tbuckley/cabot-search huggingface dataset:
Use of alkylating chemotherapy in high-grade neuroendocrine tumours: Evaluation of real-world data.
Authors: Arani Sathiyapalan, Michael Susmoy Sanatani, Stephen Welch, Walter Ilarion Kocha, Sue Richter
Journal: Journal of Clinical Oncology (2016)

78 Background: High-grade neuroendocrine tumours (NETs) are believed to have activity to certain alkylating agents, although data are scant. These regimens include streptozotocin (STZ) (used in combination with doxorubicin or 5-fluorouracil) and dacarbazine (DTIC). Current series report variable responses between 6 – 69%. Our objective was to evaluate our real world data to better understand treatment decision-making and clinical outcomes with alkylating agents in advanced high-grade NETs. Methods: We reviewed the medical records of 36 patients with metastatic NETs who received alkylating systemic chemotherapy with either a DTIC regimen (n = 15) or STZ based regimen (n = 21). Patient cases were evaluated for age, time to treatment failure (TTF), time to progression (TTP Results: Among 36 patients treated, the predominant primary NET was pancreas (n = 28) with a median age at treatment of 61.9 years. Observed TTF was similar with both regimens (STZ: 3 months and DTIC: 4 months), however there was prolonged TTP of 11 months with STZ vs. 5.3 months with DTIC (p = 0.047). There was no significant difference in OS with a mean of 48.7 months (DTIC) vs. 47.6 months (STZ) (p = 0.47). Baseline progression at treatment initiation was higher in DTIC at 77% versus 57% in STZ. The predominant cause of treatment discontinuation in both groups was progressive disease; DTIC (71%) versus STZ (42%). Toxicity resulted in treatment discontinuation in 19% for STZ vs 7% for DTIC. Other causes of treatment cessation were completion of the intended treatment. Conclusions: In the groups evaluated, STZ containing regimens demonstrated prolonged PFS in comparison to DTIC, but there was no difference in OS between the two groups. Additionally, despite STZ appearing to have an increased toxicity rate, the rate of cessation between the groups was similar. This real world evaluation suggests similar efficacy with improved tolerability of DTIC based chemotherapy as a potential alternative to other alkylating agents.
A phase I study of a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody “EMD72000 (Matuzumab)” administered weekly in Japanese patients with advanced solid tumors; safety, PK and PD results of skin biopsies
Authors: T. Doi, A. Ohtsu, N. Saijo, H. Takiuchi, Y. Ohhashi, D. Weber, J. Tillner, T. Sakata, H. Sun, F. Rojo
Journal: Journal of Clinical Oncology (2005)

3077 Background: Matuzumab is a humanized monoclonal antibody binding to the EGFR with higher affinity than natural ligands (eg. TGF alpha,EGF) leading to inhibition of signal transduction pathways which are activated through ligand-binding and subsequent phosphorylation. Matuzumab has shown anti-tumor activity in xenograft models. Several clinical studies, which showed to be effective, have already been conducted in Europe and the US.Methods: We have conducted a phase I study of matuzumab administered as a 1 hour IV infusion weekly at 4 fixed doses: 400mg, 800mg, 1200mg and 1600mg. PK samples from different timepoints and PD using skin biopsies were also investigated. The primary objective was to assess safety profile of EMD72000 as single agent. The secondary objectives were DLT assessment, PK, PD, tumor response and human anti-humanized antibody (HAHA) measurement. PD studies determined the occurrence of protein makers related to EGFR signaling pathways in skin biopsies taken before and on day 29 (pEGFR, pMAPK, Ki67) by IHC. Results: A total of 26 pts (400mg; 6pts, 800mg; 7pts, 1200mg; 7pts, 1600mg: 6pts;doses were not adjusted to BM or BSA) with EGFR+ tumors have been included: colorectal (18), gastric (7) and esophagus (1), median age of 61 (range: 33–72), and a median of 2.5 prior chemotherapy regimens (range: 1–5). One subject occurred with DLT at 1600mg (increased total-bilirubin). However, other toxicities were Grade 1 - 2 in severity. There have been 2 PR, and 10 SD in pt with colon cancer. EMD72000 exposure increased in proportion to dose with slightly higher values for the 1200mg dose group. Half life was around 110h for all dose groups. PK data were consistent with results of other studies of EMD 72000 monotherapy. Preliminary analysis of the PD assessments showed that matuzumab produced complete inhibition of pEGFR & pMAPK at higher doses with a decrease in Ki67 and an increase in p27 in skin samples even in the lowest dose group.Conclusions: Matuzumab in biologically effective doses appeared very well tolerated. PD and PK data corresponded to recent study results of matuzumab monotherapy. No significant financial relationships to disclose.
