to measure wet to dry (W/D) weight ratio and the expression of eNOS and phospho-eNOS by western blotting. Macrophage recruitment was assessed by CD68 immunostaining.

Results: Right ventricular systolic pressure before ischemia (average 45.2±2.8 mmHg) was not significantly different among all the groups. Rosvastatin significantly improved P/F ratio, W/D ratio and recruitment of macrophage (IR+R vs control: 442±38 vs 272±42, 4.6±0.3 vs 5.7±0.2, 3.4±1.1 vs 10.5±1.8 /field; P<0.03, respectively). These beneficial effects were blunted by adding mevalonate which is downstream metabolite of HMG-CoA. The expression of eNOS was augmented by Rosvastatin to the level of sham group, which was diminished by mevalonate to the level of control. On the other hand, no significant difference was observed in terms of phospho-eNOS/eNOS between the groups.

Conclusions: Single dose Rosvastatin ameliorates lung IR injury even in PH by way of two anti-inflammatory synergic mechanisms, upregulation of eNOS and inhibition of macrophage recruitment.
Randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a neoadjuvant treatment in patients with HER2-negative primary breast cancer.
Authors: Norio Kohno, Yoshie Hasegawa, Jun Horiguchi, Takashi Ishikawa, Daishu Miura, Mitsuhiro Hayashi, Shintaro Takao, Seung Jin Kim, Hirokazu Tanino, Kohei Akazawa
Journal: Journal of Clinical Oncology (2012)

TPS1141 Background: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate, and it induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. ZOL has also been found to have antitumor effects that include an angiogenesis inhibiting action, an inhibitory effect on tumor cell adhesion to and invasion of the extracellular matrix, and activation of a gdT cells. In addition, it has been found to have a synergistic apoptosis-inducing effect when used in combination with antitumor drugs. In this study we will investigate the pCR rate when ZOL is added to anthracycline followed by taxane to treat T2 and T3 breast cancer patients. Methods: Women with resectable invasive StageIIA-IIIB (T ≥ a3 cm or T ≥ a2 cm and lymph node positive) breast cancer who are HER-2-negative, between 20 and 70 years of age, and ECOG PS 0-1 are eligible. Patients with distant metastasis, patients who have had received chemotherapy, hormone therapy, or radiotherapy for breast cancer, patients with serious complications, such as heart disease or an infection, patients with a complicating dental or jaw infection or traumatic condition of the teeth, and patients with a history of treatment with a bisphosphonate within the previous 12 months are excluded. A total of 4 courses of FEC100 are administered every 3 weeks followed by weekly paclitaxel for 12 courses. ZOL 4mg is administered every 3-4 weeks a total of 7 times. Patients are randomized 1:1 to chemotherapy + ZOL group or chemotherapy alone group, according to the presence or absence of lymph node metastasis, estrogen receptor (ER) status, and their menopausal status. The primary endpoint is pCR. Secondary endpoints are tumor response rate, the breast-conserving surgery ratio, and disease-free survival (DFS). We calculated the sample size on the basis of a pCR rate of 18% in the chemotherapy alone group and 35% in the chemotherapy + ZOL group, at a one-sided significance rate of 5%, and test power of 80%, and as a result we will target a patient sample size of 180 patients. 162 of planned 180 patients have been enrolled as of January 24, 2012.
Prognostic significance of tumor infiltrating immune cells and PD-L1 expression in gastric carcinoma in Chinese patients.
Authors: Ruixuan Geng, Congqi Dai, Angela Wong, Min Qing, Jianjun Hu, Yu Sun, Anthony W.I. Lo, Jin Li
Journal: Journal of Clinical Oncology (2015)

4042 Background: Programmed death-1 receptor (PD-1) and its ligand (PD-L1) play an integral role in the immune response against cancer. This study in Chinese patients (pts) with gastric carcinoma (GC) investigated the prognostic significance of PD-L1 expression on tumor cells and its association with tumor-infiltrating lymphocytes (TILs). Methods: 398 archived, formalin-fixed, paraffin-embedded GC samples were collected Oct 2007–Feb 2010 at a single institution from pts with stage I–IV GC after gastric resection and no prior chemo- or radiotherapy. The median age was 60 years (range 21–87 y). TILs were phenotyped and PD-L1 expression on tumor cells was assessed immunohistochemically, using a pre-defined cutoff ( ≥ 5% tumor cells with ≥ 1+). Associations of TIL and PD-L1 expression with clinico-pathologic features were evaluated using a non-zero correlation test. Survival distribution among different subgroups was compared by Kaplan-Meier and a log-rank test. A multivariate Cox regression model was used to investigate prognostic factors (TNM stage, Lauren type, TIL density, PD-L1 expression) for overall survival (OS). The median follow-up time was 44.3 months (range 0.1–79.9 m). Results: PD-L1 expression was observed in 14% of pts. The median OS for PD-L1(-) pts was 61.1 m. The median OS time for the PD-L1(+) pts had not yet been reached. In specimens with PD-L1(+) tumor cells, 96% (55/57) were associated with TILs, and PD-L1 expression on tumor cells was positively associated with TIL densities (P= 0.0018). There was no correlation between PD-L1 expression and Lauren type or TNM stage. Multivariate analysis identified both moderate (HR 0.585; 95% CI, 0.346–0.989; P= 0.045) and high TIL densities (HR 0.109; 95% CI, 0.026–0.462; P= 0.003) as independent factors associated with OS. The association between PD-L1 expression and OS did not reach statistical significance (HR 0.766; 95% CI, 0.452–1.299; P= 0.322). Conclusions: Within the tumor microenvironment, a moderate to high number of TILs is associated with a better clinical outcome and elevated tumor PD-L1 expression. These observations support a possible therapeutic role for PD-L1 inhibitors in a subset of GC pts.
Prostate specific antigen five years following stereotactic body radiation therapy (SBRT) for low and intermediate risk prostate cancer: An ablative procedure?
Authors: Shaan Kataria, Harsha Koneru, Shan Guleria, Malika Danner, Marilyn Ayoob, Thomas M. Yung, Siyuan Lei, Brian Timothy Collins, Simeng Suy, Anatoly Dritschilo, John Lynch, Thomas Pedicino Kole, Sean P. Collins
Journal: Journal of Clinical Oncology (2017)

