tbuckley/cabot-search huggingface dataset:
A randomized phase II, open-label trial of orally administered SAR302503 in patients with polycythemia vera (PV) or essential thrombocythemia (ET) who are resistant or intolerant to hydroxyurea.
Authors: Ayalew Tefferi, Jorge E. Cortes, Andreas Hochhaus, Jean-Jacques Kiladjian, Ruben A. Mesa, Animesh Dev Pardanani, Claudia Lebedinsky, Frank Neumann, Karl Hsu, Alessandro M. Vannucchi
Journal: Journal of Clinical Oncology (2012)

TPS6641 Background: Hydroxyurea is widely used to treat patients with high-risk PV and ET. However, some patients are either clinically resistant to hydroxyurea or have unacceptable side effects, supporting the need for active therapeutic options in this setting. SAR302503 is an orally administered selective JAK-2 inhibitor that reduced symptom burden and provided a durable clinical benefit, including a reduction in the JAK2V617F allele burden, with an acceptable safety profile in a Phase 1/2 trial of patients with primary myelofibrosis (MF), post-PV MF, or post-ET MF (J Clin Oncol 2011;29:789; Pardanani, ASH 2011; Abs 3838). Based on the results in MF, in October 2011 we initiated a Phase 2 trial to evaluate SAR302503 for the treatment of patients with PV and ET who are resistant or intolerant to hydroxyurea (NCT01420783; ARD12042). Methods: Eligibility criteria include age of at least 18 years, ECOG PS 0–2, and hydroxyurea resistant PV or ET as defined by European LeukemiaNet Consensus Criteria (Blood 2009;113:4829). Patients are being randomized (1:1:1) to receive 100, 200, or 400 mg of SAR302503 orally once daily in consecutive 28-day cycles for at least 8 cycles in the absence of progression or unacceptable toxicity. The primary end points will be assessed after the completion of 8 cycles and are: for PV, the proportion of patients maintaining a hematocrit below 45% without phlebotomy for at least 3 months; for ET, the proportion of patients with a platelet count lower than 400 × 10 9 /L for at least 3 months. Secondary objectives include safety, response rate, pharmacokinetics, pharmacodynamics as measured by JAK2V617F allele burden and STAT3 phosphorylation inhibition, assessment of disease-related symptoms, and quality of life. Enrollment of the planned total of 90 patients is ongoing at approximately 45 sites globally. Twelve patients have been enrolled as of January 2012.
Long-term result of a multicenter clinical study of cetuximab combined with intensity modulated radiotherapy (IMRT) plus concurrent chemotherapy in locoregionally advanced nasopharyngeal carcinoma (NPC).
Authors: Chun-yan Chen, Chong Zhao, Li Gao, Jin-yi Lang, Jian-ji Pan, Chao-su Hu, Feng Jin, Ren-sheng Wang, Conghua Xie, Tongyu Lin, Tai-xiang Lu
Journal: Journal of Clinical Oncology (2015)

