tbuckley/cabot-search huggingface dataset:
A single center experience with high-dose (HD) IL-2 treatment for patients with advanced melanoma and pilot investigation of a novel gene expression signature as a predictor of response
Authors: R. J. Sullivan, Y. Hoshida, J. Brunet, S. Tahan, J. Aldridge, C. Kwabi, E. Gardiner, D. McDermott, T. Golub, M. B. Atkins
Journal: Journal of Clinical Oncology (2009)

9003 Background: HD IL-2 remains one of two FDA-approved therapies for the treatment of patients (pts) with advanced melanoma. Initial studies conducted 15–20 years ago reported 16% response rate with 8% of pts achieving durable responses. The toxicity of HD IL-2 limits its application to pts treated in specialized centers. We present the clinical outcome of pts treated over a recent 2 year period with HD IL-2 at a single institution and an associated retrospective pilot study evaluating the predictive value of a novel tumor gene expression signature. Methods: Clinical and radiological data were collected and analyzed on 49 consecutive pts treated with HD IL-2 at Beth Israel Deaconess Medical Center from 10/05 - 10/07. Response was evaluated via RECIST. Formalin-fixed paraffin embedded tumor was obtained on consenting pts and classified as either Class 1, defined by melanocyte-specific genes including MITF, or Class 2, represented by immune genes, using the DNA-mediated Annealing, Selection, and Ligation (DASL) technique. Two-sided Fisher's Exact test was used to compare the proportion of responses for pts in the two classes. Results: Clinical response occurred in 16 of the 49 pts (32.6%), with 5 pts (10.2%) having a CR. Two other pts had stable disease &gt; 12 mos; 3 pts who progressed after response had resection to NED. 10 pts remain disease/progression free at a minimum of 16 mos following treatment. 28 pts (including 13 of 16 responders) had sufficient tumor for DASL analysis. Among the 21 categorized as Class 1, 7 (33%) were responders. Of the 7 classified as Class 2, 6 (86%) were responders. This difference in response was statistically significant (p = 0.0286). Conclusions: The overall and CR rates in a contemporary series of pts with metastatic melanoma treated with HD IL-2 are twice that reported in initial studies suggesting some treatment selection on clinical grounds since the 1990s. Pts with tumors expressing an immune signature by DASL appeared more likely to respond. This finding requires prospective validation, but suggests immune-related gene expression might contribute to IL-2 responsiveness. [Table: see text]
Results of an analysis of cardiac function in 2,812 patients treated with lapatinib
Authors: E. A. Perez, J. A. Byrne, I. W. Hammond, R. Rafi, A. M. Martin, M. S. Berger, T. Z. Zaks, C. R. Oliva, D. F. Roychowdhury, S. H. Stein
Journal: Journal of Clinical Oncology (2006)

583 Background: Lapatinib is an orally bioavailable reversible, dual tyrosine kinase ErbB1 and ErbB2 inhibitor. Trastuzumab, an ErbB2 inhibitor, has been associated with cardiotoxicity. Methods: Left ventricular ejection fraction (LVEF) was monitored every 8 weeks using MUGA or echocardiogram. Cardiac risk factors including age, underlying cardiovascular disease, previous exposure to AC, trastuzumab, or mediastinal/left sided radiation (XRT) were also collected. LVEF data were evaluated for ≥ NCI CTC grade 3, or ≥ 20% decline relative to baseline (&amp; below institutional LLN). Results: 1.3%, 37 of the 2812 subjects who have received lapatinib in all trials to date have experienced decreased LVEF. 22 of 37 patients received lapatinib monotherapy, the remaining 15 received lapatinib in combination with other chemotherapeutic agents. 68% (25/37) of patients were female, median age was 59 years. Decreased LVEF occurred within 9 weeks of treatment onset in 68% of cases. The event resolved/improved in 57% of cases: in 50% of these, lapatinib treatment was continued. Average event duration was 5 weeks. Four of 37 patients were symptomatic (0.1% incidence). Most symptomatic events responded promptly to standard CHF therapy. The majority of patients (92%, 34/37) had confounding factors that may have contributed to the event, including previous exposure to AC, trastuzumab or XRT, and/or medical history. 8 of 34 patients had a positive lapatinib dechallenge (LVEF recovered): 3 were symptomatic (signs of CHF) and 5 asymptomatic. 3 patients had no contributing factors: 1 experienced symptomatic decreased LVEF, the remaining 2 died due to disease progression whilst LVEF decrease was ongoing. 16 of 1307 patients participating in placebo controlled studies experienced decreased LVEF. Of these 8 are known to have received lapatinib, giving an incidence of 1.2% (8/654). Conclusions: Lapatinib-associated LVEF decrease is rarely symptomatic and generally reversible/non-progressive. Incidence was 1.3% in our population, less than the 3–6% incidence of asymptomatic LVEF decreases observed in the general population. Pharmacogenetic studies are ongoing to determine whether there is a link between ErbB2 polymorphisms and lapatinib cardiotoxicity. [Table: see text]
CONKO-101: Results of a multicenter phase II study of an outpatient regimen consisting out of gemcitabine, 5-FU (24h CI), folinic acid and cisplatin for patients with inoperable esophageal cancer
Authors: J. M. Stieler, A. Hilbig, U. Pelzer, L. Roll, B. Dörken, H. Riess, H. Oettle
Journal: Journal of Clinical Oncology (2006)

