tbuckley/cabot-search huggingface dataset:
Use of survivorship care plans to re-engineer breast cancer follow-up.
Authors: Grace Makari-Judson, Sandra Hubbard, Tamara Wrenn
Journal: Journal of Clinical Oncology (2012)

162 Background: Use of survivorship care plans (SCPs) was recommended by the IOM in 2005, but benefits are a subject of ongoing debate. ASCO’s Cost of Cancer Care Task Force cited use of unnecessary imaging and tumor markers in breast cancer follow up amongst the “top five” list to improve quality. Communication with breast cancer survivors about guideline based post-treatment follow-up may be improved with SCPs, however few studies have addressed measurable outcomes. We describe use of SCPs to coordinate follow-up care in a multidisciplinary practice. Methods: In 2009, our breast surgeons, medical oncologists, and nurse practitioners agreed upon guidelines for follow up of breast cancer patients, developed a Survivorship Care Program to follow active treatment and implemented use of SCPs. Prior to 2009, follow up was partly determined at physician discretion and partly patient-driven, often with both medical and surgical providers seeing patients within short spans of time. To improve access to two part-time breast surgeons, guidelines were established to shift follow-up to medical oncologists and nurse practitioners. After diagnosis, patients were given comprehensive SCPs, which included recommended follow-up visits and testing. Wait times and numbers of new surgical patients were measured before and after use of SCPs. Results: Implementation of SCPs occurred during 2009; data from time periods two years before and after SCPs is listed below. Wait times were measured from call to first appointment. New patients included both benign and malignant breast disease. Conclusions: SCPs were useful in re-engineering follow-up habits of clinicians, adding value to each visit and gaining acceptance from established patients regarding recommended surveillance. Patients expressed that uncertainty experienced at the end of active treatment is mitigated by remaining in an environment that can be easily transitioned back to other clinical services. SCPs contributed to reduced wait times and increase in volume of new patients seen by breast surgeons. Future studies should assess contribution of SCPs to reducing unnecessary tests and improving compliance with ASCO guidelines. [Table: see text]
Death rates, survival time, and disease progression in high risk and metastatic melanoma: Evidence from the SEER-Medicare linked database
Authors: K. L. Davis, S. Kotapati, D. Mitra, U. Iloeje
Journal: Journal of Clinical Oncology (2008)

17544 Background: Clinical research has shown survival times in advanced melanoma to be short. Our objective was to estimate rates of death, length of survival, and disease progression using real-world administrative data from an elderly Medicare population with high risk (stages IIB/C, IIIA/B, IIIC) or metastatic (stage IV) malignant melanoma. Methods: Data were taken from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, which combines clinical information on incident cancer cases in the US between 1991 and 2002 with longitudinal (1991–2005) Medicare claims for patients (pts) aged ≥65 years. Subjects with ≥1 SEER- reported melanoma diagnosis of stage IIB or higher were selected. An index date was defined as the date of the first observed stage IIB or higher diagnosis. Outcomes were evaluated from index date until end of follow-up as defined by death, interruption of benefits coverage (≥6 months [mos]), or database end (12/31/2005). Kaplan-Meier analyses were conducted to evaluate survival time. Disease progression was identified based on a subsequent SEER-reported melanoma diagnosis of a higher stage than reported at index date or a subsequent ICD-9 diagnosis code (197.xx, 198.xx) for secondary metastases. Results: 6,470 subjects met all inclusion criteria. Stage distribution at index date was: IIB/C (37.6%); IIIA/B (45.9%); IIIC (1.4%); IV (15.2%). Median follow-up was 56, 39, 16, and 6 mos for each stage, respectively. Subjects were evenly distributed by age; 61% were male. Death rates were 54%, 70%, 90%, and 95% for stages IIB/C, IIIA/B, IIIC, and IV, respectively. Median survival times were 38, 26, 15, and 6 mos for each stage, respectively. Among pts with stage IIB/C melanoma at index, 21% progressed to a more advanced stage. Disease progression was observed in 29% and 51% of pts in stages IIIA/B and IIIC at index, respectively. Conclusions: Study findings were consistent with previous clinical research showing a near 100% death rate and median survival time of 6 mos for stage IV metastatic melanoma (MM). Median survival times for high risk disease stages were consistent with prior research. New therapies aimed at prolonging life and lowering progression rates are needed for pts diagnosed with high risk or MM. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
Helical tomotherapy for anal cancer: Initial clinical outcomes and organ motion.
Authors: M. L. Siker, X. S. Qi, B. Hu, S. J. Wong, X. A. Li, B. Erickson
Journal: Journal of Clinical Oncology (2011)