e17020 Background: To evaluate the long term treatment outcome of cetuximab combined with IMRT + concurrent cisplatin in patients with locoregionally advanced NPC in a multicenter clinical study. Methods: Primary NPC patients with stage III - IVb disease were enrolled. The planned dose of IMRT to GTV was 66 - 75.9 Gy in 30 - 33 fractions. Cisplatin and cetuximab were given concurrently. The treatment response was evaluated according to RECIST 1.0 criteria, and adverse events (AEs) were graded according to CTCAE v3.0. Results: From July 2008 to April 2009, 100 patients were enrolled. Besides two cases of mucositis, no other grade 4 AEs were observed during treatment, and no toxic death was observed. With a median follow-up of 4.9 years, 5-year OS, disease-free survival, relapse-free survival (RFS), and distant metastasis-free survival (DMFS) was 82.1%, 69.0%, 74.9% and 75.2%, respectively. Multivariate analysis showed that only masticator space invasion was the prognostic factor for OS (p = 0.0232, HR = 6.64, 95%CI: 1.295～34.039). Within the follow-up period, nine cases of recurrence at the nasopharynx cavity and five at cervical lymph nodes occurred. No statistically significant difference existed among clinical stage III, IVa and IVb for OS or RFS. Distant metastasis occurred in six patients including liver, lung and bone metastasis. For DMFS, only clinical stage was with marginal significance as the prognostic factor (p = 0.0908, HR = 3.06, 95%CI: 0.837～11.161). Long-term AEs of this combined modality treatment mainly consisted of xerostomia, hearing loss, tympanitis, cervical fibrosis, trismus and radiation encephalopathy, etc. Dry mouth and hearing loss were observed in 74% and 57% patients, respectively. Only 12% patient experienced trismus. The incidence of radiation-related encephalopathy was 10%. Conclusions: For locoregionally advanced NPC, the combined treatment modality of IMRT + concurrent chemotherapy + cetuximab was well tolerated. Long-term OS, loco-regional control rate and DMFS at 5 year were very encouraging, with no significant difference among different clinical stage. Clinical trial information: NCT00700440.
Intratumoral heterogeneity in colorectal cancer: Can histology be used as a guidance for molecular testing?
Authors: Xavier Sagaert, Sabine Tejpar, Linde Desmedt, Marijke Spaepen, Gert Matthijs, Daan Andel
Journal: Journal of Clinical Oncology (2017)

611 Background: Intratumour heterogeneity is a key challenge in colorectal cancer management. We have recently shown high levels of morphologic heterogeneity in microsatellite unstable (MSI) colorectal tumours (CRC). In this study we verified whether morphologic intratumour heterogeneity can be used as a guidance to test for molecular heterogeneity. Methods: 15 MSI CRCs tumour, characterized by a heterogenous morphology, were selected together with the associated metastasis. Macrodissection of the distinct morphologic tumour components was followed by MSI testing according to the Bethesda guidelines and Sanger sequencing for BRAF V600E mutations. In addition, 2 MSI CRC underwent macrodissection of the distinct morphologic components, followed by nanostring ncounter analysis. Results: MSI status varies between MSI-H and MSI-L in the primary tumours and 35% of the metastasis of MSI-H primary tumours presented as MSI-L or MSS. BRAF mutations status was constant throughout the primary tumours, but two BRAF mutated tumours presented with a BRAF wild type metastasis. Nanostring analysis revealed that ùorphologically identical clones clustered separately from tumour clones with a different morphologic display. Conclusions: Morphologically heterogeneous tumour compartments have less related gene expression profiles, linking morphologic homogeneity to molecular homogeneity. Our findings support the hypothesis that morphologic heterogeneity reflects molecular intratumour heterogeneity and can be used as a guidance for molecular testing of colorectal cancers.
Regional variation in treatment costs and survival for elderly patients with myelodysplastic syndromes.
Authors: Xiaomei Ma, Rong Wang, Jessica B. Long, Heather Taffet Gold, Stephanie Halene, Cary P. Gross
Journal: Journal of Clinical Oncology (2012)

