tbuckley/cabot-search huggingface dataset:
Molecular profiling of appendix-derived pseudomyxoma peritonei (PMP).
Authors: Elizabeth Gleeson, Rebecca Feldman, Sherri Z. Millis, Beth Mapow, Lynn Mackovick, Sandeep K. Reddy, Wilbur B. Bowne
Journal: Journal of Clinical Oncology (2016)

571 Background: PMP is a rare malignancy originating from the appendix, characterized by disseminated mucinous tumor implants on peritoneal surfaces. Cytoreductive surgery and intraperitoneal chemotherapy offers optimal outcomes for most patients; however, for patients that progress, there are few treatment options. We examined the role of multiplatform molecular profiling to study biomarker-guided treatment strategies for this rare malignancy. Methods: 54 patients with appendix-derived PMP were included in the study and tested centrally at Caris Life Sciences (Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (C/FISH). Results: Targeted sequencing of 47 genes detected variants in KRAS (79%), GNAS (73%) and SMAD4 (18%). Mutations were found at low frequencies (n = 1-2) in APC, ATM, BRAF, PIK3CA, MLH1 and TP53. GNAS and KRAS co-occurrence was found in 38%. High rates of protein overexpression were found in EGFR (83%), cMET (59%), cKIT (58%) and PDGFRA (58%), respectively. Immune checkpoint expression was found in 36% (PD1-positive tumor infiltrating lymphocytes) and 9% (PDL1 tumor expression). Expression of surrogate markers of cell proliferation were found at low rates (TLE3 27%, TOP2A 22%), consistent with the slow-growing biology of PMP. PTEN was intact (wild type [100%] and positive IHC [80%]) in the majority of PMP. Patients exhibit stable microsatellite status and mismatch repair proficiency in 93% of patients. Importantly, multidrug resistance protein expression was found at high levels (100% BCRP, 94% MRP1, 88% PGP). Markers for gemcitabine (RRM1), fluorouracil (TS), oxaliplatin (ERCC1) and irinotecan (TOPO1) chemo-sensitivities were found to be favorable in 93%, 87%, 77% and 65%, respectively. Conclusions: Molecular profiling by multiple platforms identified potential therapy options in the non-targetable setting of a KRAS-mutated population. The role of cMET-targeted therapies and immune checkpoint inhibitors merit further investigation. Biomarker-guided selection of cytotoxic chemotherapies may facilitate responses to systemic treatment.
Irradiation effect on telomerase- and angiogenesis-related gene in human umbilical vein endothelial cells.
Authors: H. Chang, S. Y. Rha, H. Jeung, K. H. Park, T. S. Kim, Y. B. Kim, H. C. Chung
Journal: Journal of Clinical Oncology (2011)

e21048 Background: Radiotherapy is important in the treatment of many human cancers, but the effect of irradiation on angiogenesis still remains largely unknown. We investigated the effects of irradiation on telomerase- and angiogenesis-related genes in human umbilical vein endothelial cells (HUVECs). Methods: HUVECs at passage number (PN)1, PN2 and PN3, respectively, were exposed to irradiation (2 Gy). Changes in cellular growth, senescence, telomerase activity, and expression of telomerase-, angiogenesis- and pan-endothelial marker-related genes were then investigated. Results: Both senescence and growth delay were observed in irradiated HUVECs. Compared to controls, telomerase activity, expression of human telomerase reverse transcriptase (hTERT) and c-myc in irradiated HUVECs were down-regulated in all PNs, and Mad1 was up-regulated at PN3. Down-regulation of vascular endothelial growth factor (VEGF) was observed in irradiated HUVECs as PN increased. Other angiogenesis-related factors [vascular endothelial growth factor receptor (VEFGR)-1, VEGFR-2, VEGFR-3, Tie-1, and Tie-2] and pan-endothelial cell markers [collagen type IV alpha 2, collagen type VI alpha 1, collagen type XVIII alpha 1, insulin-like growth factor-binding protein (IGFBP)-4, IGFBP-7, connective tissue growth factor, interferon-induced transmembrane protein, melanoma cell adhesion molecule, and von Willebrand factor] were also down-regulated in irradiated HUVECs. Conclusions: Irradiation at doses relevant to clinical radiotherapy can induce endothelial cell senescence. Irradiation-induced cell senescence could be related with the down-regulation of hTERT. Change in the expression of c-Myc, Mad1, and VEGF could contribute to the irradiation-induced down-regulation of hTERT.
Kinase gene expression profiling of metastatic tumor tissue to prioritize therapeutic targets in clear cell renal cell carcinoma.
Authors: Pooja Ghatalia, Eddy Shih-Hsin Yang, Dongquan Chen, Shi Wei, Tiffiny Cooper, Sunil Sudarshan, Gurudatta Naik, Guru Sonpavde
Journal: Journal of Clinical Oncology (2015)