Outcomes associated with adjuvant radiation after lumpectomy for elderly women with T1-2N0M0 triple-negative breast cancer: SEER analysis.
Authors: Sean Szeja, Sandra S. Hatch
Journal: Journal of Clinical Oncology (2015)

39 Background: Adjuvant Radiation (RT) may be omitted for elderly women with early stage breast cancer having favorable estrogen receptor status, however in the setting of triple negative breast cancer (TNBC), less evidence exists to guide decision making. As some findings thus far have shown TNBC to have an increased recurrence rate, this is an important subject to address. The purpose of this study is to use the Surveillance, Epidemiology, and End Result (SEER) database to evaluate how the addition of adjuvant radiation affects the survival of women ages 70 and above with T1-2, N0, M0 TNBC that undergo Lumpectomy (L). Methods: Cases diagnosed from 2010-2011 were downloaded from the SEER Database. Inclusion criteria were ages 70 and above, with T1-2N0M0 TNBC. Kaplan meier curves calculated overall survival (OS) and disease specific survival (DSS) in months (m). Log-Rank tests were performed to compare survival. Cox multivariate regression was performed to calculate Hazard Ratios (HR) and control for confounding variables including neoadjuvant chemotherapy, number of lymph nodes sampled, age, laterality, grade, T stage, extent of surgery, existence of other cancers. Results: From 2010-2011, SEER contained 109,559 cases of breast cancer with recorded results of Her-2-neu (H2N) status. Combining other receptor values, showed 12,620 triple-negative, which was 12% of cases. Of these, 6980 (55%) had stage T1-2, N0, M0. Lumpectomy was used in 4002 of these cases. There were 974 lumpectomy cases of women aged 70 and above. RT was given in 662 (68%) cases. After 23 months, L+ RT was associated with improved OS at 98.2% compared to 85.6% for L only (p=&lt;0.001), as well as DSS at 99% for L+RT better than 94% for L only (p=0.003). Cox Regression showed radiation demonstrated improved OS (HR=0.14, p&lt;0.001) and DSS (0.14, p=0.01). Conclusions: The use of adjuvant RT after lumpectomy for elderly women with early stage TNBC was associated with improved OS and DSS. Noting the potential for selection bias in this study, future prospective study is required to define the management of early stage triple negative breast cancer.
Immunomodulatory effects of bevacizumab in metastatic malignant melanoma.
