tbuckley/cabot-search huggingface dataset:
Landscape of genetic alterations in non-smoking patients with oral tongue carcinoma: An analysis of The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma data.
Authors: Nabil F. Saba, Scott Newman, Michael R. Rossi, Conor Ernst Steuer, Hongzheng Zhang, Mihir Patel, J. Trad Wadsworth, Mark El-Deiry, Kelly R. Magliocca, Taofeek Kunle Owonikoko, Fadlo Raja Khuri, Dong Moon Shin, Zhuo Georgia Chen
Journal: Journal of Clinical Oncology (2015)

6073 Background: Despite the overall decreased incidence of oral cavity carcinoma a recent surge in the diagnosis of oral tongue cancers (OTC) in younger predominantly female non-smokers has been noted. We sought to explore the landscape of mutational and transcriptional alterations in non-smoking patients with OTC using the TCGA data. Methods: We queried the TCGA data utilizing a novel R-based software Cancer Genome ExploreR (http://sourceforge.net/projects/cancergenomeexplorer/) to compare coding mutations, mutation spectra, gene expression and copy number profiles between groups of interest. Results: Sixty two female lifelong non-smokers or current reformed smokers ( > 15 years) having cancers of the oral cavity including OTC (n = 29), oral cavity not otherwise specified (n = 17), floor of mouth (n = 6), alveolar ridge (n = 4), buccal mucosa (n = 3) or hard palate (n = 3) were identified in the TCGA clinical data. Seventy life-long non smoker or reformed smoker male with a similar distribution of oral site cancers were also identified (n = 33, 18, 5, 8, 5, 1 cases respectively). Female versus male OTC exhibited very similar genomic profiles, as did a combined analysis of all of the above sites between males and females. The genomic differences we did detect came primarily from expression and mutation of X and Y chromosome genes. However, male and female OTC (n = 62) had several genomic features that distinguished them from other oral cavity sites (n = 77). These included relative differences in the frequency of CDKN2A, CASP8 and NOTCH1 coding mutations and differential rates of deletion of chromosomes 11q and 13q. Conclusions: Our results point to genomic differences in non-smoking OTC patients when compared to all other oral cavity tumors from non-smokers regardless of gender. These results present an opportunity to develop better understanding of the biology of OTC in non-smokers in addition to an exploration of targeted therapeutic approaches in this group. (This research was supported by a grant NCI R21 CA182661-01A1 to NFS and GZC).
Survival and risk of second primary malignancy (SPM) in essential thrombocythemia (ET): An analysis of the Surveillance, Epidemiology and End Results (SEER) database.
Authors: Rajesh Shrestha, Smith Giri, Ranjan Pathak, Vijaya Raj Bhatt
Journal: Journal of Clinical Oncology (2015)

e18083 Background: ET patients have better overall survival (OS) than other myeloproliferative disorders; however, patients may have worse OS than general population as a result of thrombohemorrhagic complication or SPM. Methods: We identified all adult patients with ET diagnosed during 1973-2011 from SEER 18 database, using histology code. Actuarial survival method was used to calculate OS and was age standardized to the International Cancer Survival Standard for age 15+ years. We utilized SEER 13 database of ET patients diagnosed between 1992-2010 to calculate SPM (meta-chronous malignancy developing 6 months after ET diagnosis). We used multiple primary standardized incidence ratio (SIR) session of the SEER*Stat software to calculate SIR and excess risk of SPM. Results: The study population (n = 8152) included 39% males, 78% Whites and 12% African Americans and had a median age of 68 years (range 18-107). Age standardized cause-specific 5-year survival was better for patients < 50 years vs. ≥ 50 years (99.4% vs. 93.5%, p < 0.01) and women vs. men (96.0% vs. 93.1%, p < 0.01). Additionally, 5-year OS was lower for men vs. women (70.2% vs. 79.7%, p < 0.01). During a median follow-up of 3 years, of 2913 patients in SEER 13 database, 201 patients (2.46%) developed SPM at a mean age of 73 years (range 54-84). SPMs occurred at an observed/expected (O/E) ratio of 1.26 (95% confidence interval, CI 1.09-1.45; p-value = 0.002) with an absolute excess risk (AER) of 37.4 per 10,000 population. A significantly higher risk was noted for leukemia (O/E 3.78; 95% CI 2.20-6.05, p < 0.001; AER 11.2/10,000), particularly acute myeloid leukemia (AML) (O/E 7.74; 95% CI 3.71-14.24, p < 0.001; AER 7.8/10,000), and kidney cancer (O/E 2.40; 95% CI 1.15-4.42, p value 0.001; AER 5.2/10,000). The risk of SPM was higher after 24 months of ET diagnosis. After 24 months follow-up, a significantly higher risk was noted for myeloma (O/E 3.20; 95% CI 1.04-7.46, p < 0.027; AER 4.7/10,000). Conclusions: ET patients have an excellent cause-specific 5-year survival but are at an increased risk of SPM, particularly AML, which may contribute to excess deaths. Early detection of SPM has a potential to improve OS in ET.