476 Background: Kinase inhibitors are the mainstay of therapy for patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC). Since kinases are actionable and lethal metastatic tumor tissue has not been comprehensively studied, we hypothesized that paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may help identify drivers of metastasis and potential therapeutic targets. Methods: Total mRNA isolated from macrodissected formalin fixed paraffin embedded tissue from T, N, and M from 35 pts (total 105 samples) with ccRCC underwent expression profiling for 519 kinase genes using the nCounter System by Nanostring Technologies. Digital raw counts of mRNA abundance were normalized using internal positive and negative controls as well as 7 housekeeping genes. The mean signals from N, T, and M sites were used to calculate change in gene expression, and a p value by t test &lt;0.05 was considered significant. To identify genes unique to metastasis, kinases with significant expression in the M compared to N or T were selected. Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Results: The median age of pts was 56 years and 30 were male. Fifteen pts had metastatic disease at presentation and the remaining developed subsequent metastasis. Clustering analysis for all 105 samples separated normal tissues from tumor or metastasis. The top pathways involved in the kinases overexpressed in M compared to N or T involved Pyridoxal 5'-phosphate Salvage, Salvage Pathways of Pyrimidine Ribonucleotides, NF-kB Signaling, NGF Signaling and Cell Cycle Control of Chromosomal Replication. The top kinases over-expressed in M compared to T include: EPHB2, AURKA, GUCY2C, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7, and MAP3K8. Conclusions: Multiple pathways and kinase genes wereover-expressed in metastatic ccRCC, which suggests a major role for agents targeting metabolic pathways and inhibitors of kinases not currently recognized as therapeutic targets. These data warrant validation and suggest potential drivers of metastasis and actionable therapeutic targets in metastatic ccRCC.
Results of a Phase I/II-Study on PCR-Based Pre-Emptive Therapy with Valganciclovir or Ganciclovir for Active CMV Infection Following Reduced Intensity Allogeneic Stem Cell Transplantation.
Authors: ZiYi Lim, Gordon Cook, Peter R. Johnson, Anne Parker, Mark Zuckerman, Ghulam J. Mufti, David Marks, Antonio Pagliuca
Journal: Blood (2007)
Does breast cancer in Asian geriatric patients have the same biological characteristics as in their Western counterparts? A comparison between Shanghai and Vienna.
Authors: M. M. Tea, L. Tang, G. Di, Z. M. Shao, C. F. Singer
Journal: Journal of Clinical Oncology (2011)

1550 Background: By 2030 it is estimated that 20% of the population will be 75 years of age or older. The incidence of breast cancer in Asia is especially rising, while the proportion of the population that is 60 and older is also growing. Today, approximately one-third of breast cancer occurs in women over the age of 65. The aim of this study was to investigate the biological differences of breast cancer older than 69 years in Asia and Europe. The results, including the stage at diagnosis and surgical therapy of Chinese breast cancer, were compared with their western counterparts. Methods: A total of 630 women, 70 years of age and older, with operable breast cancer were investigated in Shanghai and Vienna. Histopathological findings of 198 Austrian women seen during 2005 and 2010 were reviewed. The results were compared with 432 Chinese (time matched) obtained from the Breast Cancer Database in Shanghai. Results: The mean patients’ age in the Viennese and Shanghainese study groups were 75.3 and 77.9 years, respectively. In Austria, the breast-conserving surgery rate was 73.7% (n=146) compared to 10.4% (n=45) in China. Sentinel lymph node biopsy was performed in 40.4% (n=80) in Vienna vs. 8.3% (n=36) in Shanghai. More large tumors (tumor size > 2 cm) were detected in China (41.3%, n=169) than in Austria (34.7%, n=66) (p=0.033). No differences were found in axillary lymph node involvements (p=0.052). However, more grade-3 breast cancers were detected (p<0.001) in Austrians. Furthermore, there was a greater incidence of estrogen receptor-negative breast cancer in Chinese women (27%, n=113) compared to Austrian women (16.2%, n=32) (p<0.001). Conclusions: Chinese women present with a lower rate of grade-3 breast malignancies. As expected, a higher breast conserving surgery rate was noted in Vienna. Interestingly less Chinese women, although older than 69 years, were presented with estrogen receptor-positive breast cancer. We conclude that breast cancer characteristics are different in diverse ethnic groups. Ethnic-specific screening/therapy protocols may benefit this special Asian population, especially Asian women in western countries.
Establishment and validation of prognostic nomograms including HER2 status in metastatic gastric cancer.
Authors: Takeshi Kawakami, Yukiya Narita, Isao Oze, Shigenori Kadowaki, Nozomu Machida, Hiroya Taniguchi, Takashi Ura, Masashi Ando, Seiji Ito, Yasushi Yatabe, Masahiro Tajika, Yosuke Kito, Yutaka Haraguchi, Hirofumi Yasui, Kei Muro
Journal: Journal of Clinical Oncology (2016)