Authors: Aaron Scott Mansfield, Wendy Kay Nevala, Svetomir Markovic
Journal: Journal of Clinical Oncology (2012)

82 Background: Metastatic malignant melanoma is a nearly uniformly fatal disease. Systemic therapy has notable but limited success. Novel therapeutic strategies are urgently needed. To that end, we’ve pursued combinatorial therapeutics using conventional chemotherapy added to an inhibitor of angiogenesis (bevacizumab) with some evidence of clinical benefit. Preliminary analysis of one of our trials suggested a previously unrecognized immunomodulatory effect of bevacizumab when added to chemotherapy in patients with metastatic melanoma, and this may have a potential impact on clinical outcome. Herein we evaluate the immunomodulatory effect of bevacizumab when added to chemotherapy in patients with metastatic melanoma. Methods: We measured levels of peripheral blood mononuclear cell phenotypes in addition to 42 cytokines, chemokines and growth factors in plasma of 55 patients who received albumin-bound paclitaxel and carboplatin (AC) and of 73 patients who received AC with bevacizumab (ACB) on clinical trials N057e and N0775 respectively. The relative percent change in PBMC cell counts and cytokine levels were determined from baseline at their restaging evaluation after two cycles of therapy. The Mann Whitney U test was used to compare responses between the groups. Results: There was a significant increase in CD197 + type 1 macrophages in the group that received ACB (35.3%, -11.8-142.7%) compared to AC (-11.6%, -45.9-38.3%; p=0.004). There was a significant decrease in IL-6 in the group that received ACB (-42.4%, -87.7-0.0%) compared to AC (28.4%, -37.4-480%; p=0.0018). Conclusions: The addition of bevacizumab to chemotherapy for the treatment of metastatic melanoma modulates cellular immunity and a pro-inflammatory cytokine. Patients who received bevacizumab had a significant increase in CD197 + type 1 macrophages and a significant decrease in IL-6. Clinical significance of these findings is the subject of ongoing work.
Earlier access to palliative medicine: An experience of integration into a community oncology practice.
Authors: Sandra Burcham, Jacqueline Matthews
Journal: Journal of Clinical Oncology (2016)

92 Background: A growing body of evidence supports the integration of palliative care as a standard for comprehensive cancer care. Through our experience as an inpatient palliative care provider, with 50% of our population having advanced cancer, we recognized the value proposition to provide continuity in the outpatient setting. Innovative Care Solutions developed a partnership with a large, community oncology program late 2015 for a palliative care multidisciplinary team to be embedded into one location of their practice. Methods: A full-time palliative licensed independent social worker (LISW) was dedicated to educate and engage screening process development. Utilizing the NCCN Distress Thermometer, referrals for care provision were then directed by the LISW to the most appropriate palliative care provider. The LISW addressed communication, goals of care discussions and advance directives. Identification of symptoms, including high level distress or mental health needs, were scheduled to see the palliative physician or advanced practice nurse, available two half days per week within the cancer center. Results: In the first quarter of service, the LISW screened a total of 85 patients, with 54 requiring PC interventions. Complex symptom needs were identified in seventeen percent, thirty percent were seen for psychosocial needs, and twenty percent were seen for completion of an advance directive. Thirty-six percent were seen for medical decision making. Conclusions: Integrating palliative care services in a community-based oncology practice has realized numerous positive patient outcomes and opportunities for further design. Using an evidenced based screening tool, identification of needs in an early access model appear to enable the patient to improve adherence to the medical plan care and avoid ER utilization. Symptom management has shown improved quality of life scores and PPS, and patient’s seen for psychosocial needs are able to explore aspects of person, as opposed to illness, that has improved overall well-being. Further program design will focus on integration of screening for all patients with advanced solid tumor, recurrent/refractory, and formalization of quality data tracking benchmarked to a web-based registry.