4066 Background: Standard therapy for inoperable esophageal cancer is a combination of cisplatin and 5-FU combined with radiation for locally advanced stages. As gemcitabine shows synergy with cisplatin and 5-FU, we evaluated the combination of cisplatin 30 mg/m 2 (90 min), Gemcitabine 1000 mg/m 2 (30 min), FS 200 mg/m 2 (30 min) and 5-FU 750 mg/m 2 24h CI) d1,8 q d22 for patients with inoperable esophageal cancer. For locally advanced stages, patients received sequential radiochemotherapy with 5-FU CI. Methods: 89 (75 m/14 w) pts. were included into this multicentrical phase 2 study. 58 had SCC, 30 AC, 1 pt. had undifferentiated carcinoma. Median age was 61 (22–86), Median KI 90 (60–100). 2 pts. had stage IIa, 4 stage IIb, 30 stage III, 16 stage IVa and 37 stage IVb. Results: 71 pts. are so far evaluable for response and 84 for toxicity. 2 pts. (2.8%) had CR (1 pathologically confirmed), 27 pts. had PR (38.1%), 33 pts. had SD (46.5%) and 9 pts. had PD (12.6%) as best response. MS was 10.7 months (13.1 for stage II/III and 9.1 for stage IV). Median TTP was 6 months, and PFS was 6 months. Observed toxicity was low and predominantly hematologic with Leukopenia Grade III/IV in 10% of cycles, Hb Grade III/IV in 5.3% of cycles and Thrombopenia Grade III/IV in 2.4% of cycles. Conclusion: This regimen is well tolerable and can easily be applied on an outpatient base. The remission rates and survival data are within the range previously reported in other phase II studies. No significant financial relationships to disclose.
Tumor characteristics and patient outcomes in ductal compared with lobular carcinoma.
Authors: S. Nour, M. Mokri, H. Afshin Alavi, S. Shariat Torbaghan, M. Atri, K. Visvanathan
Journal: Journal of Clinical Oncology (2010)

