tbuckley/cabot-search huggingface dataset:
Treatment patterns and progression-free survival (PFS) in first-line metastatic colorectal (mCRC) patients (pts) on an oxaliplatin-based chemotherapy (OX-t): A Canadian retrospective chart review.
Authors: Petr Kavan, Aline Mamo, Young Soo Rho, Gerald Batist
Journal: Journal of Clinical Oncology (2014)

e14627 Background: Pts with mCRC receiving a first-line (1L) OX-t exhibit a PFS that extends beyond their treatment duration. However, the perception is that neurotoxicity limits OX-t treatment duration and hence the benefit that could ensue. Methods: To quantify these aspects (treatment duration and PFS), a chart review was conducted to investigate real-world PFS observed in these pts. In this retrospective cohort study, we collected first- and second-line (2L) therapy data from 89 unselected mCRC pts who received an OX-t between January 2010 and May 2013. Treatment patterns were captured. As a proxy for clinical PFS, PFS was defined as time from 1L to 2L start, death, lost to follow-up or date of last visit. The time between 1L OX start to 2L FOLFIRI initiation was also recorded, understanding progression would occur prior to 2L FOLFIRI initiation. Results: 60% (54) of pts received mFOLFOX6 (mean: 10 cycles, RDI 92%, average treatment duration of 5.6 months (26 weeks)), 69% (37/54) received bevacizumab (mean: 10 cycles). 40% (35) of pts received XELOX (mean: 7 cycles, RDI 84%, average duration of 5.5 months (25 weeks)), 78% (28/35) with bevacizumab (mean: 5 cycles). Among mFOLFOX6 pts, 18 pts (33%) went on to 2L FOLFIRI, 6 (11%) went on to another 2L therapy. As of January 2014, 19 pts (35%) were still alive and not on 2L, 5 died before 2L (9%) and 6 (11%) were lost to follow-up. Among XELOX pts, the numbers were 8 (23%), 4 (11%), 16 (46%), 6 (17%) and 1 (3%) respectively. Among pts still alive who received mFOLFOX6 and XELOX, 79% (15/19) and 88% (14/16) had a resection of their primary and/or metastatic tumor. Median PFS were 16.0 months (mean 18.2) and 24.0 months (mean 24.0) in mFOLFOX6 and XELOX treated patients respectively. For pts who received 2L FOLFIRI, median interval from 1L start to 2L start was 7.3 months (mean 8.9) in the mFOLFOX6 group and 11.3 months (mean 12.3) in the XELOX group. Treatment durations were similar to the overall group. Conclusions: These results help quantify the treatment benefits that can be expected from an OX-t beyond the specific treatment duration and are aligned with an 8 months median PFS reported by Tournigand 2004.
Trial in progress: A phase II study of second-line FOLFIRI plus panitumumab after first-line FOLFOX plus panitumumab for RAS wild-type colorectal cancer with evaluation of circulating tumor DNA.
Authors: Hiromichi Maeda, Naoki Nagata, Takeshi Nagasaka, Koji Oba, Hideyuki Mishima, Takeshi Kato, Kazuhiro Yoshida, Kei Muro, Junichi Sakamoto
Journal: Journal of Clinical Oncology (2018)

TPS886 Background: The mechanisms underlying the acquired resistance of metastatic colorectal cancer (mCRC) against panitumumab treatment is not fully understood. The efficacy and safety of FOLFIRI with panitumumab as the second-line chemotherapy after failure of FOLFOX with panitumumab treatment has yet to be determined. To address these two points, a multicenter single-arm Phase II clinical trial is being conducted with evaluation of circulating tumor DNA (ctDNA). Methods: The major inclusion criterion is that the patient has refractory measurable tumor that has progressed after the first-line therapy with FOLFOX plus panitumumab. After registration, treatment with the FOLFIRI and panitumumab will be continued in 2-week cycles until disease progression, unacceptable toxicity and/or patients’ refusal. The primary endpoint for this study is six-month progression-free survival (PFS) rate, a simple surrogate endpoint of PFS. According to a clinical trial revealing the median PFS of 4.6 months for FOLFIRI alone and 6.4 months for panitumumab plus FOLFIRI treatment in RAS wild-type patients (Peeters et al. Clin Cancer Res. 2015; 21: 5469-79), we assume the threshold and expected 6-month PFS rate as 35% and 50%, respectively. Under the settings of one-sided alpha = 0.10 and power = 80%, the required sample size is 53 patients. The target number of cases in this study is 55 patients, considering a dropout rate of 5%. The secondary endpoint includes the tumor-related gene mutation status assessed by liquid biopsy. Primary tumor and/or metastatic site tissue samples will be collected by formalin-fixed paraffin-embedded specimens at the time of registration. Blood samples will be collected at 3 time-points: (1) before second-line treatment, (2) at 6 ± 2 weeks after initiation of the treatment protocol, and (3) after confirmation of acquired resistance to this second-line therapy. The multiple evaluation of ctDNA will provide the meaningful information concerning relationship between the tumor resistance against treatment and alterations in gene mutation status. Clinical trial information: UMIN000026817.
An adoptive immunotherapy approach for colorectal cancer (CRC) patients.
Authors: Marco Bregni, Serena del Bue, Paquale Ferrante, Silvia Carluccio
Journal: Journal of Clinical Oncology (2014)

