tbuckley/cabot-search huggingface dataset:
Effect of pattern of lymphocyte infiltration in NSCLC on outcome
Authors: D. O'Callaghan, E. Rexhepaj, K. Gately, W. M. Gallagher, D. Delaney, E. Kay, K. O'Byrne
Journal: Journal of Clinical Oncology (2009)

11079 Background: The role played by the immune system in determining survival in non-small-cell lung cancer (NSCLC) is unclear. The aim of this study was to investigate the prognostic significance of T-lymphocyte infiltration in NSCLC focusing on CD3 + , cytotoxic CD8 + and FOXP3 + T regulatory (Treg) cells. Methods: Immunohistochemistry was used to detect CD3 + , CD8 + and FOXP3 + lymphocytes in the tumor islets and tumor stroma in 186 patients with surgically resected NSCLC with a minimum follow-up of 3 years. Quantification of immune infiltration was performed using the Aperio automated image analysis system incorporating the Genie software tool. The median of tumor:stroma CD3 + , CD8 + and FOXP3 + infiltration ratios were used as thresholds to dichotomise patients to either high or low infiltration rates. Prognostic variables were identified using univariate and Cox multivariate analysis. Kaplan-Meier analysis and the log-rank test were used to illustrate differences in overall survival. Results: Patients with a higher intratumoral CD3 + and CD8 + lymphocyte infiltration ratio had significantly better survival compared to those with a low tumour/stroma infiltration ratio (p=0.023 &amp; &lt;0.001 respectively). Conversely high intratumoral T-regulatory FOXP3 + positive lymphocyte infiltration rates were associated with a particularly poor prognosis independent of surgical stage (p&lt;0.001). Conclusions: Microlocalization of infiltrating T-lymphocytes, in particular Treg cells, is a powerful predictor of outcome for surgically resected NSCLC and compares favourably with recently published prognostic genomic approaches. Assessment of inflammatory cell infiltrates may help determine which patients should receive adjuvant chemotherapy and, in the future, in predicting benefit from novel adjuvant vaccine/immunotherapies. No significant financial relationships to disclose.
Recent trends in the management of localized prostate cancer: Results from the National Cancer Data Base.
Authors: Phillip John Gray, Chun Chieh Lin, Ahmedin Jemal, Jason Alexander Efstathiou
Journal: Journal of Clinical Oncology (2014)

5066 Background: The management of localized prostate cancer (PC) is evolving. Using a large national database, we sought to analyze recent trends in practice patterns for this common disease in the United States. Methods: Data on all patients presenting with a new diagnosis of PC between 2004 and 2011 were extracted from the National Cancer Data Base. Patients with nodal or distant metastases were excluded. Patients were categorized as low risk (LR), intermediate risk (IR) or high risk (HR) according to the National Comprehensive Cancer Network's (NCCN) guidelines. P-values correspond to trend tests for the described treatment modality. Results: 823,977 patients met the study criteria, with 38.5% of these patients classified as LR, 42.7% as IR and 18.9% as HR. For LR patients, rates of observation after diagnosis between 2004 and 2011 increased from 12.4% to 18.5% while receipt of prostatectomy increased from 40.3% to 54.4% (p both <.001). In contrast, receipt of brachytherapy fell from 24.4% to 11.4% and receipt of external beam radiation monotherapy fell from 18.2% to 13.4% (p both <.001). For IR patients, rates of observation increased from 6.1% to 7.3%, prostatectomy increased from 48.1% to 58.5% (p both <.001), brachytherapy fell from 12.1% to 6.4% (p <.001), receipt of external beam monotherapy remained relatively unchanged (~15%) while external beam radiation plus androgen deprivation therapy (ADT) fell from 14.7% to 8.7%. For HR patients, receipt of observation and external beam monotherapy were unchanged (~8% and ~10% respectively) while receipt of surgery increased from 30.6% to 41.3% (p< .001). In contrast, receipt of external beam therapy plus ADT fell from 30.4% to 28.0%, receipt of brachytherapy fell from 8.7% to 4.1% while receipt of ADT alone dropped from 7.2% to 5.8% (p all <.001). Conclusions: Utilization of prostatectomy for patients with localized PC increased significantly across risk groups from 2004 to 2011 while utilization of radiotherapy (especially brachytherapy) decreased. Rates of observation have increased in LR disease while rates of combined ADT and radiotherapy in IR and HR PC are declining. Further work is needed to elucidate the causes and appropriateness of these trends.
Association of YAP1 activation with poor patient prognosis and effect on chemoresistance in gastric cancer.
Authors: Sung Sook Lee, Sang Cheul Oh, Woojin Jeong, Sang Ho Lee, Sang-Bae Kim, Yun-Yong Park, Bo Hwa Sohn, Jae-Ho Cheong, Jae Yong Cho, Jae Yun Lim, Eun Sung Park, You-Jin Jang, Young-Jae Mok, WonKyung Jung, Baek-Hui Kim, Keun-Wook Lee, Patrick Tan, Sung Hoon Noh, Jaffer A. Ajani, Ju-Seog Lee
Journal: Journal of Clinical Oncology (2013)