10614 Background: Clinicopathological features of invasive ductal and lobular carcinoma suggest that they may be etiologically different. However, data on prognostic markers such as cathepsin D have been less consistent. Therefore we examined the association between protein expressions of p53, cathepsin D and both disease free survival (DFS) and overall survival (OS) in women with invasive ductal and lobular breast cancer. Methods: The study population included 2,422 consecutive incident invasive breast carcinoma cases diagnosed between January 1998 and June 2008 at Days Hospital in Tehran by a single breast surgeon. Protein expression of p53 (Dako) and cathepsin D (Dako) were assessed by immunohistochemistry (IHC) prospectively from formalin-fixed paraffin breast tumor tissue. The odds of p53 and cathepsin D expression by tumor type, recurrence and death among ductal and lobular carcinoma was determined using logistic regression. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were calculated for DFS and OS adjusting for known prognostic markers including age, stage, treatment, Ki67. Results: Median follow up for the cohort was 31 (0-144) months. Lobular carcinoma constituted 8% (n = 168) of the total invasive breast cancer patients (n = 2,422). The mean age of the lobular carcinoma was 51 years (range: 26-75) compared to 49 years (range: 20-85) for invasive ductal carcinoma (p = 0.004). There were no significant differences in grade and stage between the two groups. P53 was less likely to be expressed in invasive ductal carcinoma (OR = 0.44, 95% CI: 0.30-0.65) while cathepsin D was more likely to be expressed in invasive lobular carcinoma (OR = 1.51, 95% CI: 0.97-2.34). There was no difference in recurrence or mortality among ductal or lobular carcinoma based on P53 positivity. However cathepsin D expression was associated with increased recurrence (HR = 1.60, 95%CI 0.93-2.27) and mortality (HR = 3.70, 95% CI:1.84-7.42). Conclusions: Differences in P53 expression and cathepsin D expression exist between invasive ductal and lobular carcinomas. Further cathepsin D was associated poor prognosis in invasive ductal carcinoma. No significant financial relationships to disclose.
OP0201 Exomewide Association Study of Ankylosing Spondylitis Identifies Additional Coding Region Genetic Associations with as and Strengthens Evidence of Shared Genetic Background with Inflammatory Bowel Disease
Authors: P.C. Robinson, P. Leo, J.J. Pointon, J. Harris, K. Cremin, L.A. Bradbury, S. Stebbings, A. Harrison, E. Duncan, P. Wordsworth, M.A. Brown
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Ankylosing spondylitis is a common chronic immune-mediated arthropathy affecting primarily joints of the spine and pelvis. The condition is strongly associated with HLA-B27, and association with other HLA variants has been demonstrated. In addition to these effects, to date 30 non-MHC loci have been associated with the disease, and significant additional heritability remains. <h3>Objectives</h3> To identify further genetic variants associated with ankylosing spondylitis. <h3>Methods</h3> We undertook a study of ankylosing spondylitis using 5,040 patients and 21,133 healthy controls using the Illumina Exomechip microarray. This assays all coding variation in the genome along with genomewide association hits and major histocompatibility tag single nucleotide polymorphisms. Analysis was carried out with logistic regression using principal component analysis to correct for any population stratification. <h3>Results</h3> Novel associations achieving genomewide significance were found in <i>USP8</i> (<i>P</i> =3.5 x 10<sup>-52</sup>, OR =1.97) and <i>CDKAL1</i> (<i>P</i> =1.8 x10<sup>-8</sup>, OR =1.18). Suggestive associations with common variants in <i>FAM118A</i> (<i>P</i> =5.9 x 10<sup>-8</sup>, OR =1.16), <i>C7orf72</i> (<i>P</i> =1.9 x 10<sup>-7</sup>, OR =1.14) and <i>FAM114A1</i> (<i>P</i> =1.4 x 10<sup>-6</sup>, OR =1.14) were also found. A low frequency association (MAF cases/controls: 0.0044/0.0017) was found in patatin-like phospholipase domain containing 1 (<i>PNPLA1)</i> at a suggestive level of significance (<i>P</i> =1.5 x 10<sup>-6</sup>, OR =2.6). <h3>Conclusions</h3> This study describes novel genetic associations with ankylosing spondylitis. Three of the variants have been previously associated with inflammatory bowel disease, and one variant with low hip bone mineral density. These findings further increase the evidence for the marked similarity of genetic risk factors for IBD and AS, consistent with the two diseases having very similar aetiopathogenesis. <h3>Disclosure of Interest</h3> None declared
Outcomes of a two-drug chemotherapy regimen for retinoblastoma
Authors: P. E. Zage, J. Weinstein, M. B. Mets, J. B. Lasky, S. Goldman
Journal: Journal of Clinical Oncology (2006)

9064 Background: Retinoblastoma is the most common intraocular tumor of childhood in the U.S. and has an overall survival rate of over 90%. The optimal treatment regimen for intraocular retinoblastoma has not yet been established. Current treatment regimens for retinoblastoma involve combinations of chemotherapy with focal therapy. We report here the results of an institutional retinoblastoma treatment trial to determine the vision- and globe-salvage rates and associated toxicity of a regimen combining carboplatin and etoposide with focal therapy. Methods: 29 patients diagnosed with either bilateral retinoblastoma or unilateral retinoblastoma in infants under 12 months of age were treated prospectively with carboplatin and etoposide plus focal therapy between 1992 and 2004 at Children’s Memorial Hospital in Chicago. External beam radiation therapy (EBRT) and enucleation were utilized as needed. Results: The regression rate after 6 cycles of chemotherapy was 85.4%. 7 eyes received EBRT and 22 eyes were enucleated. The overall vision salvage rate without EBRT was 50%, with a vision salvage rate of eyes with Reese-Ellsworth (R-E) groups I-IV tumors of 82.6%. The vision salvage rate of eyes with R-E group V tumors was 20%. The vision salvage rate for eyes with Murphree groups A and B was 77.3%, but only 26.9% for groups C and D. The 10-year estimated EBRT/enucleation-free survival rate was 47%. There were no treatment related mortalities and minimal long-term side effects, with one case of secondary malignancy. Conclusions: The combination of carboplatin and etoposide with focal therapy is a well-tolerated regimen that avoids EBRT and has acceptable vision salvage rates for R-E groups I-IV and Murphree groups A and B retinoblastoma. Patients with R-E group V and Murphree groups C and D retinoblastoma do less well with chemotherapy and require more intensive or novel approaches to therapy. No significant financial relationships to disclose.
Is boost therapy necessary in the treatment of DCIS?
Authors: T. B. Julian, S. R. Land, Y. Wang, F. Vicini, D. Arthur, E. P. Mamounas, J. P. Costantino, N. Wolmark
Journal: Journal of Clinical Oncology (2008)