3074 Background: Adoptive T-cell transfer (ACT) refers to an immunotherapeutic approach in which anti-tumor T lymphocytes are identified, grown ex vivo and re-infused into the cancer patients. This strategy was successfully applied in metastatic melanoma and renal cell carcinoma. However, adoptive immunotherapy do not play an important role in the treatment of advanced CRC. We developed an ACT protocol for CRC using as source of tumor antigens the irradiated primary CRC cell lines, captured by dendritic cells (DC) to stimulate in vitro a specific autologus activation of patient’s T cytotoxic lymphocytes (CTL) against tumor. Methods: 78 CRC patients were enrolled. Tumor tissues were obtained at surgery, together with 100 ml of heparinized peripheral blood. Tumors were mechanically dissociated to a single-cell suspension and cultured to obtain a primary cell line from each patient. DCs were generated from monocytes, cultured with recombinant human Interleukin-4 and recombinant human Granulocyte- Macrophage Colony-Stimulating Factor for 6-7 days. Anti-tumor CTLs were elicited in co/micro-cultures using DCs, autologous apoptotic tumor cells and T CD8+ lymphocytes enriched effectors, in presence of weakly irradiated T CD4+ lymphocytes, Interleukin 7 and Interleukin 12, with weekly stimulation. CTLs Interferon-γ (IFN-γ) secretion was assessed by ELISpot assay. Results: Primary tumor cell lines were obtained from 20 out of 78 patients, with a success rate of 25,6%. DCs were generated from 26 patients, and 6 had the corresponding primary tumor cell line. Co/micro-cultures were set up for 6 patients. ELISpot results showed a strong and significant IFN-γ secretion at the third, fourth and fifth stimulations for one patient and at the second for another patient, whereas for three patients a weak secretion was detected during the second and third stimulations. Conclusions: The percentage of success in the establishment of primary colon cell lines was higher than those reported in literature, although the intestinal flora adversely affected their obtainment. The generation of tumor-specific CTLs could be useful for supporting an ACT approach in CRC.
Comprehensive genomic profiling of gallbladder adenocarcinoma and frequent genomic-derived targets of therapy.
Authors: Phil Stephens, Kai Wang, Norma Alonzo Palma, Juliann Chmielecki, Rachna T. Shroff, Chaitanya Churi, Garrett Michael Frampton, Siraj M. Ali, Milind M. Javle, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2014)

4142 Background: Metastatic gallbladder adenocarcinoma (GBCA) has a poor prognosis and systemic therapies are commonly extrapolated from those used in other gastrointestinal malignancies. In this study, next generation sequencing-based comprehensive genomic profiling of 83 clinical GBCA samples was performed to identify genomic-derived targets of therapy for patients with this lethal cancer. Methods: Hybridization capture of 3,769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to ≥ 50ng of DNA extracted from 83 GBCA FFPE specimens and sequenced to high, uniform coverage. Potentially actionable alterations were defined as those identifying anti-cancer drugs on the market or in registered clinical trials. Results: Sequencing was performed on 34 primary and 49 metastatic GBCA biopsies, Grade I/II/III, 5, 55 and 23 cases, respectively. A total of 329 alterations were identified with an average of 4.0 alterations per tumor (range 1-15). The most frequently altered genes were: TP53 (63%), CDKN2A (49%), ARID1A (18%), ERBB2 (17%), PIK3CA (12%), SMAD4 (11%) and CCNE1 (11%). Forty-three additional genes were altered in multiple cases including: BRCA2, CCND1, ERBB3, EGFR, FGFR3, GNAS, KRAS, MET, NF1, NF2, NRAS, PDGFRA, PTEN, STK11 and TSC2. One case of FGFR3-TACC fusion gene was noted. At least one alteration associated with agents that are FDA approved or being studied in clinical trials was identified in 71/83 (86%) of cases. Clinical follow up of a small subset of patients to date, revealed two patients with focal amplification of EGFR and ERBB2 had sustained PR with erlotinib and trastuzumab, respectively. Conclusions: This is the largest known series of GBCA cases analyzed using next generation sequencing-based genomic profiling. The long tail of genomic-derived targets of therapy identified, necessitate broad diagnostic assays capable of accurately profiling tumors from limited biopsy material to maximize targeted treatment options. Our results indicate that genomic profiling can identify clinically meaningful alterations that can potentially guide targeted treatment decisions in the majority of patients with this orphan tumor.
Survival of patients with different AIDS-related lymphoma subtypes.
Authors: Marcus Hentrich, Christoph Wyen, Daniel Gillor, Christian Hoffmann, Alexander Zoufaly, Jan-Christian Wasmuth, Markus Mueller, Timo Wolf, Jan M. Siehl, Gerd Fätkenheuer, Philipp Schommers
Journal: Journal of Clinical Oncology (2014)