4113 Background: Clinical heterogeneity in gastric cancer is likely due to biological differences among patients. Molecular subtypes and their associated biomarkers need to be established to improve treatment of this disease. We aimed to uncover subgroups of gastric cancer that have distinct biological characteristics associated with clinical outcome and to identify potential best treatments or therapeutic targets for each subgroup. Methods: We analyzed gene expression profiling data from gastric cancer cell lines and 267 patients with gastric cancer to uncover tumor subtypes and identify a gene expression signature associated with prognosis and response to adjuvant chemotherapy. The association of the signature with prognosis was validated in an independent cohort of 200 patients, and its association with response to adjuvant therapy was validated by cell culture experiments. Results: We identified an expression signature of 88 genes that specifically reflected activation of the oncogene YAP1. Compared with patients without this signature, patients with the YAP1 signature had significantly poorer prognosis. In multivariate analysis, the signature was the strongest indicator of overall survival among all demographic and clinical variables examined together (hazard ratio, 2.1; 95% confidence interval, 1.3-3.3;P = .002). Activation of YAP1 was significantly associated with resistance to adjuvant chemotherapy. We also demonstrated that the Notch pathway is a potential therapeutic target for overcoming chemoresistance mediated by YAP1. Conclusions: Activation of the oncogene YAP1 is significantly associated with poorer survival of patients with gastric cancer and induces chemoresistance to this disease. Therefore, YAP1 may be highly attractive therapeutic target for patients with gastric cancer resistant to standard chemotherapy.
Response to pembrolizumab in patients with mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC).
Authors: Alexis Diane Leal, Jonas Paludo, Heidi D. Finnes, Axel Grothey
Journal: Journal of Clinical Oncology (2017)

714 Background: Mismatch repair deficient (dMMR) colorectal cancer (CRC) has been shown to be responsive to blockade with anti-programmed death-1 (PD-1) antibodies. We describe a cohort of 17 patients with dMMR mCRC receiving treatment with pembrolizumab. Methods: Patients were identified through review of the Mayo Clinic electronic medical record (EMR) and chemotherapy administration records from May 2015 through September 2016. All patients with dMMR mCRC who received treatment with pembrolizumab were included. The EMR was reviewed to identify demographic, clinical, pathologic and treatment details. Overall survival (OS), progression free survival (PFS) and disease control rate (DCR=CR+PR+SD) are reported. Time to event analysis was calculated using the Kaplan-Meier method. Results: A total of 17 patients were included in this analysis; median age at diagnosis was 48.5 years (range 25-93); 59% were female. Most primary tumors were right sided (n=12; 71%), 4 (24%) were left sided and 1 (5%) was a tumor of unknown primary within the bowel. Thirteen (75%) patients received 2 or more lines of therapy prior to pembrolizumab (range 1-4). All patients received 2 mg/kg every 3 weeks, with the exception of two patients on a clinical trial; one who received 200 mg every 3 weeks, the other received 10 mg/kg every 2 weeks. The most common mutations (mut) identified were loss of MLH1 (9/12) and PMS2 (10/12), 4 patients had germline mut. KRAS mut was identified in 6/15 patients and only 1 patient had BRAF mut. Number of cycles of pembrolizumab ranged from 1 to 35, with 10 (59%) patients receiving 6 or more cycles. DCR at first assessment was 57%, with 7% CR and 50% PR. Median follow-up was 28 months (95% CI 18-55). Median OS was 103 months (95% CI NR-NR); 12-month OS was 88% and 24-month OS was 81%. Median OS post-PD-1 therapy was NR (95% CI 2-NR). Median PFS was 19 months (95% CI 5-19); 12-month PFS was 64% and 24-month PFS was 0%. At time of analysis, 11 patients remain on PD-1 therapy; 4 patients have died. Conclusions: Anti-PD1 blockade with pembrolizumab can provide long lasting benefit in dMMR mCRC, even in heavily pretreated patients.
Correlation of circulating tumor cells (CTCs) and clinical biomarker endpoints in metastatic prostate cancer patients.
Authors: Robert J. Amato, Vladislava O. Melnikova, Yujian Zhang, Wen Liu, Yuan Wang, Parth K. Shah, Brett T Jensen, Karen E. Torres, Darren W. Davis
Journal: Journal of Clinical Oncology (2012)