537 Background: Whole breast irradiation therapy following lumpectomy for invasive breast cancer (IBC) and non-invasive breast cancer (DCIS) significantly reduces the risk of local recurrence. Boost radiation therapy to the tumor bed has been proven to additionally lower the risk of recurrence for IBC. The benefit of boost therapy in patients with DCIS is less certain. We carried out a review of NSABP B-24 to assess the benefit of boost therapy in this randomized trial. Methods: 1,804 women with DCIS were randomized in NSABP B-24 following lumpectomy and radiation therapy to placebo (902) or tamoxifen (902). Whole breast irradiation therapy (50 Gy) was mandatory. Boost radiation therapy was optional. 1,569 patients (86.97%) were identified as having complete data for analysis. 692 of these patients received boost therapy ranging from 1 Gy -20 Gy with 81.5% receiving 10 Gy. Median follow-up time was 14.2 years for the boost group and 14.3 years for the non-boost group. Results: Patients receiving a boost had a significantly higher rate of involved margins (21.0% vs. 14.7%, p=0.002) and comedo necrosis (52.1% vs.45.3%, p=0.008). Margin status (HR: 2.31, p=0.0026), comedo necrosis (HR: 1.5, p=0.031), and age (HR: 0.96, p<0.001) were significant predictors of ipsilateral breast tumor recurrence (IBTR). Boost had no significant impact on IBTR (HR:1.12, p=0.69). There was no significant interaction between boost and treatment (HR: l.04, p=0.91), boost and margin status (HR: 0.77, p=0.52), and boost and comedo necrosis (HR: 0.74, p=0.31). The lack of boost interaction was true for both invasive and non-invasive IBTR. Conclusions: In this unplanned analysis of NSABP B-24 the addition of boost radiation therapy was not found to be of value in reducing the recurrence of invasive or noninvasive breast cancers for patients with DCIS. No significant financial relationships to disclose.
Identification of tyrosinase polymorphisms for use in melanoma risk assessment.
Authors: E. Pervolaraki, I. Lobach, I. Belitskaya-Levy, H. Ostrer, J. D. Goldberg, D. Polsky, R. L. Shapiro, R. S. Berman, I. Osman, P. Manga
Journal: Journal of Clinical Oncology (2010)

8570 Background: Most skin cancer-related deaths are due to malignant melanoma. Risk assessment criteria for melanoma currently include skin phenotype, family and sun exposure history, factors that are subject to observer and recall bias. Genetic markers of susceptibility have been identified in association studies; however little progress has been made in developing them to improve screening and identification of individuals at risk of melanoma. Tyrosinase (TYR), a known susceptibility gene and a determinant of skin pigmentation, was thus investigated further to characterize its association with melanoma susceptibility and to identify markers which can be used in a risk assessment model. Methods: The cohort consisted of 326 individuals diagnosed with melanoma and 400 control subjects. TYR was interrogated using fifteen tag single nucleotide polymorphisms (SNPs) spanning the gene and statistical association tests performed. Additionally, ancestry informative markers were utilized to correct for population genetic sub-structure. Haplotype analysis was performed to determine if specific regions of the gene contributed more significantly to susceptibility. Coding regions of the gene are currently being sequenced and identified variants will be tested for impact on enzymatic function. Results: Of the 15 SNPs, 8 were associated with melanoma; 4 with decreased risk (Odds ratios 0.41-0.71) and 4 with increased risk (Odds ratios 1.43-1.96). SNPs localized to 2 regions of the gene (spanning exon 1 to intron 2 and intron 3 to 4) with markers of increased as well as decreased susceptibility present in both areas. With the exception of one coding region variant, SNPs were localized to introns. Conclusions: SNPs localized to TYR may serve as useful biomarkers for determining susceptibility to melanoma. We are currently sequencing the gene in our population in order to identify additional and potentially more potent markers of melanoma susceptibility. Coding region variants are being characterized for their effect on protein stability and enzyme activity such that functional active variants (most likely to affect susceptibility to melanoma) can be identified and assessed for their utility in melanoma risk assessment. No significant financial relationships to disclose.
Breast cancer patients' rights: How can they be respected in Iran?
Authors: Azadeh Joulaee, Soodabeh Joolaee, Naser Bahrani, Maryam Kadivar, Mojgan Kalantari
Journal: Journal of Clinical Oncology (2012)