8548 Background: Previous data indicated that the overall survival (OS) of patients (pts) with AIDS-related Burkitt lymphoma (BL) is inferior to that of diffuse large B-cell lymphoma (DLBCL), and that the OS of pts with plasmablastic lymphoma (PBL) is inferior to that of BL and DLCBL. We aimed to analyse the OS of pts with these lymphoma subtypes enrolled in the German AIDS-related Lymphoma (ARL) Cohort Study. Methods: The prospective observational cohort study includes all adult HIV-infected pts with biopsy proven ARL diagnosed in 31 participating German centers since January 2005. Data on HIV-infection and lymphoma characteristics, treatment and outcomes were recorded until December 2012. OS was calculated from the date of ARL diagnosis until death of any cause or last follow-up. Results: Of 291 pts included in the analysis 154 (53%) had DLBCL, 103 (35%) BL, and 34 (12%) PBL. The mean CD4-count at ARL diagnosis was significantly higher in pts with BL (349/µl) compared to DLBCL (209/µl) or PBL (205/µl) (P < 0.001 and P = 0.008, respectively). After a median follow-up of 1.3 years there was no significant difference in the 2-year OS rates (2yOS) between pts with BL (69% [95%CI 59-79]) and DLBCL (63% [55-71]) (P = 0.65). By contrast, the 2yOS of PBL was significantly lower (43% [23-63]) compared to that of DLBCL and BL (P = 0.024). The OS rates for pts with low risk vs. intermediate/high risk international prognostic index (IPI) were 82% (70-95) vs. 52% (40-63) for DLBCL (P = 0.001), 87% (74-101) vs. 60% (47-73) for BL (P = 0.011) and 83% (60-105) vs. 20% (-2.8-42.6) for PBL (P = 0.003), respectively. Pts with DLBCL and CD4 cells >100/µl had significantly better OS than those with CD4 cells ≤100/µl (66% [55-77] vs. 51% [36-66], P = 0.022). However, this was not true for pts with BL (OS 74% [63-85] vs. 51% [24-77], P = 0.069) and PBL (36% [12-59] vs. 63% [32-93], P= 0.459). Prior AIDS defining illnesses did not adversely impact OS of each lymphoma subtype. Conclusions: In contrast to previous data the present study showed no significant difference in the 2yOS rates between DLBCL and BL while the OS of pts with PBL remains poor. The improvement in survival of BL may be explained by the widespread use of antiretroviral therapy and the more frequent use of intensive chemo-immunotherapy regimens.
Goblet cell scarcity and conjunctival inflammation during treatment with dupilumab in patients with atopic dermatitis
Authors: D.S. Bakker, L.F.M. Ariens, C. Luijk, J. Schaft, J.L. Thijs, M.L.A. Schuttelaar, F. Wijk, E.F. Knol, D.M.W. Balak, M.R. Dijk, M.S. Bruin‐Weller
Journal: British Journal of Dermatology (2018)