e15124 Background: Circulating tumor cells (CTCs) are found in human blood when cancers undergo metastatic dissemination, and CTCs have been reported as a surrogate marker for tumor response and linked to shorter survival in metastatic prostate cancer patients. This study assessed the use of CTCs as a continuous factor for clinical monitoring of prostate cancers patient in real time and evaluated the association between baseline CTC number, various clinical characteristics, and survival. Methods: CTCs were enumerated using the CellSearch FDA cleared CTC kit in 206 patients with metastatic prostate cancer. Variables including metastatic site, PSA, Gleason score, level of testosterone and androgen treatment were tested for association with CTC number. The probability of patient survival over time was estimated by the Kaplan-Meier method. Results: Baseline CTC numbers were strongly associated with survival (p&lt;0.0001), with overall survival being significantly poorer in patients with ≥5 CTCs. Significantly higher CTC numbers were observed in patients with bone metastasis (mean=41.1 CTCs) compared to those with lymph node metastasis (mean=2.5 CTC, p=0.026). Analysis of the association between CTC counts and PSA level revealed a weak positive correlation between CTC number and PSA (Correlation coefficient r=0.269, Significance level p&lt;0.001). CTC number further correlated with the Gleason score (p=0.009) and lower testosterone levels (p&lt;0.0001). Patients with no androgen depletion had significantly lower numbers of CTCs (median=3.94) compared to those with androgen depletion (median=406, p&lt;0.001). Conclusions: Baseline CTCs are predictive of patient survival and are significantly correlated with clinical characteristics in prostate cancer patients.Our study confirms previous findings that support the use of CTC levels as a prognostic biomarker for prostate cancer patients.
Initiatives to improve minority participation in cancer clinical trials
Authors: K. J. Mathews, D. Farria, B. C. Springer, G. Randall
Journal: Journal of Clinical Oncology (2006)

1029 Background: Barriers to minority research participation fall into two categories with respect to research institutions: 1) Community-based factors: historical events, attitudes towards the medical system, trust in research, and referral patterns and geographic distribution of providers serving minority patients. 2) Institutional factors: system and policy issues that define where patients receive care, researcher and staff attitudes and practices, and infrastructure availability to support minority accrual. Much attention has focused on community factors but with little evidence to support specific interventions. Recent studies suggest that internal barriers may play an even more significant role. The Siteman Cancer Center’s Program for the Elimination of Cancer Disparities (PECaD) uses several internal strategies as part of its comprehensive program. Methods: First, the Siteman Cancer has raised substantial funds and changed institutional policies to improve access to cancer services for minority populations, particularly from the African-American community. Second, PECaD implemented a trial monitoring program requiring cancer investigators to set and achieve appropriate accrual based on the patient population treated in each disease area. Third, through trial monitoring and consultation with investigators, PECaD is developing core resources to help recruit and retain minority participants. Results: This approach has led to marked improvement in representative participation in cancer research. In all categories of breast research, African-American participation has climbed from 9% to 28% over five years. In nearly all disease areas, African American participation in therapeutic trials has increased steadily and in some cases exceeds the proportion of African-American patients treated in that disease area. Conclusions: Eliminating cancer disparities requires representative research participation. To achieve this goal, research institutions need to critically examine and implement changes in systems, practices and culture. Leadership, institutional commitment, and operational restructuring can result in significant change even with relatively modest financial investment. No significant financial relationships to disclose.
Elevated serum activin A and survival in CRPC.
Authors: Suhail M. Ali, Lindsey Zubritsky, Susanna J. Jacobus, Kim Leitzel, Meredith M. Regan, Mari Nakabayashi, Robert D. Knight, Abderrahmane Laadem, Matthew L. Sherman, Allan Lipton, Philip Kantoff
Journal: Journal of Clinical Oncology (2012)