81 Background: The revolutionary concept in breast cancer diagnosis and treatment has significantly changed many aspects of cancer treatment in favor of patients' rights. The best useful targeted treatment is offered to them with the least harm and invasion. As the most common cancer, breast cancer incidence is 24/100, 000 or one-fourth of all new cancers. The aim of this study is to compare the international rights for breast cancer patients with actual situation in Iran. Methods: All published data in Iran are reviewed since 2001 to 2012 to see the actual care in Iran. Codification of new radiology, surgical and pathologic procedure and insurance coverage are searched through available national references. These data are compared with international references. Results: Diagnosis is done by excisional/incisional biopsy or frozen section. Trucut biopsy is done in a low minority of cases. Insurance system does not cover vacuum assisted biopsy. Only mastectomy and axillary dissection are accepted by insurance. No codification exists for conservative surgery, oncoplastic surgery and sentinel node biopsy and the rate for these surgeries are low. Breast reconstruction, conservative surgery as bilateral mammoreduction, and symmetrization of controlateral breast are considered as cosmetic surgery with no coverage. The majority of cases are treated in general surgical wards. There are very few breast nurses and few centers for rehabilitation, lymphedema treatment, and psychological support of survivor. Conclusions: The ministry of health insists on full respection of the patient’s rights in medical practice. The new rights of breast cancer patients based on new treatment strategy are not highlighted in Iran. Valid evidence must be provided for policy makers about the rights of these vulnerable patients to consider them in Iranian health care delivery system. Specialized breast unit can improve significantly the quality of breast cancer care toward the patients' right. Pre-operative confirmation of cancer by trucut biopsy seems to be the key point. This gives the patient the opportunity to know more about the disease and to search for the best therapeutic plan according to international guideline.
Antigen presenting cell based immunotherapy targeting HER2/Neu positive solid tumors: Results of a phase 1 study of APC8024
Authors: P. Peethambaram, S. Alberts, K. Rinn, L. A. Jones
Journal: Journal of Clinical Oncology (2004)

2528 Background: APC8024 is a cellular vaccine therapy derived from autologous antigen (Ag) presenting cells (APC) loaded ex vivo with the HER2/Neu tumor Ag HER500/GM-CSF, designated BA7072. The BA7072 Ag consists of recombinant sequences of the extracellular and intracellular domain of HER2 fused to GM-CSF Methods: Patients (pts) with metastatic solid tumors that were HER2 (+) were eligible. Autologous mononuclear cells were collected and APC precursors were isolated and then loaded with the fusion protein BA7072. The concentration of BA7072 in culture was either 10μg/ml or 40μg/ml. The loaded APCs were collected, fresh cells were reinfused at Week 0, and aliquots were cryopreserved. Thawed cells were then reinfused at Weeks 2 and 4. A total of 1 x 109 cells were reinfused at each time point. Pts were followed without further therapy until either Week 52 or documented disease progression, whichever occurred first. Immune response (IR) was evaluated at Weeks 0, 4, 8, and 16. Results: Ten pts (8 females, 2 males) received vaccine therapy and were evaluable. The mean age was 55 (range 34–76). All pts had advanced, metastatic disease and had received a mean of 3 prior chemotherapy regimens (range 0–6). All pts were HER2/Neu positive (1–3+) by IHC. Cancer types included ovarian (4), colorectal (3), and breast (3). The treatment was generally well tolerated. The adverse events (AE) most frequently associated with APC8024 were fatigue (n=5), rigors (n=5), and pyrexia (n=2), all of which were Grade 1–2. All higher grade and serious AEs were judged to be unrelated to the therapy. An antigen specific T cell response, as measured by IFNγ ELISPOT and T cell proliferation, was induced after treatment compared to baseline (ELISPOT P=0.0153, Proliferation P<0.0001). Based on the investigator's assessment, 2 subjects had stable disease for 16 and 24 weeks. Both subjects had Stage 4 ovarian cancer, and had been heavily pretreated. Conclusions: APC8024 was a safe and well tolerated cellular vaccine therapy in this Phase 1 study. The robust T cell IR data supports further evaluation of administration of frozen/thawed product. Phase 2 studies in breast cancer are planned. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Dendreon Corp. Dendreon Corp. Dendreon Corp.