tbuckley/cabot-search huggingface dataset:
Induction docetaxel, cisplatin, and cetuximab (TPE) followed by concurrent radiotherapy, cisplatin, and cetuximab and maintenance cetuximab in patients with locoregionally advanced head and neck cancer (HNC): Mature results with HPV analysis.
Authors: R. L. Ferris, D. E. Heron, S. Kim, M. K. Gibson, D. Posluszny, R. R. Seethala, W. E. Gooding, J. T. Johnson, J. R. Grandis, A. Argiris
Journal: Journal of Clinical Oncology (2010)

5515 Background: We report updated survival with human papillomavirus (HPV) status analysis, late toxicities and quality- of-life (QOL) from a phase II trial that incorporated cetuximab (E) into induction therapy and subsequent concomitant chemoradiotherapy of HNC (ASCO 2008;A6002). Methods: Patients (pts) had previously untreated, stage III or IVA-B HNC (including squamous and undifferentiated histologies), ECOG performance status 0-1, and adequate laboratory parameters. Treatment consisted of docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, and E 250 mg/m2 days 1,8, and 15 (after an initial dose of 400 mg/m2 on cycle 1, day 1), termed “TPE” and repeated every 21 days x 3 cycles, followed by radiotherapy to 70 Gy (2 Gy/day) with concurrent cisplatin 30 mg/m2 and E 250 mg/m2 weekly (“XPE”), and maintenance E for 6 months (mo). QOL was assessed using FACT-HN. P16 and HPV in situ hybridization was done on baseline tissue. Results: Of 39 enrolled pts, 35 had stage IV disease. Primary sites were the oropharynx, 23; larynx, 5; hypopharynx, 3, oral cavity, 3; nasopharynx, 3; and unknown, 2. There were 28 active, 6 former, 5 never smokers; all smokers but 3 had >= 20 pack-year history. 2/3 planned neck dissections showed a pCR. With a median follow-up of 36 months, 2- and 3-year PFS was 70% and 67%, respectively; 2-and 3-year OS was 77%. HPV positivity was found in 67% of 27 evaluable tumor specimens, and did not alter PFS or OS. Recurrence in 12 pts was locoregional only in 8 pts, including local only (3), regional only (3), local and regional (2), distant only in 3, and locoregional and distant in 1. Of 4 pts who underwent salvage surgery, 2 were rendered disease free. Late toxicities included gr 2 neuropathy (2), chondronecrosis (1), and gr 3 laryngeal edema (1). No progression-free pt is G-tube dependent. FACT-HN showed a significant decrement at 3 mo after XPE, with return to baseline at 1 year. Conclusions: This E-based regimen has excellent long-term survival, safety and QOL and warrants further evaluation in both HPV positive and negative HNC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb
A phase I/II trial of intrarterial infusion of CDDP, 5-FU and gemcitabine in combination with intravenous epirubicin in unresectable pancreatic cancer
Authors: K. Miyanishi, J. Kato, K. Takada, T. Hayashi, Y. Sato, T. Takayama, R. Takimoto, Y. Niitsu
Journal: Journal of Clinical Oncology (2005)

4225 Background: We have previously reported an arterial infusion chemotherapy (5-FU plus CDDP) after vasucular supply destibution via superselective embolization is more effective than systemic infusion in the treatment of patients with advanced pancreatic cancer. Among phase II and III trials in which many agents and combination schedules have been evaluated, a CDDP(P), epirubicin(E), 5-FU(F), and gemcitabine(G) schedule on advanced pancreatic cancer has been proved to obtain a very high rate of durable responses. In this study, we performed a phase I/II trial of an arterial infusion chemotherapy (PFG) in combination with systemic chemotherapy (E) in patients with advanced pancreatic cancer to evaluate the efficacy and toxicity of this therapy. Methods: Six patients with unresectable pancreatic cancer underwent this clinical trial. For the phases I study, with the fixed dose of P (13mg/ m2;day1,3,5,15,17,19), F (300mg/m2;day1–5,15–20) and E (20mg/m2;day1), the doses of G(day1,15) were escalated as following schedule: level 1: 600mg/ m2; level 2: 700mg/ m2; level 3: 800 mg/ m2 . The cycle was repeated every 4 weeks. The phase II study was planned in all enrolled patients. To restrict the blood flow into the pancreas, the peripancreatic blood vessels were embolized superselectively with microcoils. The catheter tips for the arterial infusion were placed in the splenic artery and common hepatic, as described previously (Cancer 2000). Results: During 1st session, no DLT among 3 patients at dose level 1 were obserbed. At dose level 2, 2 DLTs (neutropenia) among 3 patients were experienced, which made the dose level 2 as MTD. All 6 patients were evaluated for phase II portion of the study. After median 14 sessions of chemotherapy, there were 4 PRs, with the overall response rate of 66.7% in intention-to-treat analysis. Median over all survival was 14 months. Conclusions: Neutropenia was DLT in this therapy. The dose of P (13mg/ m2;day1,3,5,15,17,19), F (300mg/m2;day1–5,15–20), G(600mg/m2; day1,15) and E (20mg/m2;day1) was recommended for this therapy. This treatment was highly effective and tolerable for the unresectable pancreatic cancer. No significant financial relationships to disclose.
SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery
Authors: Neetu Saxena, Nunziata Maio, Daniel R. Crooks, Christopher J. Ricketts, Youfeng Yang, Ming-Hui Wei, Teresa W-M. Fan, Andrew N. Lane, Carole Sourbier, Anamika Singh, J. Keith Killian, Paul S. Meltzer, Cathy D. Vocke, Tracey A. Rouault, W. Marston Linehan
Journal: JNCI Journal of the National Cancer Institute (2015)