The natural history, treatment, and survival of 199 patients with sarcomatoid carcinoma of the prostate.
Authors: Sreeja Biswas Roy, Scott Cheney, Daniel Brunnhoelzl, Jue Wang
Journal: Journal of Clinical Oncology (2017)

278 Background: Sarcomatoid carcinoma of the prostate (SCP) is a rare and aggressive subtype of prostate cancer. Current data on clinical features, appropriate management and long-term outcomes of SCP are limited. Methods: A systematic review of literature was performed to identify published reports on SCP using keywords “sarcomatoid”, “prostate”, and “carcinosarcoma”. No randomized trials were identified. Four single-center case series and one registry-based study were included in final analysis. Results: In total, 199 patients were included in the review (54 from the SEER registry, 145 from the four case series). SCP occurs more frequently in the late sixth to seventh decade of life (age range: 28-91 years). Many patients with SCP (range, 48%-78%) have a history of prostate adenocarcinoma, with variable time to SPC onset (range, 0.5-20 years). Most tumors are high grade, with locally advanced or distant stage. Urinary obstruction was the most common symptom (50%-92%). Advanced stage was associated with poor prognosis in all reports. Although prostatectomy as part of multimodality treatment likely affected cancer-specific survival in select patients, large variation was observed in prostatectomy and adjuvant therapy rates. No effective systemic chemotherapy was reported. Conclusions: SCP is an aggressive variant of prostate adenocarcinoma. Molecular studies are needed to illuminate their aggressive underlying biology and develop individualized therapeutic approaches. The results of this analysis may help increase awareness of this rare malignancy and serve as a baseline for future clinical studies. [Table: see text]
Accrual patterns of the Southwest Oncology Group (SWOG) by sex, race/ethnicity, and age: Updated and expanded analyses
Authors: J. M. Unger, J. J. Crowley, C. A. Coltman, L. F. Hutchins, S. Martino, J. S. MacDonald, D. S. Gandara, E. D. Crawford, R. B. Livingston, K. S. Albain
Journal: Journal of Clinical Oncology (2004)

6014 Background: Analyses of 1993–1996 SWOG therapeutic trials showed adequate accrual of African Americans and women, but substantial underrepresentation of older patients (≥65).(Hutchins NEJM 1999) We updated these analyses and added Hispanic and Asian/Pacific Islander (Asian/PI) race/ethnicity categories to determine if heightened national awareness and Medicare coverage of clinical trial costs impacted these rates. Methods: Female, African American, Hispanic American, Asian/PI and older patient (≥65) incidence rates were computed for 1997–2000, with additional analysis of age from 2001-July 2002. Corresponding population rates were derived from projected 1998 US Census data and 1997–1998 NCI SEER data. SWOG and SEER rates were compared within 15 different disease sites. Results: 14,632 patients were accrued from 1997–2000 (and 5,645 from 2001- July 2002). In the analysis by sex, non-gender-specific diseases (and non-military/VA affiliation) were studied (n=8,450). Overall, female SWOG accrual was 41% compared to 44% in SEER. Adequate representation was also found in African Americans (9.3% v 9.5% SEER), Hispanic Americans(4.1% v 3.8% SEER), and Asian/PIs (2.2% v 1.7% SEER). Patients ≥65 accounted for 31% of enrollments in SWOG trials (37% in 2001-July 2002), compared to 61% in SEER (prior analysis: 25% SWOG v 63% SEER). Rates for the common cancers are shown in the table. Conclusions: There was adequate representation of women, African Americans, Hispanic Americans, and Asian/PIs in SWOG clinical trials. Older patients continue to be substantially underrepresented, but the overall trend is promising. However, rates in common tumors remain significantly below SEER estimates, except for prostate cancer. These results mandate increased national attention to this issue and prospective study of accrual barriers. No significant financial relationships to disclose.