530 Background: Helical tomotherapy (HT) delivers rotational IMRT with megavoltage CT (MVCT) guidance for patient positioning, offering improved dose conformality and accuracy. We report preliminary clinical outcomes using HT in patients with anal cancer with estimated organ motion and delivered doses. Methods: From 9/2005-8/2009, 15 patients with anal cancer were treated with HT and concurrent chemotherapy (MMC 10 mg/m 2 IV bolus d1 and 29; 5FU 1,000 mg/m 2 /day CI d1-4 and 29-32). Median doses for primary tumor, involved lymph nodes and uninvolved lymph nodes were 50.5, 50.4 and 45 Gy. Dose specifications and target definitions were per RTOG 0529 for the majority. Treatment plans, daily MVCT, and initial clinical outcomes and toxicity were retrospectively analyzed. Center-of-mass (COM) locations and volumes of the targets and OAR with daily shifts were analyzed on selected patients. Doses actually delivered daily were reconstructed. Results: At median follow-up of 15 months, all patients were alive without any evidence of recurrence. There were 40% male, 27% HIV+, 13% T3/4, and 47% lymph node positive. Four patients required treatment break of ≤ 1 week. There were no non-hematologic grade 4/5 toxicities. Overall non-hematologic grade 3 toxicity was 33.3% (GI and skin). All other patients had ≤ grade 2 GI or skin toxicity that completely resolved with aggressive supportive care. There was 40% overall hematologic grade 4 toxicity. Overall hematologic grade 3 toxicity was 60%. Daily shifts were 0.6 ± 3.3, 0.4 ± 3.0, and 0.5 ± 2.2 (SD) mm in lateral, longitudinal and vertical directions. Average daily displacements of the COM from their locations on the planning CT were 9 ± 3, 7 ± 4, 9 ± 2, and 7 ± 2 (SD) mm, for anus, rectum, bladder and vulva. Interfractional organ motion and deformation resulted in variations in the dose delivered in each fraction.For example, daily dose covering 95% of PTV varied by 4%, and vulva volume covered by 50 Gy changed by 23% daily. Conclusions: HT with concurrent chemotherapy is well-tolerated compared to historical reports. Interfractional organ motion is significant and can result in deviations in dose delivery to the target and OAR. Such deviations should be considered in analyzing dose response outcome. No significant financial relationships to disclose.
Epigenetic alterations in peripheral blood cell DNA and implications for breast cancer detection, prognosis, and treatment.
Authors: B. Torres-Torres, J. Martínez-Galán, R. Del Moral, M. Núñez, B. González-Astorga, V. Castellón, A. González-Vicente, J. Soberino, J. Delgado, M. Ruiz de Almodóvar
Journal: Journal of Clinical Oncology (2010)

e13619 Background: The CpG islands of many genes, which are usually unmethylated in normal tissue, are methylated in cancer. The aim of the study was to investigate the association between gene hypermethylation and the major clinicopathological features of breast cancer, diagnosis, and treatment response. Methods: We quantified methylation levels of promoter of 5 genes ESR1, RAR-β, 14-3-3 sigma, APC, E-Cadherin which are to confer growth adventage to cells in 107 patients (pts) breast cancer and 108 control by Real Time QMS-PCR SYBR. Serum were collected in 107 operable breast cancer pts previously surgery and in 60 of those pts after treatment. Respect controls, 34 had benign breast disease and 74 with no evidence of breast disease. Results: We found significant differences between breast cancer pts and healthy controls in relative serum levels of methylated gene promoters ESR1 (p=0.0112) and 14-3-3s (p=0.0047). We observed that hypermethylation of these combined two genes differentiated between breast cancer pts and healthy controls (p<0.0001) with a sensitivity of 81% (95% CI:72–88%) and specificity of 88% (95%CI:78–94%). Presence of methylated ESR1 in serum of breast cancer pts was associated with ER(-) phenotype (p=0.0179); and presence of methylated 14-3-3-σ was associated with T3-4stage (p<0.05) and nodal positive status (p<0.05). We observed lower methylated ESR1 or 14-3-3-σ values after surgery, respect pretreatment levels, but without an overall statistically significant difference.With a median follow up of 6 years, we found that patients with a significant decrease of sera methylated levels of both genes after surgery had better time to progression an overall survival respect patients without this observation. Conclusions: These results also suggest that this panel of genes,capable of identifying nearly all breast carcinomas,could be useful as markers for early detection of breast carcinoma cells in ductal lavage and blood specimens. Although numerous issues remain to be resolved, the quantitative measurement of circulating methylated DNA is a promising tool for cancer risk assessment. No significant financial relationships to disclose.
Phase II study of irinotecan and S-1 combination therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC): (WJTOG3505)
Authors: O. Ishimoto, I. Okamoto, T. Nishimura, H. Yoshioka, A. Kubo, K. Takeda, N. Ebi, N. Katakami, H. Saka, M. Fukuoka
Journal: Journal of Clinical Oncology (2008)