Preoperative radiation and irinotecan in combination with 5 fluorouracil (5-FU) and low-dose leucovorin (LV) in locally advanced rectal cancer (LARC)
Authors: D. Sebag-Montefiore, S. Falk, R. Glynne-Jones, T. Maughan, H. M. Meadows
Journal: Journal of Clinical Oncology (2005)

3576 Background: The aim of this study is to determine maximum tolerated dose (MTD) and recommended scheduled dose of irinotecan on days 1–5 and 29–33, in combination with LV 20mg/m2 and 5-FU 350mg/m2 (1 hour infusion) synchronously with pre-operative radiotherapy (RT) days 1–5, 29–33. Methods: Toxicity and effectiveness of the schedule is studied in LARC. Escalating dose levels of 2 mg/m2 irinotecan were used starting at 6 mg/m2. Preoperative pelvic RT comprises 45Gy in 25 fractions (1.8Gy per fraction), and is CT planned and delivered with patients prone using a 3/4 field technique. Surgery is performed 6–8 weeks later. Results: The MTD was determined when dose-limiting toxicity (DLT) of grade 3 diarrhoea was experienced in Cohort 8 (20 mg/m2 x 5) in 3/4 patients. All 4 patients at this dose level completed treatment as per protocol. The median age is 62 (range 44–73). A further 14 patients will be treated at 18mg/m2. 41/43 patients completed RT without interruption and 40/43 without chemotherapy dose reduction. 5 patients did not proceed to surgery due to a persistant inoperable mass (3) and presence of metastatic disease(2). To date 34 patients have had surgical resection. Histopathology demonstrated pCR 8/34 (24%), Tmic 3/33 (9%), pCR+ Tmic 11/33 (33%), pT0–2 14/34 (41%) and histologically confirmed clear CRM in 29/34 (85%). Conclusions: DLT with irinotecan given days 1–5 and 29–33 when added to the described 5FULV and 45Gy radiation pre-operatively is 20mg/m2. The toxicity and compliance at 18mg/m2 may be suitable for testing in future phase II studies. This study has successfully integrated irinotecan into the EORTC 22921 CRT trial regimen. Acceptable low levels of acute toxicity were seen in the first seven cohorts and the high histologically confirmed CRM -ve rate is encouraging. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Aventis
AMC075: A sequential phase I/randomized phase II trial of vorinostat and risk-adapted chemotherapy with rituximab in HIV-related B-cell non-Hodgkin’s lymphoma.
Authors: J. C. Ramos, J. A. Sparano, P. C. Moore, R. F. Ambinder, A. Noy, R. T. Mitsuyasu
Journal: Journal of Clinical Oncology (2011)

e13002 Background: HIV infected individuals are at an increased risk of developing NHL and they usually present with more aggressive disease. Diffuse large B-cell lymphoma (DLBCL) is the most commonly encountered HIV-NHL. Unlike non-HIV, one-third of these cases are EBV+. Recent phase II trials suggest a superior outcome using infusional EPOCH over conventional CHOP, especially in high-risk groups. This warrants the investigation of risk-adapted chemotherapy and new drugs which can target the biology of HIV-DLBCL. At the AIDS Malignancy Consortium we have developed a phase I/randomized phase II trial using risk-adapted chemotherapy with the histone deacetylase inhibitor (HDAC-I) vorinostat (V) for untreated HIV-DLBCL. HDAC-Is have anti-tumor activity in lymphomas. These drugs alter the functional state of chromatin, facilitating the expression of abnormally silenced genes in neoplastic disease and latent viruses. We hypothesize that V will enhance the anti-tumor effect of chemotherapy in HIV-DLBCL and transiently activate HIV and latent oncogenic γ-herpesviruses thus eliminating infected reservoirs under antiviral treatment and inducing lysis of EBV infected tumor cells. Methods: Eligibility: HIV+ subjects with untreated CD20+ DLBCL and CD4 count ≥50 cell/mm3 Phase I (27-40 subjects): Will determine the recommended phase II dose (RPTD) of V in combination with R-CHOP in low risk disease (aa-IPI 0-1, Ki-67<80%, GCB subtype) and R-DA-EPOCH in high risk groups (aa-IPI 2-3, Ki-67≥80% or ABC subtype). The starting dose of V will be 300 mg on Days 1-5 on each 21-day cycle, and will be escalated to a maximum of 500 mg on a 3 + 3 design. Randomized phase II (90 subjects): Will determine the overall toxicity and efficacy of R-CHOP (in low-risk disease) or R-DA-EPOCH (in high-risk disease) with and without V. Correlative studies will measure the effect of V and chemotherapy on latent HIV infected reservoirs, and EBV and HHV-8. Results: This study is currently open to accrual nationwide. Conclusions: We have designed a risk-adapted chemotherapy approach for the treatment of HIV-DLBCL incorporating the novel use of an agent which can target the biology of these tumors.