EUTROC PiSARRO: A phase Ib study combining APR-246 with standard chemotherapy in platinum sensitive relapsed high grade serous ovarian carcinoma (HGSOC).
Authors: Charlie Gourley, Hani Gabra, Ignace Vergote, Bristi Basu, James Brenton, Mikael Von Euler, Ulf Björklund, Austin M. Smith, John Green
Journal: Journal of Clinical Oncology (2015)

TPS5605 Background: p53 mutations are associated with increased chemoresistance. APR-246 is a small molecule that restores mutant p53 to wild type conformation and function (Lambert et al., Cancer Cell. 2009; 15(5):376-88). APR-246 also increases reactive oxygen species levels and ER stress; acts synergistically with DNA damaging drugs in vitro; resensitizes ovarian cancer cells to cisplatin and doxorubicin in vitro and reduces glutathione levels thereby decreasing cellular drug efflux. APR-246 showed no end-organ toxicity in the non-clinical toxicity studies but Cmax related reversible CNS effects were identified. In a previous single agent dose finding study recommended phase II dose and safety profile was determined and signs of clinical activity and p53-dependent biological effects were observed in several patients (Lehmann et al., J Clin Oncol. 2012; 30(29):3633-9). As in animals dose limiting toxicity (DLT) was mainly Cmax related reversible CNS effects. PK was linear and displayed no accumulation. APR-246 was concluded to have a safety and PK profile suitable for further development in combination with chemotherapeutic drugs. The rationale for this study was that p53 mutation occurs in > 97% of HGSOC, thus identifying an appropriate study population for targeted therapy. Methods: Patients with relapsed platinum sensitive HGSOC and positive p53 immunostaining were treated with APR-246 in combination with carboplatin AUC 5 and pegylated liposomal doxorubicin 30 mg/m2every 4 weeks for 6 cycles. APR-246 was dosed as a 6h IV infusion on 4 consecutive days; on day 4, chemotherapy was given concomitantly with APR-246. A 3+3 dose escalation design with 3 dose levels (35, 50 and 67.5 mg/kg) was used. Endpoints include determination of the appropriate combination APR-246 dose, safety, PK, progression free survival, response rate, overall survival and multiple translational readouts (transcriptomic and proteomic). Matched pre-treatment and on-treatment radiologically guided biopsies are mandatory. The first two dose cohorts have been recruited with one DLT (GI perforation) in cohort 2. Recruitment to cohort 3 commenced in December 2014. Clinical trial information: NCT02098343.
Breast cancer with extensive regional lymph node involvement: Toward optimizing local management.