Mutations in the Fe-S cluster-containing SDHB subunit of succinate dehydrogenase cause familial cancer syndromes. Recently the tripeptide motif L(I)YR was identified in the Fe-S recipient protein SDHB, to which the cochaperone HSC20 binds. In order to characterize the metabolic basis of SDH-deficient cancers we performed stable isotope-resolved metabolomics in a novel SDHB-deficient renal cell carcinoma cell line and conducted bioinformatics and biochemical screening to analyze Fe-S cluster acquisition and assembly of SDH in the presence of other cancer-causing SDHB mutations. We found that the SDHBR46Q mutation in UOK269 cells disrupted binding of HSC20, causing rapid degradation of SDHB. In the absence of SDHB, respiration was undetectable in UOK269 cells, succinate was elevated to 351.4±63.2 nmol/mg cellular protein, and glutamine became the main source of TCA cycle metabolites through reductive carboxylation. Furthermore, HIF1α, but not HIF2α, increased markedly and the cells showed a strong DNA CpG island methylator phenotype (CIMP). Biochemical and bioinformatic screening revealed that 37% of disease-causing missense mutations in SDHB were located in either the L(I)YR Fe-S transfer motifs or in the 11 Fe-S cluster-ligating cysteines. These findings provide a conceptual framework for understanding how particular mutations disproportionately cause the loss of SDH activity, resulting in accumulation of succinate and metabolic remodeling in SDHB cancer syndromes.
Pulmonary and hepatic metastasectomy in colorectal cancer–is it worth it
Authors: G. Demir, R. U. Gürsu, S. Pekmezci, K. Kaynak
Journal: Journal of Clinical Oncology (2007)

14574 Forty eight patients (24 males and 24 females) with colorectal carcinoma and lung or hepatic metastasis who had undergone metastasectomy were evaluated retrospectively. The mean age was 58.12±8.34 years (43–79 years). The mean age of the males was 60.16±8.21 years (47–79 years), while it was 56.08±8.13 years in the females (43–71 years). Among the 48 metastasectomies that were performed, 11 were pulmonary metastases, and 37 were hepatic metastases. The mean time to the hepatic metastasectomy after primary surgery was 324.37±420.04. Among the hepatic metastases, one was located in the caudate lobe, 16 were located in the right lobe, and 20 were located in the left lobe. Thirty of the patients had received postoperative chemotherapy after liver metastasectomy. Twenty two of the patients who underwent liver metastasectomy (59%) had a recurrence. In 14 of these, (38%) the recurrence was in the liver. Overall survival of the patients with liver metastasectomy was 914.19±577.08 days. Survival after metastasectomy was 578.80±331.54 days. On the other hand, the mean time to pulmonary metastasectomy after primary surgery was 811.81±552.06 days. Eight of the lung metastases were located in the right lobe, whereas 3 were located in the left lobe. Three patients had concomittant metastases in the right upper and lower lobes, and one patient had additional liver metastasis. Eight of the patients who underwent pulmonary metastasectomy had received postoperative chemotherapy. Five of the patients who underwent pulmonary metastasectomy (45%) had a recurrence. Two of the patients had recurrence in the lung, while 3 had recurrence elsewhere. Overall survival of the patients who underwent pulmonary metastasectomy after initial surgery was 1341.54±816.21 days. Survival after metastasectomy was 528.81±365.45 days while recurrence-free survival after pulmonary metastasctomy was 342.18±125.71 days. Conclusion: This study suggests that patients with pulmonary metastasectomies have even beter clinical outcomes then hepatic metastasectomies in patients with metastatic coloercatla cencer. Every effort should be made to perform both pulmonary and hepatic metastasectomies in this group of patients. No significant financial relationships to disclose.
A study of <i>methylated glutathione s-transferase 1</i> (<i>mGSTP1</i>)as a potential plasma epigenetic marker of response to chemotherapy and prognosis in men with castration-resistant prostate cancer (CRPC).
Authors: L. Horvath, K. L. Mahon, W. Qu, J. Devaney, M. D. Chatfield, C. Paul, R. Wykes, M. J. Boyer, M. R. Stockler, G. M. Marx, R. L. Sutherland, S. J. Clark
Journal: Journal of Clinical Oncology (2011)