Prevalence and Prognostic Significance of c-KIT Mutations in Core Binding Factor Acute Myeloid Leukemia: A Comprehensive Large-Scale Study from a Single Chinese Center
Authors: Ya-Zhen Qin, Honghu Zhu, Qian Jiang, Hao Jiang, Le-Ping Zhang, Jin-Lan Li, Ling-Di Li, Yan-Rong Liu, Yue-Yun Lai, Hong-Xia Shi, Bin Jiang, Xiao-Jun Huang
Journal: Blood (2014)
Technical feasibility and cosmetic advantage of hybrid endoscopy-assisted breast-conserving surgery.
Authors: Shinji Ozaki, Masahiro Ohara, Hideo Shigematsu, Takayuki Kadoya, Tsuyoshi Kataoka, Morihito Okada
Journal: Journal of Clinical Oncology (2013)

80 Background: We developed a new procedure called hybrid endoscopy-assisted breast-conserving surgery (EBCS), which consists of a combination of plastic surgery and endoscopic surgery techniques. The purpose of this study was retrospectively to analyze the clinical outcome of hybrid-EBCS and compare the cosmetic outcomes between hybrid-EBCS and conventional breast-conserving surgery (CBCS). Methods: We reviewed medical records of patients who had undergone hybrid-EBCS (n = 73) or CBCS (n = 90) between May 2005 and April 2011 and had been followed-up in our department until March 2012. The clinical outcomes, and cosmetic outcomes of these 2 groups were compared. The safety of hybrid-EBCS was also analyzed by confirming its complications and pathological surgical margin. Results: In the hybrid-EBCS group, operation time was longer by 30–50 minutes. Blood loss was not significantly different between the 2 groups. The surgical margin of hybrid-EBCS was as follows: 1 patient (1.4%) had a positive margin; 4 patients (5.5%) had a margin of less than 2 mm; in 9 patients (12.3%), the margin was &gt; 2 mm and &lt; 5 mm; and in 59 patients (80.8%), it was more than 5 mm. Seven cases (9.6%) of postoperative complications occurred in 6 hybrid-EBCS patients. To date, no local recurrence has been observed in hybrid-EBCS patients (postoperative observation period: 18.1 ± 5.6 months). Compared with the CBCS group, the hybrid-EBCS group had better cosmetic results, especially with a less noticeable operative scar (p &lt; 0.01). Conclusions: Hybrid-EBCS can provide sufficient free margin, and its surgical curability is acceptable. Additionally, this method is superior to CBCS in terms of cosmetic outcome.
Prognostic Relevance of Lipoprotein Lipase (LPL) Expression in B-CLL.
Authors: Daniel Heintel, Dirk Kienle, Bilban Martin, Medhat Shehata, Alexander Kroeber, Dieter Mitteregger, Edith Porpaczy, Birgit Kainz, Michael Auer, Andreas Gleiss, Hartmut Dohner, Alexander Gaiger, Oswald Wagner, Stephan Stilgenbauer, Ulrich Jaeger
Journal: Blood (2004)
Epigenetic silencing and variable expression of SRD5A2 in specific compartments of human prostate.