Authors: Lior Zvi Braunstein, Sigolene Galland, Saveli Goldberg, Betro T. Sadek, Mina Shenouda, Rita Abi-Raad, Shannon M. MacDonald, Alphonse G. Taghian
Journal: Journal of Clinical Oncology (2015)

1053 Background: Extensive lymph node (LN) involvement portends significant risk for distant metastasis (DM) among breast cancer patients. As a result, local management may be of secondary import to systemic control in this population. We analyzed patients with ≥ 10 involved LNs (N3) to evaluate the outcomes of breast conserving surgery (BCS) vs modified radical mastectomy (MRM) in this high-risk cohort. Methods: From 1973-2011, 98 women with N3 disease were treated at our institution. Of these, 46 (46.9%) underwent BCS and 52 (53.1%) received MRM. Adjuvant chemotherapy was administered in 79 (80.1%) cases, and hormonal therapy in 56 (57.1%). Nearly all patients (92%) received comprehensive radiotherapy including axillary and supraclavicular fields. The Kaplan-Meier method was used to estimate local regional control (LRC), disease-free survival (DFS) and overall survival (OS). Results: At a median age of 51.5 years (range 26-82), 54% of patients had disease in 10-14 nodes, 26% in 15-19, and 20% had > 19 involved nodes. Median follow-up was 76 months, with a 5-year DFS of 64.9% and OS of 71.9% among the cohort. Multivariate Cox regression revealed that age < 50 years was unfavorable with regard to LRC (p = 0.02), although young age did not influence DFS (p = 0.12) or OS (p = 0.31). However, poorly differentiated (p = 0.007), ER-negative tumors (0.015) heralded adverse DFS outcomes. 10-year LRC was 91.4% following MRM and 89.3% following BCS (p = 0.15). Notably, treatment groups did not differ with regard to 10-year DFS (45.4% for MRM vs 57.6% for BCS; p = 0.31), or OS (61.4% vs 63.7%; p = 0.79). Though only 12 local regional recurrences were observed, 47 patients developed DM with a DM-free survival of 48.9% following MRM and 60.6% following BCS (p = 0.19). The use of contemporary chemotherapy improved 5-year OS (82.0% following doxorubicin, cyclophosphamide and taxol vs 61.3% for other regimens; p = 0.04). Conclusions: Patients with ≥ 10 involved LNs have similar outcomes following BCS or MRM, suggesting that radiotherapy may obviate the need for more-extensive surgery. While local regional control is comparably-favorable regardless of surgical approach, systemic control remains a challenge in this population.
Effects of change in surgical approach in T3 renal cell carcinoma (RCC) with intracaval thrombus on complications and survival.
Authors: Marleen Suzanne Vallinga, Anna Maria Leliveld, Paul M.J.G. Peeters, Igle J. De Jong
Journal: Journal of Clinical Oncology (2017)

471 Background: In patients with T3 RCC with venous tumor thrombus reaching the inferior vena cava, without metastatic disease, a nephrectomy with cavotomy is performed. Before 2000, surgical approach of level 3-4 caval tumorthrombus included sternotomy and cardiopulmonary bypass with circulatory arrest, with high morbidity and mortality rates. After the routine use of liver mobilization around 2000, sternotomy became less necessary. We compared perioperative characteristics, complications and survival pre- and post-2000. Methods: We retrospectively studied 91 patients, operated between 1984 and 2016 in a referral hospital. Patients with a T3 RCC and caval thrombus underwent a radical nephrectomy with thrombectomy. Data on patient and tumor characteristics, operation approach, complications (Clavien-Dindo classification), hospital stay, progression and survival were collected and analyzed using Mann-Whitney U, Chi-Square, and Log-Rank tests. Results: 91 patients (56 male) with a mean age of 65 years were included. 33% had a level 3 or 4 cava thrombus. Surgical management before 2000 included sternotomy with circulation arrest in 32% and liver mobilization in 10%. After 2000, the number of sternotomies lowered to 8% while liver mobilization increased to 74%. See table 1 for perioperative outcomes and complications. Disease specific survival was significant longer in patients operated after 2000 (estimated mean 70 vs. 94 months, p = 0.03). Only N stage influenced progression free survival, patients N+ showed worse survival (p &lt; 0.01). Conclusions: The change in surgical approach including liver mobilization significantly decreased complication rates, blood loss, transfusion rate, hospital stay and increased disease specific survival. [Table: see text]
Patient reported distress is predictive of survival in patients with gastrointestinal tumors.