8084 Background: S-1 is an oral anticancer drug combining tegafur, oxonic acid, and CDHP. We have conducted a phase II trial to evaluate the efficacy and toxicity of irinotecan in combination with S-1 for patients with advanced NSCLC. Methods: Chemotherapy-naïve pts with advanced stage (IIIB/IV) NSCLC, ECOG PS of 0–1, and adequate organ functions were treated with i.v. irinotecan 150 mg/m2 on day 1 and oral S-1 80 mg/m2/day on days 1 to 14 every 3 weeks. The primary objective of this study was to determine the objective response rate. With the target activity level of 35% and the lowest response rate of interest set at 20%, 50 eligible patients were required with an 80% power to accept the hypothesis and a 5% significance level to reject the hypothesis. Results: Of 59 pts enrolled in the study, 56 pts (median age, 63 years; range, 40–74 years) were eligible and analyzed. The median number of cycles administered was 5 (range, 1–15). The overall response rate was 31% (95% CI, 19–45%) and the progression free survival was 4.9 months (95% CI, 4.0–6.4 months). The median survival time was 15 months and 1-year survival rate was 62.5% (95% CI, 49.8–75.2%). The most common grade 3 to 4 hematologic toxicities were neutropenia (25%), leukopenia (8.9%) anemia (3.6%) and thrombocytopenia (3.6%). Nonhematologic toxicity of grade 3 or 4 included anorexia (14.3%), fatigue (8.9%), diarrhea (8.9%) and febrile neutropenia (7.1%). Conclusions: The combination of irinitecan/S-1 chemotherapy showed a promising effectiveness with acceptable toxicity rates in patients with advanced NSCLC. These results warrant further investigation of this regimen including a randomized controlled trial for its use as a first line treatment for NSCLC. No significant financial relationships to disclose.
Impact of intermittent (I) first-line docetaxel (D)-based chemotherapy on quality of life (QL) of patients (pts) with castration-resistant prostate cancer (CRPC): Results of a phase II randomized trial.
Authors: Orazio Caffo, Teodoro Sava, Umberto Basso, Sebastiano Buti, Giovanni Lo Re, Cosimo Sacco, Michele Lodde, Gaetano Facchini, Fable Zustovich, Alessandra Perin, Lucianna Russo, Antonello Veccia, Enzo Galligioni
Journal: Journal of Clinical Oncology (2013)

90 Background: Eight consecutive courses of D are usually considered a standard first line treatment for CRPC pts. The pts quality of life (QL) may be worsened and an I administration could mitigate this effect. We verified if an I therapy may reduce the impact on pts’ QL compared to continuous (C) treatment. Methods: The treatment was D 70 mg/m 2 IV q 3 wks ± estramustine (E) 280 mg/TID PO for 5 days. Pts were randomized to receive 8 courses D±E continuously (C) or intermittently, with a 3-month rest period after the first 4 courses. QL was evaluated by EORTC QLQ C30 at baseline and every 6 weeks. For the study aim, we considered evaluable for QL pts who received at least 5 D±E courses and filled the QL instruments. Results: 148 CRPC pts were enrolled from 11/06 to 10/10 with 94 pts evaluable for QL (53 and 41 treated with I with C therapy, respectively). No statistically differences were observed between C and I treatments for QL outcomes: the table shows the median value of single EORTC QLQ C30 scales scores at each assessment time-point. Conclusions: The present study failed to demonstrate that I treatment may produce a QL advantage compared to C treatment which remains the reference therapy for first-line of CRPC pts. Clinical trial information: 2006-005728-17. [Table: see text]
Towards an absolute bilirubin threshold for preoperative biliary decompression in patients undergoing whipple.
Authors: Catalina Mosquera, Vanessa G. Dorismond, Emmanuel E. Zervos
Journal: Journal of Clinical Oncology (2016)