4603 Background: GSTP1 is inactivated in >98% of all prostate cancers through aberrant DNA methylation. A urinary mGSTP1 assay has been developed as a diagnostic test for localized PC. Serum mGSTP1is predictive of biochemical relapse after surgery for localized PC. The aim of this study was to assess whether quantitative assessment of mGSTP1 as a marker of tumour burden could predict response to chemotherapy and overall survival (OS). Methods: Plasma samples were collected prospectively from 75 men with CRPC. mGSTP1 levels were measured using a sensitive methylation-specific head-loop PCR assay from DNA isolated from either (1) immunomagnetic separation of circulating tumor cells (CTCs) or (2) free plasma DNA. The associations between mGSTP1levels, PSA response to chemotherapy and OS were tested using non-parametric tests and survival analyses. Results: mGSTP1 was measured from CTCs and free plasma DNA in the first 34 patients. The ability to detect mGSTP1 was significantly higher for the plasma free DNA assay compared to DNA from CTCs (p<0.0001), so for the remainder of the study only the plasma free DNA assay was used. Of the 75 men, 67 had chemotherapy (50 docetaxel only, 4 mitoxantrone only, 13 both treatments sequentially) and 40 had plasma samples obtained pre-cycle 1 and pre-cycle 2 of treatment. A decrease in mGSTP1 levels after cycle 1 predicted a subsequent >50% decrease in PSA prior to cycle 4 (p=0.008). After a median follow-up of 16 months (range 1-44 months) and 51 deaths, detectable mGSTP1at presentation predicted poorer OS (HR 4.2, 95%CI 2.1-8.2; p<0.0001). The 2-year survival for men with no detectable plasma mGSTP1 was 71% compared to 23% for men with detectable mGSTP1. Conclusions: These results suggest that plasma mGSTP1 levels can predict for OS in men with CRPC and that changes in the mGSTP1 level after cycle 1 of chemotherapy may predict for subsequent response. Furthermore, the plasma free DNA assay was superior to the DNA assay from CTCs. Larger studies are needed to validate the potential of mGSTP1 as an epigenetic marker of prognosis and therapeutic response in CRPC.
Gene expression panel (TheraPrint) analyzed as predictors of response to neoadjuvant chemotherapy (NCT) in patients (pts) with stage II-III and inflammatory breast cancer (BC).
Authors: Femke De Snoo, Justine Peeters, Kim Robinson, Lisette Stork-Sloots, Iris Simon, George Somlo
Journal: Journal of Clinical Oncology (2012)

e21013 Background: TheraPrint is a microarray-based gene expression panel of 125 genes identified as potential targets for prognosis and therapeutic response. These genes may hold the key to a greater level of personalized prognosis and therapy for BC pts. The aim of the current study was to assess the clinical relevance of the TheraPrint genes for either predictive and/or prognostic value in 2 patient cohorts treated with NCT. Methods: The 1 st patient cohort are 68 Stage II-III BC pts treated with NCT. Expression data from Agilent full genome arrays, containing the MammaPrint, BluePrint and TheraPrint diagnostic profiles/probes (Somlo et al, 2009). Median FU 2.3 years. The 2 nd patient cohort are 230 Stage I-III BC pts treated with NCT. Expression data from Affymetrix probe sets was publically available (Iwamoto et al, 2011). Median FU 5.2 years. To identify genes that are differentially expressed between responders (pCR/RCBI) and non-responders, a supervised analysis was performed. The analysis was performed across all pts and also within groups of HER2+ and HER2-. Univariate t-tests were performed, with results filtered by permutation p-value (p&lt;0.05) and fold change of &gt;1.5. Global test was also reported. In addition, survival data analysis was performed across all pts. Results: Overlapping genes between the 2 datasets that were significantly differentially expressed between responders and non-responders include: BCL2 (down-regulated) and CDH3, GRB7, KRT6B, KRT17 (up-regulated). When analysing the HER2- subgroup, 3 genes turned out to be differentially expressed between responders and non-responders in the 2 datasets: FLT1, PIK3R1 (down-regulated) and KRT6B (up-regulated). For the HER2+ subgroup, only one gene overlapped for the 2 datasets: IL2RA (up-regulated). The top canonical pathways for the significant genes have been analyzed, and in addition correlation of the TheraPrint gene expression with survival for these pt groups. Conclusions: This study has identified several genes from a panel of 125 TheraPrint genes with statistically significant correlation between expression and response to NCT.
Anastrozol (Ana) versus tamoxifen (Tam) treatment in postmenopausal breast cancer women with tamoxifen treatment and abnormal vaginal bleeding: Results from an open-label randomized trial
Authors: A. Krause, W. Janni, T. Reimer, B. Gerber
Journal: Journal of Clinical Oncology (2005)