e15170 Background: The prognosis of castration-resistant prostate cancer (CRPC) varies widely. Activin A is a ligand in the TGF-B superfamily that regulates cell proliferation, apoptosis, differentiation, and immune responses. In patients with multiple myeloma, elevated activin A is associated with advanced disease and poorer overall survival (OS). Methods: 60 Metastatic CRPC patients whose serum samples were stored at the Dana-Farber Cancer Institute were used for this study. Plasma activin A levels were measured using ELISA (R&amp;D Systems, Minneapolis, MN). Levels of activin A within key patient and disease characteristics were analyzed using the Wilcoxon rank sum test. OS distributions by activin A tertile status were estimated with Kaplan-Meier (KM) and compared with the logrank test. Cox regression was used to produce hazard ratios (HR). Results: In this cohort of 60 patients with metastatic CRPC, median age at diagnosis was 62y, median PSA was 15.3 ng/mL and 37% had a biopsy Gleason score (GS) &gt;8. The index blood draw was a median of 32.9 mo from androgen-deprivation therapy. Median age and PSA at blood draw were 71y and 23.5 ng/mL. At the time of blood draw, 57% of patients had bone only metastasis, 30% were receiving primary or 38% secondary hormonal therapy, and 30% were receiving chemotherapy. Median survival follow-up was 17 months after blood collection (27 deaths). Activin A levels were 621.9 pg/mL (median) and 1382.7 pg/mL (mean). Activin A levels were elevated among older patients (&gt; 65y) and only within patients with higher PSA (&gt;20 ng/mL) at blood draw. KM estimates of median OS (months) for the low, mid and high serum activin A tertile groups were 19.7, 13.8 and 5.4, respectively (p&lt;0.001). The HR (referent low) was 1.4 (95% CI: 0.5-4.5) for the mid and 5.6 (95% CI: 2.1-14.9) for the high tertile. OS was significantly different within age and GS groups, but not within PSA groups. In multivariable analysis, tertile activin A remained significant (p&lt;0.02) when adjusted separately for age at diagnosis, biopsy Gleason score, and serum TIMP-1 (reported previously). Conclusions: Elevated serum activin A predicted for shortened OS in metastatic CRPC, and deserves further study as a biomarker of aggressive disease.
Advance care planning (ACP) among hematopoietic cell transplant (HCT) patients and bereaved caregivers.
Authors: Elizabeth T Loggers, Stephanie Lee, Kate Chilson, Anthony Back, Susan Block, Fausto R. Loberiza
Journal: Journal of Clinical Oncology (2012)

9139 Background: HCT remains a high risk, potentially curative treatment typically offered to young, otherwise healthy patients with hematologic malignancies. Given this, patients and caregivers may not have considered end-of-life ACP. This study investigated the effect of pre-transplant ACP in surviving patients or bereaved caregivers. Methods: A retrospective, mixed-methods, audio-taped telephone survey adapted from validated instruments was conducted by a trained interviewer with English-speaking HCT survivors (n=18) and bereaved caregivers (n=11), 6-12 months post-HCT. Subjects were identified via HCT databases at two high-volume, tertiary centers between 2001-2003. Analysis included percentages from quantitative sections and qualitative transcripts coding by 2 investigators, with differences resolved by consensus. Results: HCT survivors [median age 47 years (range 33-67); 50% college-educated; all white] were interviewed a median of 13 months after HCT for acute leukemia (7), lymphoma (5), or other (6). Twelve (67%) had discussed mortality risk pre-HCT with the medical team; of these, 83% felt hope was increased or unchanged (I/U) and 100% felt clinician commitment to transplant was I/U by the conversation. Regardless of whether mortality was discussed, 50% had living wills and &gt;75% had a formal proxy, yet 67% didn’t discuss mortality with family members pre-HCT. “Ignorance is bliss” was expressed by 6 survivors while 2 survivors regretted not discussing mortality risk. Bereaved caregivers [73% spouses; all W] were interviewed a median of 10 months after their loved one’s death, which occurred a median of 31 days (range 13-152) post-HCT. 100% were the patient’s proxy. Nine (82%) had discussed mortality risk pre-HCT with the medical team; of these, 78% felt hope was I/U, 100% felt clinician commitment to transplant was I/U, and 78% discussed EOL preferences with the patient pre-HCT, with 67% feeling ACP reduced burden. Four expressed appreciation for “the straight story.” Conclusions: Discussions of potential mortality with patients and caregivers before HCT did not affect hope, and supported confidence in medical teams.
Treatment patterns and survival in elderly women with HER2-negative, hormone receptor positive metastatic breast cancer: Analysis of the SEER-Medicare database.
Authors: Sudeep Karve, Manjiri Pawaskar, Keith L. Davis, Tapashi Dalvi, Robert Deeter
Journal: Journal of Clinical Oncology (2013)