Authors: Dale Alan Whitaker, Lauren L. Hintenlang, Niveditha Jagadsh, Gerald Strong, Steven J. Buskirk, Jennifer Layton Peterson, Katherine S. Tzou, Stephen Ko, Laura Vallow, Byron C. May, Jacob Habboush, Laeticia Hollant, Robert Clell Miller
Journal: Journal of Clinical Oncology (2017)

764 Background: Psychosocial distress screening and assessment in patients with gastrointestinal (GI) cancers has an established importance due to the distress experienced during and post treatment. GI cancer patients receiving radiotherapy (RT) for curative or palliative measures were reviewed in order to determine if there was a relationship between patient reported distress (PRD) and survival. Methods: Patients at our institution who receive external beam RT for GI cancers completed a 30 question PRD survey that also included a linear analog measure of overall distress, the National Comprehensive Cancer Network (NCCN) Distress Thermometer, which ranged from 1 (low overall distress) to 10 (high overall stress) at the start of and/or during treatment. Each question on the PRD questionnaire concentrated on a possible cause of distress. It allowed patients to rate distress levels for each question from 1 to 5 (1 being the least distressed and 5 being the most distressed), and also overall distress according. The reported clinical results of the PRD questionnaire were retrospectively reviewed in patients receiving RT for GI cancers from Jan 2012 to Aug 2015. Patients were considered distressed if their overall PRD score was 5 or greater (PRD+) or not distressed (PRD-) if their score was 4 or under. Overall survival between PRD+ and PRD- was compared using the Kaplan-Meier method. Results: PRD surveys were completed by 134 consecutive patients, 67 (50%) male and 67 (50%) female within 30 days of starting RT. The median age was 65 years (range 28 to 93). The top histological finding was adenocarcinoma, 90 patients (60%). 113 (84%) received chemotherapy and 64 (48%) underwent surgery. 102 (75%) treatments were curative and 32 (25%) were palliative. Overall NCCN distress thermometer results ranged from 0 to 10, with a median of 4. Median follow-up was 2.7 years. Distressed patients (PRD+) had inferior survival to those not distressed (PRD-) at 2 years, 52% vs. 72%, p&lt;0.02. Conclusions: Patient reported distress is associated with an inferior survival in patients receiving radiotherapy for gastrointestinal tumors.
Re: Kontadakis et al.: Long-term comparison of simultaneous topography-guided photorefractive keratectomy followed by corneal cross-linking versus corneal cross-linking alone ( Ophthalmology . 2016;123:974-983)
Authors: Abhishek Dave, Manisha Acharya, Vinay Arora, Ankit Sharma
Journal: Ophthalmology (2017)
Primary malignant melanoma of the esophagus: Clinical features, signaling pathway, management, and survival.