648 Purpose: To compare the effects of switching from adjuvant Tam treatment to Ana in postmenopausal breast cancer women with abnormal vaginal bleedings during Tam treatment and histologically proven benign endometrial pathology. Patients & Methods: 110 postmenopausal women who had received Tam 20 mg/day (312 months, £48 months) and developed abnormal vaginal bleeding were subjected to hysteroscopy as well as dilation and curettage (D&C). Thereafter they were randomized to continue Tam treatment (n=88) or switch to Ana 1 mg/day (n=83). Patients were monitored for £42 months using transvaginal ultrasound (TVUS) at 6 monthly intervals. Results: At the time of study entry, there was no significant difference between vaginal bleeding, endometrial thickness and histological findings between the two treatment groups. Six months after randomization, the mean endometrial thickness in patients who switched to Ana was significantly reduced compared with those who continued Tam treatment (p<0.0001). This significant difference was sustained throughout the treatment period. There was a significant difference in recurrent vaginal bleeding (Tam: 32%, 17/53 and Ana: 4/57, 7% respectively; p<0.0001). In consequence patients receiving anastrozole required fewer repeat hysteroscopy and D&C compared with those who continued Tam treatment. Repeat hysteroscopy and D&C revealed endometrial atrophy in all four cases in the Ana group and 10 polyps, 6 hyperplasias and one endometrial cancer in the Tam group. The first and second histological findings were consistent in 12 (71%) of the 17 patients assessed (p=0.001). Conclusions: Anastrozole represents an effective treatment for the prevention of repeated endometrial pathology in postmenopausal HR-positive breast cancer patients with Tam-induced abnormal vaginal bleedings. No significant financial relationships to disclose.
A multicenter phase II clinical study evaluating the deferral of rectal surgery following a continued response to preoperative chemoradiotherapy (CRT).
Authors: I. Y. Chong, G. Brown, R. J. Heald, K. Thomas, I. Chau, A. Wotherspoon, D. M. Tait
Journal: Journal of Clinical Oncology (2010)

TPS191 Background: Rates of pathological complete response (pCR) following CRT for rectal cancer are approximately 10- 25% (Sauer et al, NEJM 2004, Chau et al, JCO 2006). Identifying pts with pCR remains a challenge, but may be worthwhile considering the significant morbidity and mortality associated with abdominoperineal resection (Tan et al, Eur J Cancer 2007). Rectal surgery usually takes place 6-8 weeks after CRT, but maximal tumor downstaging may require longer depending on individual tumor response (Francois et al, JCO 1999). The purpose of this study is to 1) establish the safety of deferring surgery in rectal cancer pts with no visible disease after CRT, with its omission in cases of continued response, and 2) show that surgery can be safely delayed until time of maximal response after CRT in pts with a good partial response (PR). Methods: Eligible pts must have locally invasive, nonmetastatic rectal adenocarcinoma with no visible tumour after pre-operative long-course CRT at 4 week MRI or evidence of good PR 4 week MRI, with incremental response at 8 week MRI. Pts are seen monthly for the first 4 months, 3 monthly for the first 2 years, 6 monthly for years 3 to 5, then annually until year 10. Disease response is assessed using DRE, sigmoidoscopy, and CEA levels. MRI, CT, and PET are performed at predefined time points. Surgery is offered immediately in cases of tumor regrowth. Correlative biomarker studies with pretreatment rectal biopsies are performed. The primary endpoints are 2-yr failure rate (FR) and the proportion of pts safely omitting surgery. Using a single-stage exact phase II design, the 2- yr FR from completion of CRT of ≤5% is considered acceptable and ≥15% would be unacceptable. 59 pts will be recruited (1-sided α=0.05, 80% power). 59 pts would provide ≥ 90% power to show that the proportion of pts safely omitting surgery is >10%, if the true rate is ≥ 25%. The trial would be a success according to these endpoints if ≤4 pts have local failure at 2 years and if ≥11 have safely omitted surgery. 18/58 pts have been recruited. This trial has recently been endorsed for multicenter recruitment. No significant financial relationships to disclose.
Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level
Authors: Lars Nilsson, Ingbritt Åstrand-Grundström, Ingrid Arvidsson, Björn Jacobsson, Eva Hellström-Lindberg, Robert Hast, Sten E. W. Jacobsen
Journal: Blood (2000)
Interference of amphiregulin and EGFRvIII expression with outcome of patients with squamous cell carcinoma of the head and neck (SCCHN) receiving cetuximab-docetaxel treatment.
Authors: I. Tinhofer, K. F. Klinghammer, W. Weichert, M. Knoedler, A. Stenzinger, T. C. Gauler, V. Budach, U. Keilholz
Journal: Journal of Clinical Oncology (2011)