6628 Background: Myelodysplastic syndromes (MDS) occur primarily in the elderly (≥65 years). The expected 5-year cost for an elderly MDS patient tops $63,200 in 2009 US$. This study assessed regional variation in the cost of care and survival for elderly MDS patients. Methods: Using the Surveillance Epidemiology and End Results–Medicare data, we identified primary MDS patients aged 66-99 years diagnosed from 2001-2007, had continuous fee-for-service coverage for Parts A and B, and had no history of other cancer. We assigned patients to Dartmouth Atlas of Health Care Hospital Referral Regions (HRRs) based on their residence at time of diagnosis. We also selected controls from a 5% sample of Medicare beneficiaries without cancer and matched controls 1:1 to patients by HRR, age, sex, pre-diagnosis cost and comorbidity. All Medicare claims through 2009 were tallied, and MDS-related costs were defined as the difference between the payments for a patient and a matched control. Results: With 6244 patients in 73 HRRs, the average 3-year MDS-related cost varied across HRRs, ranging from $12,900 to $83,600 (2009 US$). Patients in high-spending regions had more comorbidities and higher Medicare costs before diagnosis and were more likely to be racial minorities and live in lower-income areas. Three-year survival ranged from 13.0% to 62.1%. However, there was no significant correlation between 3-year costs and 3-year survival (ρ=-0.06, p=0.61). The hazard ratios (HR) for higher spending regions compared to the lowest-expenditure region were near 1, after controlling for covariates including MDS subtype (2 nd quartile: HR=1.03, 95% CI: 0.94-1.12; 2 nd quartile: HR=1.04, 95% CI: 0.95-1.14; 4 th quartile: HR=0.98, 95% CI: 0.90-1.08). Conclusions: We observed considerable regional variation in Medicare expenditure on elderly MDS patients during the first 3 years post-diagnosis. However, patients in higher cost regions had similar 3-year survival to patients in lower cost regions. Given the substantial economic burden of MDS and Medicare’s current fiscal challenges, it is important to further assess the factors associated with higher regional costs and to improve the care of MDS patients in a cost-efficient way.
포스터발표 : 컨벤션홀 특설 발표장 ; 사염화탄소로 급성 간손상이 유발된 흰쥐에서 태반유래 줄기세포 이식의 치료적 효과
Authors: 송한얼, 황성규, 김기진, 송지예, 신규선, 오주희, 임규성, 이민재
Journal: Clinical and Molecular Hepatology (2008)
EGFR-TKI benefit for NSCLC patients with EML4-ALK rearrangement.
Authors: Zhijie Wang, Jie Wang, Yi Long Wu, Hua Bai, Xu-Chao Zhang, Tongtong An, Minglei Zhuo, Jianchun Duan, Lu Yang, Meina Wu
Journal: Journal of Clinical Oncology (2012)

e18035 Background: EML4-ALK rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). To identify the biological profiles of these patients, we examined the clinico-pathologic characteristics and treatment outcomes of NSCLC patients based on EML4-ALK and EGFR mutations. Methods: Patients with stage IV NSCLC were screened for EML4-ALK rearrangement and EGFR mutations at Peking University Cancer Hospital. EML4-ALK was identified using fluorescent in situ hybridization (FISH) confirmed by immunohistochemistry (IHC), and EGFR mutations were determined using denaturing high-performance liquid chromatography (DHPLC). Results: Of the 151 patients screened, 113 had complete follow-up data as an analysis set. The incidence of EML4-ALK was 9.7% (11/113) using FISH, in which 10 cases had sufficient specimens for IHC confirmation and all were positive. Overall, EML4-ALK and EGFR mutations were largely mutually exclusive (p = 0.033), although two patients harbored concurrent mutations. EML4-ALK rearrangement was associated with resistance to EGFR-TKIs compared with the EGFR mutant type and WT/Nonrearrangement type (p = 0.001 for objective response rate; p = 0.004 for disease control rate; p = 0.021 for progression-free survival [PFS]). In terms of patients who received platinum-based doublet chemotherapy, no significant differences were observed in PFS between the EML4-ALK type, EGFR mutant type, and WT/Nonrearrangement type. Moreover, two patients with concurrent EML4-ALK and EGFR mutations had superior PFS after EGFR-TKI compared with single EML4-ALK-rearranged patients. Conclusions: This study presents several biological features of EML4-ALK NSCLC. It is largely mutually exclusive to EGFR mutations, resistant to EGFR-TKI. Coexistence of ALK rearrangement and EGFR mutation in patients with advanced NSCLC might represent a separate genotype with unique biological characteristics.
CDKN2A-deletion to predict relapse in adult B-cell acute lymphoblastic leukemia (B-ALL).
Authors: Preet Paul Singh, Rhett Ketterling, Mark Robert Litzow, Ayalew Tefferi, Mrinal M. Patnaik, Animesh Dev Pardanani, William J. Hogan, Louis Letendre, Michelle A. Elliott, Kebede Begna, Alexandra P. Wolanskyj, Aref Al-Kali
Journal: Journal of Clinical Oncology (2012)