24 Background: It remains unclear whether human epidermal growth factor receptor 2 (HER2) status is an outcome-associated biomarker independent of known prognostic factors for metastatic gastric cancer (MGC). There are few reports on nomograms in MGC, while several studies have been published on nomograms for other cancer types. This retrospective study aimed to develop nomograms that combine HER2 status and other prognostic factors for predicting survival outcome of individual patients with MGC starting first-line treatment. Methods: We used a training set of 838 consecutive patients with MGC starting first-line chemotherapy between 2005 and 2012 in Aichi Cancer Center Hospital (ACC) to establish nomograms that calculate the predicted probability of survival at different time points; overall survival (OS) at 1 and 2 years. The covariates analyzed in this model by Cox proportional hazard models included HER2 status, Eastern Cooperative Oncology Group performance status (PS), history of gastrectomy, serum lactic acid dehydrogenase (LDH), and serum alkaline phosphatase levels (ALP). Nomograms were independently validated using data on 269 consecutive patients with MGC who underwent first-line chemotherapy between 2010 and 2012 in Shizuoka Cancer Center Hospital (SCC). Missing covariate data were estimated using multiple imputation methods. The discriminatory ability and accuracy of the models were assessed using Harrell’s c-index. IHC3+ or IHC2+/ISH+ tumors were defined as HER2-positive. Results: Patient characteristics were as follows: median age, 64 vs. 66 years; ECOG PS 0/1/2, 34%/51%/15% vs. 45%/44%/11%; prior gastrectomy, 42% vs. 39%; 1/ &gt; 1 metastatic sites, 56%/44% vs. 43%/57%; high LDH, 76% vs. 27%; high ALP, 22% vs. 26%; and positive/negative HER2 status, 10%/45% vs. 7%/53%, respectively. At a median follow-up of 12.3 (ACC) and 11.6 (SCC) months, 782 and 248 patients had died, and median OS was 12.5 and 12.4 months (P= 1.00), respectively. The nomograms were capable of predicting an OS with a c-index of 0.68 and 0.58. Conclusions: These nomograms may provide objective and approximate prediction of OS for individual MGC patients in clinical settings.
Palliative resection for stage IV gastric cancer.
Authors: O. Muto, H. Kotanagi
Journal: Journal of Clinical Oncology (2011)

148 Background: Metastatic gastric adenocarcinoma is an incurable condition and little progress has been made in its treatment. The role of palliative surgical resection is still debatable. Methods: We retrospectively evaluated the efficacy of palliative gastrectomy for treating incurable gastric cancer. In our institution 51 cases were found to have incurable tumors at laparotomy and received palliative gastrectomy from 2003 through 2009. In the analysis, particular attention was paid to the prognostic factors of age, tissue type (diffuse type and intestinal type), metastatic site (liver, peritoneal and lymph node) and postoperative chemotherapy. Results: One-year survival rate of all patients was 58% and the median survival time was 23.5 months. The median survival time was significantly greater in patients undergoing chemotherapy group than in those not undergoing chemotherapy (24.0 versus 9.4 months; p=0.016). Conclusions: Long-term survival for patients with stage IV gastric cancer who are managed with surgical resection and chemotherapy is achievable. Further study with a larger number of patients is warranted. No significant financial relationships to disclose.
Focal HIFU (high intensity focused ultrasound) treatment of unilateral localized prostate cancer: Hemiablation strategy—A prospective French multicentric study with 111 patients.
Authors: Gilles Pasticier, Sebastien Crouzet, Olivier Rouviere, Florence Mege-Lechevallier, Helene Tonoli-Catez, Jean-Yves Chapelon, Pascal Rischmann, Albert Gelet
Journal: Journal of Clinical Oncology (2016)