Authors: Aria F. Olumi, Zongwei Wang, Rongbin Ge, Shulin Wu, Shahin Tabetabaei, Chin-Lee Wu
Journal: Journal of Clinical Oncology (2016)

38 Background: The steroid-5α reductase type 2 gene (SRD5A2) and protein play a significant role in the development and growth of prostate tissue. SRD5A2 can be expressed in both the epithelial and stromal compartments of the prostate gland. Previously, we have shown that somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes associated with methylation of the promoter region of the SRD5A2 gene. Here we determined whether variability of SRD5A2 expression occurs in specific compartments of prostate tissues. Methods: Frozen and formalin-fixed sections of human adult prostate tissue was used. Laser capture microdissection (LCM) was performed to obtain a pure population of epithelial and stromal cells. Approximately 500–600 excised cells were captured, and the methylation pattern of SRD5A2 was determined by DNA methylation pull-down assay kit. The expression of SRD5A2 protein was identified with immunohistochemistry and quantitated by ELISA. Results: In the whole prostate tissue, samples with high SRD5A2 immunoreactivity had much lower levels of SRD5A2 promoter methylation compared to those with low SRD5A2 immunoreactivity. DNA methylation assay for the epithelial compartment closely resembled the findings of the whole prostate tissue. In contrast, the samples from the stromal compartment showed uniform methylation irrespective of the methylation pattern in the epithelial compartment or the whole tissue. The expression of SRD5A2 protein quantitated by ELISA further showed that the variable expression of SRD5A2 is better determined by epithelial compartment expression. Conclusions: Our data suggests that variability of SRD5A2 expression is dependent on the methylation pattern and expression of SRD5A2 in the epithelial compartment and not the stroma. Therefore, if epithelial expression of SRD5A2 is more representative of the whole prostatic tissue expression, then it is logical that SRD5A2 inhibitor’s efficacy is dependent on involution of the epithelial cells. Our findings will have broad implications for the use of 5ARIs in the treatment of BPH and for the chemoprevention of prostate cancer. Grant support: NIH/R01 DK091353
A molecular biomarker targeted approach to adjuvant therapy for resected pancreatic adenocarcinoma: Results of a phase II prospective trial.
Authors: Lauren McLendon Postlewait, Cecilia G. Ethun, David A. Kooby, Juan Sarmiento, Charles A. Staley, Edith Brutcher, Volkan Adsay, Bassel F. El-Rayes, Shishir Kumar Maithel
Journal: Journal of Clinical Oncology (2016)

230 Background: Standard adjuvant treatment for resected pancreatic adenocarcinoma is gemcitabine (Gem) (CONKO-001 trial: Gem vs placebo DFS 13.4 vs 6.7 mo; p&lt;0.001; OS 22.8 vs 20.2 mo; p=0.01). Adding cisplatin (Cis) to Gem has shown increased response rates in the metastatic setting. This benefit may be inhibited by high expression of excision repair cross-complementing gene–1 (ERCC1), the key enzyme in nucleotide excision repair. This Phase II prospective trial assesses outcomes of patients treated with adjuvant Gem/Cis chemotherapy, stratifying results by tumor ERCC1 expression. Methods: Patients with resected pancreatic adenocarcinoma at a single institution were enrolled from 2010-2013. Initially, patients received Gem (1000 mg/m 2 ) / Cis (50 mg/m 2 ) Day 1/8/15, Q28d for 6 cycles. After enrolling 5 pts, this was modified to Day 1/15 due to toxicity. Two dose reductions were permitted. Intent to treat analyses were conducted. Tumor ERCC1 expression was evaluated by immunohistochemistry and dichotomized into low and high expression groups. Primary outcomes were RFS and OS stratified by ERCC1 expression. Results: Of 22 pts, 16 (73%) had Stage IIB disease, 5 (23%) Stage IIA, and 1 (4%) Stage IA. Thirteen (59%) completed all 6 cycles of therapy, of whom 9 required dose reduction. Of the remaining 9 pts, 4 completed &gt;68% of intended therapy. Grade 3 and 4 toxicity occurred in 13 pts (59%); neutropenia was most common (n=9;41%). Median follow-up was 37.5 mo. Median RFS was 16.7 mo, and OS was 35.5 mo. ERCC1 tumor expression data were available for 20 pts: 15 low (75%) and 5 high (25%). Low compared to high ERCC1 was not associated with improved RFS (12.4 vs 16.7 mo; p=0.68) or OS (Median not reached vs 21.6 mo; p=0.22). Conclusions: Adjuvant gemcitabine/cisplatin is tolerated by patients with resected pancreatic adenocarcinoma. RFS and OS for Gem/Cis appear promising compared to historic control. Tumor ERCC1 expression can be reliably evaluated, and low expression is present in the majority of patients. Further prospective trials evaluating Gem/Cis as an adjuvant regimen and ERCC-1 as a biomarker in resected pancreatic adenocarcinoma are warranted. Clinical trial information: NCT01188109.