6614 Background: CDKN2A locus on chromosome 9p21 is implicated in altered molecular pathways leading to leukemogenesis as a tumor suppressor by inhibiting the proliferative kinases CDK4/CDK6 and blocking the cell-cycle division during G1/S phase. Deletion of CDKN2A locus is frequently seen in ALL, although prognostic significance remains unclear. Methods: Retrospective chart review at Mayo Clinic between 8/2005-11/2011 was performed on adult B-ALL patients (pts) who underwent fluorescent in situ hybridization (FISH) studies at diagnosis. Survival estimate was calculated using Kaplan-Meier statistics. Event-free survival (EFS) was defined as time between diagnosis and induction failure, relapse, or death, while overall survival (OS) as time between diagnosis and death Results: Out of 27 pts who had FISH studies for CDKN2A, 15 (56%) pts had CDKN2A deletions (8 homozygous/7 hemizygous), while 12 (44%) pts had diploid cytogenetics (none had abnormalities of MLL, bcr/abl fusion or CDKN2A deletion on FISH). There was no significant difference in median age, gender, WBC, hemoglobin, platelet count, LDH or complete remission (CR) rate (p=0.924) between the two groups. CDKN2A-deleted pts had higher circulating blasts (34% vs 16%, p=0.017). Of 13 CDKN2A-deleted pts, chromosome 9p was intact in 9 (69%) pts using routine cytogenetics. In the CDKN2A-deleted group, allogeneic stem cell transplant (ASCT) was performed in 7 (47%) pts at first CR and 1 at second CR. Four of 15 (27%) CDKN2A-deleted pts also had bcr/abl fusion. Five-year EFS was poorer in CDKN2A-deleted pts compared to normal FISH group (22% vs 60%, p=0.042), while 5-year OS was 72% vs 60% (p=0.308), respectively. Excluding the 4 bcr/abl fusion pts, 5-year EFS was still statistically significant (p=0.008). In the CDKN2A deleted group, both 5-yr EFS (80% vs 0%, p=0.006) and OS (100% vs 42%, p=0.016) were significantly superior in pts who received ASCT. Conclusions: CDKN2A deletions predict earlier relapse in pts with B-ALL. Majority of 9p abnormalities were only found by FISH testing and missed by conventional cytogenetics. In CDKN2A deleted pts, ASCT gave overall survival advantage. Further investigation through larger cohorts of pts is needed to validate these findings.
John Kenyon (“Ken”) French Mason
Authors: Ned Stafford
Journal: BMJ (2017)

Long serving Royal Air Force pathologist who later helped pioneer medical jurisprudence



Credit: University of Edinburgh

Ken Mason’s distinguished medical and medical jurisprudence career, which spanned 74 years, can be divided into three main parts.

He spent the first part serving for three decades as a forensic pathologist in the UK’s Royal Air Force. Focusing on aviation medicine, he rose through the ranks to become group captain and director of the RAF’s aviation and forensic pathology department and was regularly summoned to investigate aviation accidents. In recognition of his contributions to the forensic pathology of aircraft accidents, Mason in 1973 was awarded a Commander of the Order of the British Empire (Military Division).

“He was very much a pioneer of aviation crash pathology,” says Basil Purdue, formerly of the forensic medicine unit at the University of Edinburgh and now an independent forensic pathologist on the Home Office register.

In 1973, at the age of 53, Mason retired from the military and began the second part of his career, accepting an appointment as Regius professor of forensic medicine at the University of Edinburgh. He was well suited for academia. A dedicated and gifted teacher, he was admired not only by his students over the years but also his colleagues.