123 Background: Our previous work on early PSA kinetics following prostate SBRT showed that an initial rapid and then slow PSA decline may result in very low PSA nadirs. This retrospective study sought to evaluate the PSA nadir 5 years following SBRT for low and intermediate risk prostate cancer (PCa). Methods: 65 low and 80 intermediate risk PCa patients were treated definitively with SBRT at Georgetown University Hospital between January 2008 and October 2011. All patients were treated to 35-37.5 Gy in 5 fractions delivered via the CyberKnife Radiosurgical System. Patients who received androgen deprivation therapy were excluded from this study. Pre- and post-treatment PSA and total testosterone levels were obtained during routine follow up visits. Biochemical relapse was defined as a PSA rise &gt; 2 ng/mL above the nadir and analyzed using the Kaplan Meier method. The PSA nadir was defined as the lowest PSA value prior to biochemical relapse or as the lowest value recorded during follow up. Prostate ablation was defined as a PSA nadir &lt; 0.2 ng/mL. Univariate logistic regression analysis was used to evaluate relevant variables on the likelihood of achieving a PSA nadir &lt; 0.2 ng/mL. Results: The median age at the start of SBRT was 72 years. These patients had a median prostate volume of 36 cc with a median 25% of total cores involved. At a median follow up of 5.8 years, 84% and 37% of patients achieved a PSA nadir ≤ 0.5 ng/mL and &lt; 0.2 ng/mL, respectively. Five low and 8 intermediate risk patients experienced a biochemical relapse; those who did not experience a biochemical relapse, achieved a median PSA nadir of 0.2 ng/mL. There was no difference between the 5-year bRFS rate for low (96.6%) and intermediate risk (97.4%) patients and the median time to PSA nadir was 36 months. Initial PSA (p = 0.024) and a lower testosterone at the time of the PSA nadir (p = 0.049) were found to be significant predictors of achieving a PSA nadir &lt; 0.2 ng/mL. Conclusions: SBRT for low and intermediate risk PCa is a convenient treatment option with low PSA nadirs and a high rate of early bRFS. Less than 40% of patients achieved an ablative PSA nadir. Thus, the role of further dose escalation is an area of active investigation.
Response to radiation therapy in solitary fibrous tumor/hemangiopericytoma.
Authors: Giacomo Baldi, Michela Libertini, Silvia Stacchiotti, Andrea Marrari, Elena Palassini, Rossella Bertulli, Beatrice De Troia, Alessandro Gronchi, Claudia Sangalli, Paolo Giovanni Casali
Journal: Journal of Clinical Oncology (2012)

10065 Background: To reporton the activity of radiotherapy (RT) in a retrospective series of solitary fibrous tumors (SFT)/hemagiopericytoma (HCP), a rare soft tissue sarcoma subtype whose sensitivity to RT is poorly known. Methods: We retrospectively reviewed all patients with a diagnosis of SFT/HCP whom we saw from 2005 to 2011, focusing on cases treated with RT in neoadjuvant, adjuvant, exclusive, palliative settings. Patients who received concomitant chemotherapy were excluded. We confirmed diagnosis by review in all cases. We evaluated the overall response rate (RR) by RECIST. Results: Nineteen patients were identified (males = 9, females = 10; median age = 61 years, range 39-85; site of primary= 6 meninges, 4 pleura, 3 pelvis, 3 retroperitoneum, 2 limbs, 1 abdominal wall; site of RT= 5 bone and soft tissue, 5 pelvis, 3 soft tissue, 2 meninges, 2 retroperitoneum, 1 abdominal wall, 1 pleura; reason for RT= 3 neoadjuvant, 2 adjuvant, 2 exclusive and 12 palliative setting). Median RT dose was 42 Gy (range 12-60). Seventeen of 19 pts are evaluable for response (2 adjuvant). The RR was: 29% (4 pts) partial response, 65% (12 pts) stable disease (SD), 6% (1 pt) progressive disease (PD). All patients treated with neoadjuvant RT had a RECIST SD as best response to pre-operative treatment with evidence of pathologic response in 2 of 3 cases. Conclusions: Contrary to what is widely thought,this retrospective analysis suggests that SFT/HCP is sensitive to radiation therapy. Prospective studies are needed.
Childhood Lead Exposure and Adult Outcomes
Authors: David C. Bellinger
Journal: JAMA (2017)

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