102 Background: Up to a third of patients with localized prostate cancer (LPCa) have unilateral disease that may be suitable for a treatment of one lobe. Our aim was to evaluate the ability of HIFU to achieve a local control of the tumor in patients with unilateral LPCa. Methods: The French Urological Association (AFU) conducted a multi-institutional study, to evaluate hemi-ablation with HIFU as a primary treatment for patients &gt;50 years, T1C or T2A, PSA&lt;10ng/ml, Gleason ≤7 (3+4), and unilateral disease. 111 patients were treated: mean age 64.8 ±6.18 years, mean PSA 6.23±2.5 ng/ml. Gleason sum was ≤6 in 73.9% and 7 in 26.1%.primary outcome was the negative biopsy rate. Secondary outcomes were genitourinary side effects measured using validated questionnaires. The tumor was localized using MRI followed by random and targeted transrectal biopsies. Only the pathological prostate lobe was treated using HIFU. Results: The PSA nadir value was 1.87±1.49 ng/ml and the PSA at 12 months was 2.49±2.1 ng/ml (median 1.89). Ninety patients out of 101 (89%) in whom control biopsies were performed, had histological absence of significant disease (Gleason 7 or presence of cancer core length &gt;3mm): treated side 5%, untreated side 5.9%. However 32.6% of men had persistent cancer of any threshold. Additional therapies were proposed in 33 patients (29,7%): active surveillance (16 patients), Redo-HIFU (8 patients), external beam radiation therapy (3 patients), radical surgery (6 patients). The RTFS (radical treatment free survival rate defined as absence of whole gland therapy) at 2 Years was 89%. At 12 months pad free continence was preserved in 103/106 (97%) and erectile function (IIEF5 score ≥16) was preserved in 40 patients out of 51 patients (78%). Conclusions: HIFU hemi ablation strategy allows an encouraging local control of the cancer has minimal side effects compared with standard whole gland treatments and allows additional therapies if necessary. Clinical trial information: HIFU/AFU/08.06.
Completion and toxicity rates of adjuvant chemotherapy in rectal cancer patients previously treated with neoadjuvant therapy and resection.
Authors: C. R. Oxner, S. Choi, M. J. Hein, D. Lim, S. Shibata, A. Pigazzi
Journal: Journal of Clinical Oncology (2011)

609 Background: Adjuvant chemotherapy is recommended after rectal cancer surgery. Yet the success and complication rates of this adjuvant treatment are poorly studied. The purpose of this study is to determine the success rate and define the toxicity profile of adjuvant chemotherapy in rectal cancer patients previously treated with neoadjuvant chemotherapy. Methods: Study design is a retrospective review of patients from December 2002-December 2007 from the City of Hope database. Data is available with 66 patients diagnosed with locally advanced rectal cancer treated with neoadjuvant chemo radiation and resection. Data points analyzed included demographics, chemotherapy-related toxicity and survival. Results: Adjuvant chemotherapy was started in 35/66 (53%) of patients. In 31 cases chemotherapy was not given because of patient refusal or physician preference. 9 patients were lost to follow-up. Follow-up ranged from 9-59 months with median follow-up of 27 months. In the 26 patients with adequate follow up there were a total of 165 episodes of toxic events 3a grade 1. Most of the events were mild to moderate grade 1-2. In 10 patients (28%) 22 major toxicities 3a grade 3 episodes were observed. The median Karnofsky performance scale (KPS) showed no significant difference in patients before and after adjuvant chemotherapy (p = 0.071). The rates of 1-year, 3-year and 5-year survival were 100%, 90%, and 60%, respectively; corresponding disease-free survival was 88%, 83%, and 69% respectively. Conclusions: These preliminary data suggest that only a fraction of rectal cancer patients previously treated with neoadjuvant CRT complete a full course of adjuvant chemotherapy. Future studies will help confirm these preliminary findings and generate an outcome comparison between patients receiving and not receiving adjuvant therapy. No significant financial relationships to disclose.
An evaluation of molecular imaging with <sup>11</sup>c-PD153035 PET/CT and its association in predicting outcomes in non-small cell lung cancer treated with EGFR-TKI.
Authors: X. Meng, J. Yu, B. W. Loo, L. Ma, X. Sun, J. D. Murphy, S. Q. Zhao, L. Kong, G. R. Yang, W. L. Li, X. G. Zhao
Journal: Journal of Clinical Oncology (2011)