“He was an excellent lecturer,” says Purdue, “capable of captivating an audience with a fascinating extempore …
Impact of socioeconomic status on treatment outcome in patients with advanced esophagogastric cancer in Northern Ireland
Authors: Y. Manikyam, G. G. Hanna, R. J. Harte, P. G. Henry, R. F. Houston, M. M. Eatock
Journal: Journal of Clinical Oncology (2009)

e20531 Background: The survival advantage for combination chemotherapy in advanced gastroesophageal adenocarcinoma is well documented. Epirubicin and cisplatin in combination with either 5FU (ECF) or capecitabine (ECX) result in response rates of 35–46% and a median survival of around 9 months in RCT. We report the impact of socioeconomic status on the outcome of ECF and ECX treatment in advanced gastroesophageal cancer patients in Northern Ireland between 2000 and 2007. Methods: All patients with advanced esophageal (O), gastric (G), or esophagogastric junction (OGJ) adenocarcinoma, receiving palliative chemotherapy from January 2000 to August 2007, were identified from our institutional database. Baseline demographics, clinical characteristics, treatment details, and clinical outcomes were recorded. Patients receiving chemotherapy in a clinical trial were excluded. Survival was estimated using the Kaplan-Meier method. Deprivation was assessed using the patient's home address deprivation index (DPI) (Northern Ireland Multiple Deprivation Measure 2005; May 2005. Northern Ireland Statistics and Research Agency. www.nisra.gov.uk ). Results: 274 eligible patients (m=200, f=74, O=114, OGJ=19, G=141) were identified. Median age was 62 years (range 22–83). 172 (62.8%) had ECOG performance status 0 or 1. 231 patients (84.3%) had metastatic disease, 43 (15.7%) had locally advanced disease. 216 (78.8%) patients received ECF and 58 (21.2%) patients received ECX. Overall median survival was 7.3 months. Treatment response and performance status were strong predictors of survival, however disease extent did not influence survival. Median survival was significantly longer in those with DPIs in the upper two quintiles than the lower 3 quintiles (9.5 months vs. 6.8 months, p=0.032). Conclusions: Outcomes achieved with palliative ECF/ECX treatment are similar to the reference clinical trials. Socioeconomic deprivation is significantly associated with reduced survival in this group of patients and is unrelated to disease extent at presentation; however it may be related to nutritional status and comorbidity and requires further investigation. No significant financial relationships to disclose.
Prognostic value of miR-196, IDO, and AXL in patients (p) with localized gastrointestinal stromal tumors (GIST).
Authors: Jose Luis Cuadra-Urteaga, Carmen Balana, Olatz Etxaniz, Imane Chaib, Jose Luis Ramirez, Edwin Mejia, Isabel Ojanguren, Anna Estival, Ana Munoz, Carolina Sanz, Alberto Indacochea, Sara Ahlal, Laia Vila, Maria de los Llanos Gil, Iris Teruel, Max Hardy, Rafael Rosell
Journal: Journal of Clinical Oncology (2014)

10553 Background: GIST is the most common gastrointestinal sarcoma. Miettinen criteria (Mc) define the risk of recurrence. Overexpression of miR-196 has been associated with high risk of relapse, metastasis and poor survival. Overexpression of AXL and IDO have been related to resistance to imatinib mesilate (IM). To date, the prognostic value of these molecular markers has not been examined. Methods: We retrospectively reviewed 40 p with localized GIST diagnosed between 2003 and 2012 in a single institution. Clinical and pathological variables and the expression levels of miR-196, AXL and IDO were correlated with outcome. Results: 52.5% of p were female; mean age was 59.3 years. GISTs were located mainly in the stomach (50%) and small intestine (42.5%). 67.5% were spindle cell tumors; 70% had <5 mitoses per 50 high-power fields. Risk of relapse was high for 45% of p. The capsule was broken in 5 p, and resection was incomplete in 2. cKIT mutations were present in exon 9 in 17.5% of p and in exon 11 in 62.5%. Adjuvant IM was administered in 5 p. 22.5% of p relapsed. Median progression-free survival (PFS) was 39.5 months (m) (95% CI, 7-201 m). A negative effect on PFS was observed for Mc high risk (P=0.001), cKIT mutation at exon 9 (P=0.013), and a broken capsule (P=0.034). Overexpression of miR-196 was associated with shorter PFS in all patients (P=0.001) and in the subgroups of p with Mc high risk (P=0.023) or with cKIT exon 9 mutations (P=0.012). No correlation was observed between expression of AXL or IDO and PFS. Median overall survival was not reached. Conclusions: Among p with localized GIST, those with Mc high risk, a broken capsule, or cKIT mutations in exon 9 had shorter PFS. Overexpression of miR-196 has emerged as a potential molecular marker of high risk of recurrence in GiST p which merits further investigation.
Therapy for chemopretreated metastatic urothelial cancer (mUC) with the antibody-drug conjugate (ADC) sacituzumab govitecan (IMMU-132).
Authors: Scott T. Tagawa, Allyson J. Ocean, Elaine Tat Lam, Philip James Saylor, Aditya Bardia, Julio Hajdenberg, Alicia Katherine Morgans, Kevin Kalinsky, Matthew Galsky, Bishoy Faltas, Ana M. Molina, Emerson A. Lim, Pius Maliakal, Robert M. Sharkey, Boyd Mudenda, William A. Wegener, David M Goldenberg
Journal: Journal of Clinical Oncology (2017)