5508 Background: Constitutive activation of EGFR as a result of gene amplification, mutation or overexpression of its ligands has been associated with response to EGFR targeting strategies. The role of these molecular mechanisms for the responsiveness of SCCHN to cetuximab-containing regimens remains unknown. Methods: Tumor biopsies from forty-seven patients enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic SCCHN with cetuximab and docetaxel were analyzed by immunohistochemistry for expression of EGFR, its deletion variant III (EGFRvIII) and its ligand amphiregulin (AREG). The relation between expression levels and disease control rate (DCR) was evaluated by logistic regression. Association between expression levels, progression-free (PFS) and overall survival (OS) was determined by Kaplan-Meier analysis, log-rank test, uni- and multivariate Cox regression analysis. Results: High expression of EGFR, EGFRvIII and AREG was detected in 73%, 17% and 45% of SCCHN cases, respectively. Expression levels of EGFR had no impact on PFS or OS. High expression levels of EGFRvIII were significantly associated with reduced DCR and shortened PFS (hazard ratio [HR] 3.3, P=0.005) but not with OS. Patients with high AREG expression in tumor cells had significantly shortened OS (HR 2.2, P=0.002) and PFS (HR 2.2, P=0.019) compared to patients with low expression score. Multivariate Cox analysis revealed an independent association of AREG and EGFRvIII with PFS but only AREG was an independent predictor of OS. Conclusions: High EGFRvIII and AREG expression levels identify SCCHN patients who are less likely to benefit from combination treatment with cetuximab and docetaxel.
Late tamoxifen in patients previously operated for breast cancer without postoperative tamoxifen: 5-year results of a randomized study
Authors: G. Miolo, N. La Mura, M. D. Magri, D. Crivellari, S. Scalone, A. Freschi, R. Sorio, A. Veronesi
Journal: Journal of Clinical Oncology (2008)

594 Background: This study was aimed to evaluate the role of late tamoxifen (TAM) in patients (pts) previously operated for breast cancer (BC) who did not receive postoperative TAM. Methods: From 1997 to 2003, pts aged 35 to 75 years, operated more than 2 years previously for monolateral BC, with no signs of metastases and no contraindication to TAM were randomized to TAM 20 mg/day for 2 years or follow-up (FU) only. Event-free survival (EFS) was the primary endpoint. The sample size (197 pts per arm, plus 10% allowance) was based on the assumption of a 30% decrease in the number of events occurring at a rate of 5% yearly in the 10 years following randomization. 433 pts were randomized in the study (TAM 217, FU 216). Pt characteristics (TAM/FU) included median age 55/55 years, median time from surgery 25/25 months (range, 25–288/25–294), in situ carcinoma in 18/24, N- in 102/106, ER-positive in 75/68, ER-negative in 70/57, ER unknown in 72/91 pts. Previous adjuvant treatment included chemotherapy in 131/120 and LHRH analogue in 11/13 pts. Results: 33 pts discontinued prematurely TAM after a median of 1 month. 79 events (TAM 37, FU 42) occurred after a median of 58/44 months since randomization: local-regional relapse in 10/8, distant metastases in 11/15, metachronous BC in 3/8, secondary tumors in 10/10, death from unrelated causes in 3/1. Actuarial 5-year EFS was 82% in both arms. 14/14 deaths occurred overall. TAM was well tolerated. Conclusions: At this 5-year analysis, a trend to less metachronous BC was noted in TAM treated pts. No other difference emerged so far. No significant financial relationships to disclose.