10543 Background: Outcomes are suboptimal when molecularly-targeted therapies are used in patient populations unselected for the molecular target. This pilot study examines the correlation of positron emission tomography (PET) using 11C-labeled 4-N-(3-bromoanilino)-6,7-dimethoxyquinazoline (11C-PD153035), an imaging biomarker of epidermal growth factor receptor (EGFR), with outcomes in patients with non-small cell lung cancer (NSCLC) treated with the EGFR tyrosine kinase inhibitor (TKI) erlotinib. Methods: Patients with advanced chemotherapy-refractory NSCLC were prospectively enrolled on a trial of erlotinib at a dose of 150 mg daily and imaged by 11C-PD153035 PET/CT at baseline, after 1 to 2 weeks, and after 6 weeks from start of treatment. Overall and progression-free survival times (OS and PFS) were correlated with the 11C-PD153035 maximal standardized uptake value (SUVmax) at each of the imaging time points. Results: Twenty-one patients were enrolled. All patients had biopsy-proven adenocarcinoma or squamous cell carcinoma. Follow-up to progression was complete in all patients, and to death in 18 of 21. The median OS and PFS were 7.5 and 2.8 months, respectively. By Cox regression analysis, baseline SUVmax correlated strongly with OS and PFS (HR=0.40, p=0.0015 and HR=0.044, p=0.00013) independent of histology. Patients with higher SUVmax (≥median) survived more than twice as long as patients with lower SUVmax (median OS 11.4 vs. 4.6 months, p=0.0018; PFS 4.4 vs. 1.8 months, p=0.000016). 11C-PD153035 SUVmax early in treatment (at 1-2 weeks) also correlated with OS and PFS, albeit less well than baseline SUVmax, with HR 0.36 (p=0.0068) and HR 0.29 (p=0.00074), respectively. On the other hand, SUVmax at about 6 weeks correlated poorly with baseline SUVmax (R2=0.22, p=0.067), and insignificantly with OS (p=0.25) and PFS (p=0.066). Conclusions: Our preliminary results suggest 11C-PD153035 PET/CT may be a noninvasive and rapid method for identifying patients with refractory advanced NSCLC of adenocarcinoma or squamous histology likely to respond to EGFR-TKI, but not for monitoring treatment response.
Bevacizumab-associated erythrocytosis in metastatic renal cell carcinoma (mRCC)
Authors: L. C. Harshman, C. J. Kuo, S. Srinivas
Journal: Journal of Clinical Oncology (2008)

16096 Background: Bevacizumab (Bev), a monoclonal vascular endothelial growth factor (VEGF) antibody, has activity in mRCC. A surrogate biomarker that would accurately predict therapeutic VEGF inhibition and anti-tumor response to Bev would be useful. Preclinical work at our institution revealed that extremely stringent VEGF inhibition in mice and non-human primates resulted in increases in hemoglobin (Hgb) and erythropoietin (Epo). This Epo production originates in the liver, not the kidney, implicating endogenous VEGF as a previously unsuspected repressor of hepatic Epo synthesis and suggests that Hgb and Epo may be non-invasive markers for VEGF inhibition in vivo. We retrospectively reviewed whether erythrocytosis was evident in patients who received Bev as monotherapy or in combination for mRCC. Methods: Ten patients were eligible. Demographic data, history of anemia, baseline Hgb, treatment Hgb levels, response, and confounding factors such as recent chemotherapy, blood transfusions, iron, or growth factor use were assessed. Percent change in baseline Hgb to peak level was calculated. Correlation between the degree of change and progression-free survival (PFS) in responders was evaluated. Results: Patient characteristics: 90% male, median age 61, 60% first-line treatment, 60% bone metastases, 70% baseline anemia. Five patients were on concurrent treatment with sunitinib, sorafenib, or erlotinib. Hgb rose on Bev in 9 patients. The median change in Hgb was 1.4 g/dL (0–2.7). The median percent rise was 12.3% (6.8–22.2%); 10.9% in the monotherapy cohort and 18.6% in the combination group. The median time to initial increase in Hgb was 42 days and 84 days to peak. Best response was disease stabilization in 7 patients. Degree of peak increase correlated with longer PFS: a 5–15% increase yielded a 3.7 month median PFS and a greater than 15% increase corresponded to a 6.5 month median PFS. Conclusions: The majority (90%) experienced erythrocytosis on Bev suggesting a correlative effect. This is the first human study to identify erythrocytosis as a possible consequence of Bev treatment. The correlation between degree of increase in Hgb and longer PFS suggests that Hgb may be useful as a surrogate marker of stringent VEGF inhibition. This relationship warrants validation in a larger patient sample. No significant financial relationships to disclose.
JPLT(日本小児肝癌スタディグループ)プロトコル2によって治療される肝芽細胞腫の成績
Authors: Hiyama E, Yamaoka H, Onitake Y, Nishimura S, Hiyama K, Nishiyama M, Matshnaga T, Sasaki F, Horie H, Ohnuma N
Journal: Annals of Oncology (2006)