Authors: Xuan Wang, Lu Si, Yan Kong, Zhihong Chi, Chuan Liang Cui, Xi Nan Sheng, Bin Lian, Li Li Mao, Jun Guo
Journal: Journal of Clinical Oncology (2014)

e20015 Background: Primary malignant melanoma of the esophagus (PMME) is a rare disease that has a poor prognosis and develops multiple metastases in the early stage. Treatment protocols are not well-established. Methods: Clinical data of 28 cases of PMME were retrospectively analyzed including clinical features, signaling pathway, management and survival in Peking University Cancer Hospital between 2006 and 2013. Somatic mutations in genes in MAP kinase (c-Kit, BRAF, NRAS) were detected by DNA sequencing. PI3K-AKT-mTOR (pmTOR, pS6RP, p4E-BP1 and pAKT) were examined by immunohistochemistry (IHC) assays. Results: 1) Clinical features:The average age was 56.4 years, and 75.0% were male. Overall, most tumors were located in the lower thoracic esophagus (53.6%) and majority were in early stages (I to III-85.7% according to 7th UICC TNM) when diagnosed. 24/28 patients accepted subtotal esophagectomy with lymph node dissection. 16/24 patients underwent adjuvant chemotherapy consisted of four courses of dacarbazine or temozolomide and platinum. 2) Signaling pathway:The mutations rate in MAPK signaling pathway was much lower than previous studies: 3/28 (10.7%) patients harbored c-Kit mutations (k18:W853R; exon11:V560D; k11:L576P), no c-Kit amplification was found. 2/28 (7.1%) patients harbored BRAF mutations, in V600E. Only 1/28(3.6%) patient had NRAS mutation, with Q61K missense mutation. However, 2/5(40.0%) patients expressed activation of AKT-mTOR signaling pathway (1 positive in both pmTOR, pS6RP, p4E-BP1 and pAKT; another positive in pmTOR, p4E-BP1 and pAKT), which was much higher than previous studies (Abst.8561 in 2012 ASCO meetings). 3) Survival analysis: The median DFS and OS were 4.0 (95%CI 2.086-5.914) and 14.5 (95%CI 10.009-18.991) months in this cohort respectively. Adjuvant chemotherapy increased the DFS in univariate analyses (8.0 months VS 2.0 months p=0.004). The pTNM stage (HR 10.54) and c-Kit mutations (HR 15.05) were predictive factors of OS in both univariate and multivariate analyses. Conclusions: PMME is a highly aggressive disease with a poor prognosis. Adjuvant chemotherapy may improved DFS but didn’t show benefit in OS. mTOR may be a potential target for treatment in PMME.
Statin inhibits the proliferation of human castration-resistant prostate cancer cells by controlling NFkB-LIN28B-let7 miRNA signaling pathway.
Authors: Chang Wook Jeong, Ja Hyeon Ku, Hyeon Hoe Kim, Cheol Kwak, Minyong Kang
Journal: Journal of Clinical Oncology (2017)

269 Background: Although statin use has been associated with improved outcomes in prostate cancer, the molecular mechanism of this action is still unclear. Based on previous findings, we aimed to investigate the potential role of NFkB-Lin28B-let7 miRNA signaling pathway in human prostate cancer, particularly, castration-resistant prostate cancer (CRPC) cells, as a molecular mechanism of statin effect. Methods: Various human CRPC cell lines (PC3, DU145, 22Rv1, C42B) were used in this study. Proliferation of prostate cancer cells were measured by MTT assay and colony formation assay. Lin28B and NF-κB expression were controlled by siRNA transfection and the expression on Lin28 and let-7 miRNA were quantitated using RT-PCR and western blotting. Results: Notably, simvastatin treatment on various CRPC cell lines decreased cell viabilities in a dose dependent manner. It also significantly inhibited cell growth in clonogenic assay. In these CRPC cells, LIN28 gene was highly expressed in mRNa and protein levels. Conversely, micro RNA (miRNA) expressions of let7 family were remarkably downregulated in CRPC cells. By simvastatin treatment, mRNA and protein level of Lin28B were decreased, while let7 miRNA expressions were restored, which was the key finding of the current study. Considering NFkB is the upstream molecule of Lin28B, we found that the double treatment of statin and NF-κB inhibitor (CAPE) resulted in decreased cell viability, Lin28B and cyclin D1 expression, synergistically. Of note, let-7 miRNA levels were restored after simvastatin treatment, and further increased their expression levels by CAPE double treatment. In order to confirm this mechanistic clue, we specifically inhibited Lin28B and NF-κB genes, respectively, resulting in increased cell apoptosis signaling in the Lin28b or NF-κB knock down cells by combined treatment with simvastatin. Conclusions: In conclusion, simvastatin inhibited the cell growth of various human CRPC cell lines by controlling NFkB-LIN28B-let7 miRNA signaling pathway, and therefore; concurrent NF-κB inhibition with simvastatin treatment induce the synergistic anti-cancer effects in human CRPC cells.