e11570 Background: Although metastatic breast cancer (MBC) is a leading cause of death in elderly women, there is limited population-based data available on treatment patterns and survival in post-menopausal women with HER2 negative, hormone receptor (HR) positive MBC. This study therefore examined real-world treatment patterns and survival in this population Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database, which comprised 13,170 women aged ≥65 years diagnosed with HER–, HR+ MBC between 1/1/2000 and 12/31/2009. The index date was defined as MBC diagnosis date or date of progression to MBC. Patients were followed from index date to death or end of database. Absence of trastuzumab and lapatinib treatment, and use of immunohistochemistry and fluorescence in-situ hybridization tests, was utilized as a proxy measure for HER2– status. Descriptive statistics were used to assess treatment patterns. Kaplan-Meier curves were used to examine survival in this patient population. Results: Over 78% of women (mean age 76.7 years, 88% white) were both ER+ and PR+ and 61% had ductal histology. The majority of patients had surgery (54%), followed by radiation (50%), hormone therapy (49%) and chemotherapy (40%). Among patients receiving hormonal therapy, megestrol (20%), anastrazole (16%) and fulvestrant (11%) were the most commonly used agents. Among patients receiving chemotherapy, cyclophosphamide (21%), doxorubicin (17%) and paclitaxel (14%) were most common agents. Median overall survival in these patients was 50 months and the 5-year survival rate was 45%. Median survival was lowest for patients aged &gt;85 years (25 months), ER– PR+ (24 months), and distant stage at diagnosis (21 months). Conclusions: In spite of advances in treatment of MBC, survival remains lower in older and ER– PR+ women with MBC. This could be due to the limited access to effective treatments in elderly with HER2– and HR+ MBC patients.
Effect of benign and tumor parenchyma metabolomic profiles on compensatory renal growth in renal cell carcinoma surgical patients.
Authors: Barak Rosenzweig, Nimrod Daniel Rubinstein, Eduard Reznik, Piotr Zareba, Roman Shingarev, Krishna Juluru, Oguz Akin, James Hsieh, Edgar A Jaimes, Paul Russo, Katalin Susztak, Jonathan Coleman, A. Ari Hakimi
Journal: Journal of Clinical Oncology (2017)

446 Background: Pre-operative kidney volume is an independent predictor of glomerular filtration rate in renal cell carcinoma patients. Compensatory renal growth (CRG) can ensue prior to nephrectomy in parallel to tumor growth and benign parenchyma loss. We aimed to test whether renal metabolite abundances significantly associate with CRG, suggesting a causative relationship. Methods: Tissue metabolomics data from 49 patients, with a median age of 60 years, were previously collected and the pre-operative fold-change of their contra to ipsi-lateral benign kidney volume served as a surrogate for their CRG. Contra-lateral kidney volume fold-change within a 3.3 +/- 2.1 years follow-up interval was used as a surrogate for long-term CRG. Using a multivariable statistical model we identified metabolites whose abundances significantly associate with CRG. Results: We identified 13 metabolites in the benign (e.g. L-urobilin) and 163 metabolites in the malignant (e.g. 3-indoxyl-sulfate) tissues to significantly associate with CRG. Benign/tumor fold change in metabolite abundances revealed three additional metabolites with a significant positive association with CRG (e.g. p-cresol sulfate). At the pathway level, we show that fatty-acid oxidation is highly enriched with metabolites whose benign tissue abundances strongly positively associate with CRG, whereas in the tumor tissue significant enrichment of dipeptides (positive association) and benzoate, glycolysis/gluconeogenesis, lysolipid and nucleotide sugar pentose (negative associations) sub-pathways were observed. The effect of metabolite abundances in the benign tissue on long term CRG provided further support for positive association of fatty-acid metabolism sub-pathway enrichment, where sphingolipid, monoacylglycerol, long chain fatty acids, and mid chain fatty acids were enriched for a negative association. Conclusions: These data suggest that specific biological processes in the benign as well as in the tumor parenchyma strongly influence compensatory renal growth.