327 Background: Patients (pts) with mUC pre-treated with platinum-containing chemotherapy have limited therapeutic options, with checkpoint-inhibitor immunotherapy (IO) responses in a minority of pts. We present an interim update of the safety and activity of sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 ADC, as therapy for chemotherapy-pretreated mUC pts (ClinicalTrials.gov, NCT01631552). Methods: We enrolled 32 pts with mUC and ECOG PS 0-1 who failed ≥ 1 prior standard therapy (median=3; range, 1-5). IMMU-132 was administered at 8 or 10 mg/kg on days 1 and 8 every 21 days, continued until disease progression (PD) or unacceptable toxicity. Response-evaluable pts received ≥ 2 doses, and had ≥ 1 post-baseline response assessment. Results: Twenty-five pts [median age 68 yrs (range: 50-91), 24 males] are currently assessable for safety and response; 23 had prior platinum-containing therapy; 46% had &gt;2 prior therapies; 4 also had IO agents. Sites of metastases included liver (N=4; 16%), lungs (N=7; 28%), bone (N=4; 16%), and lymph nodes (N=16; 64%). Pts received a median of 7 cycles (range, 2-23) of IMMU-132. ORR was 36% (9/25) [1 complete (CR) and 8 partial responses (PR)]; 44% (11/25) had stable disease (SD). Further, pts with 1 line of prior chemotherapy had an ORR of 53.8% (7/13), and 16.7% for those with 2 to 5 prior therapy lines. Median PFS for all patients is 7.2 mos (95% CI, 4.9-10.7); median survival is not reached yet. Of the 4 pts with progression after prior IO, there were 1 PR and 2 SDs with IMMU-132. Duration of response for CR/PR pts is currently 5.1 mos (95% CI, 4.1-12.9) and 10/11 pts (5 with ≥ 20% tumor reduction) had stable disease &gt; 4 mos. Grade 4 neutropenia (16%) lasted &lt; 7 days, and non-hematological grade 3 AEs included fatigue (12%) and hypophosphatemia (8%). No treatment-related deaths were observed. Analysis of Trop-2 expression revealed 1+ to 3+ positive staining in 95% of 19 archival patient specimens. Conclusions: With an ORR of 36% and a median PFS of 7.2 months in a heavily pretreated population, these interim results suggest that IMMU-132 is a promising agent as 2 nd line or later therapy for platinum- or IO- pretreated mUC pts. Clinical trial information: NCT01631552.
Granulocyte transfusions in patients with chronic granulomatous disease and refractory infections: The NIH experience
Authors: Beatriz E. Marciano, Elisabeth S. Allen, Cathy Conry-Cantilena, Ervand Kristosturyan, Harvey G. Klein, Thomas A. Fleisher, Steven M. Holland, Harry L. Malech, Sergio D. Rosenzweig
Journal: Journal of Allergy and Clinical Immunology (2017)