381 Background: There is no consensus as to when preoperative biliary decompression is indicated in patients with obstructive jaundice prior to pancreatoduodenectomy. The purpose of this study is to identify a bilirubin level whereby biliary decompression provides clear benefit despite potential drawbacks. Methods: Serial logistic regression analyses were undertaken to identify the bilirubin threshold upon which biliary decompression was associated with significant improvement in overall complications, mayor complications (Clavien-Dindo ≥ 3), length of stay, readmission rates and mortality. Results: Biliary decompression independently predicted a higher incidence of overall complications in patients presenting with bilirubin ≤ 10mg/dl, (p = 0.02). For patients with bilirubin &gt; 10mg/dl - &lt; 15mg/dl, there were no differences in complications, mortality, length of stay or readmissions. Biliary decompression in patients with bilirubin ≥ 15mg/dl independently predicted fewer overall (72% vs 100%), and mayor complications (11 % vs 50%), p &lt; 0.05, and lower readmission rates (27.7% vs 62.5%), p = 0.02. Patients not undergoing biliary decompression underwent resection on average two weeks sooner than those having decompression (4.7 days vs 17.2 days), p = 0.01, with no significant change in bilirubin levels between presentation and surgery. Patients with bilirubin &lt; 15mg/dl at presentation, who underwent biliary decompression, had a bilirubin decrease of more than 50% ( 6.3mg/dl to 2.5mg/dl), and the time to resection increased by more than one week (28 days vs 20.4 days), p &lt; 0.001. Conclusions: All patients presenting with bilirubin ≥ 15mg/dl should undergo preoperative biliary decompression to minimize the risk of complications and readmissions. Patients presenting with bilirubin ≤ 10 mg/dl should forego stent placement to avoid stent related complications without clear benefit. The decision to stent between &gt; 10mg/dl to &lt; 15 mg/dl should be made on a case by case basis, taking into account anticipated bilirubin level at the time of surgery.
BRCA-1 promotor methylation as predictor of benefit from adjuvant CMF in triple-negative breast cancer not responsive to taxane-based neoadjuvant chemotherapy.
Authors: Rupert Bartsch, Mathilde Födermayr, Miriam Sebesta, Margaretha Rudas, Anna Sophie Berghoff, Regina Promberger, Matthias Preusser, Peter Christian Dubsky, Florian Fitzal, Michael Gnant, Ansgar Weltermann, Christoph Zielinski, Guenther G. Steger, Otto Zach
Journal: Journal of Clinical Oncology (2013)

148 Background: Triple-negative breast cancer (TNBC) patients (pts) without pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) have an unfavourable prognosis. ABCSG trials 14 and 24 defined 6 cycles of epirubicin/docetaxel (+/- capecitabine) as active NAC regimen; pts without pCR commonly received another 4-8 cycles of adjuvant CMF. Different studies suggested that breast tumours harbouring BRCA-1 germline mutations were resistant to taxane-based therapy while sensitivity to DNA-damaging agents was retained. BRCA-1 mutations are rare in sporadic BC; BRCA-1 promotor methylation (PM), however, is frequently observed. We hypothesized that pts with TNBC harbouring BRCA1 PM would benefit from adjuvant CMF salvage therapy. Methods: For this analysis, we included all pts with TNBC refractory to taxane-based NAC who received adjuvant CMF. DNA was extracted from formalin-fixed paraffin-embedded tissue samples, purified and bisulfite-converted. The TaqMan assay was used in order to perform a quantitative methylation-specific PCR. Actin-b was used as reference gene to normalise the amount of provided DNA; bisulfite-converted, artificially methylated DNA was used as positive control. Results: Twenty-four pts, median age 47 years, were available for this analysis. In 9/24 pts (37.5%), BRCA-1 PM was detected. At a median follow-up of 27.5 months, 1/9 pts (11.1%) with BRCA-1 PM had a disease-free survival (DFS) event, as compared to 10/15 (66.6%) in the non-methylated group (p = 0.013; Fisher’s exact test). Kaplan Meier estimation of DFS in the non-methylated group was 24 months (95% CI 14.06-33.94) and was not reached in the methylated group (n.s.). Conclusions: In TNBC refractory to taxane-based NAC, adjuvant CMF is of limited efficacy. In tumours harbouring BRCA-1 PM, however, a significant decrease of DFS events was observed. Therefore, tumours harbouring defects in genetic repair mechanism might be exceptionally sensitive to drugs causing DNA-damage. Further clinical investigation of this concept is warranted.
Ex vivo 18O-labeling mass spectrometry identifies a peripheral amyloid β clearance pathway
Authors: Erik Portelius, Niklas Mattsson, Josef Pannee, Henrik Zetterberg, Magnus Gisslén, Hugo Vanderstichele, Eleni Gkanatsiou, Gabriela A. N. Crespi, Michael W. Parker, Luke A. Miles, Johan Gobom, Kaj Blennow
Journal: Molecular Neurodegeneration (2017)

Proteolytic degradation of amyloid β (Aβ) peptides has been intensely studied due to the central role of Aβ in Alzheimer's disease (AD) pathogenesis. While several enzymes have been shown to degrade Aβ peptides, the main pathway of Aβ degradation in vivo is unknown. Cerebrospinal fluid (CSF) Aβ42 is reduced in AD, reflecting aggregation and deposition in the brain, but low CSF Aβ42 is, for unknown reasons, also found in some inflammatory brain disorders such as bacterial meningitis. Using 18O-labeling mass spectrometry and immune-affinity purification, we examined endogenous proteolytic processing of Aβ in human CSF. The Aβ peptide profile was stable in CSF samples from healthy controls but in CSF samples from patients with bacterial meningitis, showing increased leukocyte cell count, 18O-labeling mass spectrometry identified proteolytic activities degrading Aβ into several short fragments, including abundant Aβ1–19 and 1–20. After antibiotic treatment, no degradation of Aβ was detected. In vitro experiments located the source of the proteolytic activity to blood components, including leukocytes and erythrocytes, with insulin-degrading enzyme as the likely protease. A recombinant version of the mid-domain anti-Aβ antibody solanezumab was found to inhibit insulin-degrading enzyme-mediated Aβ degradation. 18O labeling-mass spectrometry can be used to detect endogenous proteolytic activity in human CSF. Using this technique, we found an enzymatic activity that was identified as insulin-degrading enzyme that cleaves Aβ in the mid-domain of the peptide, and could be inhibited by a recombinant version of the mid-domain anti-Aβ antibody solanezumab.
Generation and profiling of fully human therapeutic antibodies against CD38 for the treatment of multiple myeloma
Authors: M. Tesar, U. Jäger, D. Waldherr, S. Steidl, J. Haunschild
Journal: Journal of Clinical Oncology (2005)

6590 CD38 appears on lineage-committed progenitors of lymphoid, erythroid and myeloid cells, while the most primitive pluripotent stem cells of the hematopoietic system are CD38-negative. CD38-expression is also found on plasma cells and activated B- and T-cells. CD38-upregulation was detected on various cell-lines derived from B, T, and myeloid/monocytic tumors. Especially for the indication of multiple myeloma (MM), which remains an incurable malignancy with a median survival of 3–4 years, a strong expression has been reported in the majority of patient samples. Hence, over-expressed CD38 on malignant cells may provide an attractive therapeutic target for immunotherapy. CD38-specific human antibodies were selected from MorphoSys” proprietary HuCAL GOLD phage display library by cell panning strategies. Three antibodies recognizing different epitopes on CD38 were characterized in vitro in detail as follows: All affinities for CD38 were in the low nanomolar range with dissociation constants between 0.5 and 6.3 nM for bivalent IgG1 and between 2.4 and 56.0 nM for monovalent Fab fragments. IHC profiles with healthy and malignant tissue from MM-patients show that the antibodies were highly specific for human CD38 and correlated well with the tumor infiltration rates. Additionally, one candidate cross-reacted with non-human primate’s CD38. The human IgGs were able to kill efficiently CD38-expressing cell-lines and primary MM cells from patients by ADCC and CDC in a concentration dependent manner. EC50-values of the different antibodies in ADCC and CDC range from 40 pM to 280 pM and from 410 pM to 13.6 nM, respectively, demonstrating a similar or superior activity over the reference antibody OKT10, which is currently in phase I as immunotoxin-conjugate. Most importantly, early progenitor cells were not affected in ADCC as demonstrated by a clonogenic assay. Finally, one candidate was selected for in vivo efficacy profiling using the MM cell-line RPMI8226 in a SCID-mouse xenograft model. After the tumor became visible, the human IgG1 antibodies were given every other day over a period of 32 days at two different concentrations resulting in a significantly reduced tumor growth at 1 mg/kg and an even stronger effect at 5 mg/kg. In conclusion, CD38 appears to be a bona-fide target for immunotherapy of multiple myeloma with HuCAL anti-CD38 antibodies. No significant financial relationships to disclose.