Goblet cell scarcity and conjunctival inflammation during treatment with dupilumab in patients with atopic dermatitis
Presentation and Outcome of 199 Patients with 2016 Who Diagnosis of Early and Overt Primary Myelofibrosis Treated with Ruxolitinib
Authors: Francesca Palandri, Giuseppe A. Palumbo, Elisabetta Abruzzese, Alessandra Iurlo, Nicola Polverelli, Massimiliano Bonifacio, Micaela Bergamaschi, Elena Maria Elli, Giulia Benevolo, Alessia Tieghi, Nicola Sgherza, Alessandro Isidori, Gianni Binotto, Monica Crugnola, Costanza Bosi, Francesco Cavazzini, Roberto Latagliata, Daniele Cattaneo, Giuseppe Auteri, Luigi Scaffidi, Malgorzata Monika Trawinska, Lucia Catani, Robin Foà, Umberto Vitolo, Franco Aversa, Roberto Massimo Lemoli, Antonio Cuneo, Mauro Krampera, Gianpietro Semenzato, Francesco Di Raimondo, Michele Cavo, Daniela Bartoletti, Nicola Vianelli, Massimo Breccia
Journal: Blood (2018)
Single Centre UK Comparison of Biosimilar Rituximab (Truxima) with the Originator (MabThera) in Patients with Immune Mediated Thrombotic Thrombocytopenic Purpura
Authors: Matthew J. Stubbs, Ryan Low, Siobhan McGuckin, Rosalind Newton, John-Paul Westwood, Mari Thomas, Simon Cheesman, Marie Scully
Journal: Blood (2018)
The pharmacokinetics and safety of idelalisib in subjects with moderate or severe hepatic impairment.
Authors: Feng Jin, Michelle Robeson, Huafeng Zhou, Grace Hisoire, Srini Ramanathan
Journal: Journal of Clinical Oncology (2014)

2592 Background: Idelalisib (IDELA) is a potent inhibitor of PI3Kδ, which has been shown to be prominently expressed in cells of hematopoietic origin. IDELA is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by CYP3A and UGT1A4. The mass balance study of IDELA in healthy subjects showed the radioactive dose administered was recovered mainly in feces (~78%). The objective of this study was to evaluate the PK and safety of IDELA/GS-563117 in subjects with moderate or severe hepatic impairment following administration of a single oral dose of IDELA. Methods: Eligible subjects categorized by the Child-Pugh-Turcotte (CPT) classification system with moderate (Class B: CPT score 7-9) or severe (Class C: CPT score 10-15) hepatic dysfunction and matched healthy subjects received a single oral dose of IDELA at 150 mg under fed condition. Blood samples were collected and IDELA/GS-563117 levels were measured. Geometric least-squares mean ratio and 90% confidence interval of PK exposure parameters in the hepatic impairment group(s) versus matched controls were calculated, with clinically relevant exposure change defined as ≥ two-fold increase. Safety assessments were performed throughout the study. Results: A total of 32 subjects were enrolled in the study. The majority of subjects were white (87.5%) males (71.9%) and median age was 52 years. Most treatment-emergent AEs and laboratory abnormalities were Grade 1 or 2 in severity. Overall study treatments were generally well tolerated. IDELA Cmaxwas generally comparable in the subjects with moderate or severe hepatic impairment vs healthy controls, while mean AUC was higher (58% to 60%). GS-563117 exposures were lower in hepatic impaired vs healthy control subjects, likely due to lower formation in the setting of liver impairment. These changes are not considered to be clinically relevant. Exploratory analyses indicated no relevant relationships between the IDELA or GS-563117 plasma exposures and CPT score. Conclusions: No clinically relevant changes in IDELA and GS-563117 exposures were observed in subjects with moderate or severe hepatic impairment versus matched healthy subjects. Single oral doses of IDELA 150 mg were well tolerated.
A Protective Role for the Lectin CD169/Siglec-1 against a Pathogenic Murine Retrovirus
Authors: Pradeep D. Uchil, Ruoxi Pi, Kelsey A. Haugh, Mark S. Ladinsky, John D. Ventura, Brad S. Barrett, Mario L. Santiago, Pamela J. Bjorkman, George Kassiotis, Xaver Sewald, Walther Mothes
Journal: Cell Host & Microbe (2018)

Highlights•Lectin CD169 limits systemic murine retrovirus dissemination from lymph node to spleen•CD169 reduces virus spread and infection of erythroblast targets in red pulp of spleen•CD169 promotes cross-presentation via cDC1 to elicit effective CD8+ T cell responses•CD169−/− mice have defective antiretroviral CD8+ cytotoxic T cell responseSummaryLymph- and blood-borne retroviruses exploit CD169/Siglec-1-mediated capture by subcapsular sinus and marginal zone metallophilic macrophages for trans-infection of permissive lymphocytes. However, the impact of CD169-mediated virus capture on retrovirus dissemination and pathogenesis in vivo is unknown. In a murine model of the splenomegaly-inducing retrovirus Friend virus complex (FVC) infection, we find that while CD169 promoted draining lymph node infection, it limited systemic spread to the spleen. At the spleen, CD169-expressing macrophages captured incoming blood-borne retroviruses and limited their spread to the erythroblasts in the red pulp where FVC manifests its pathogenesis. CD169-mediated retroviral capture activated conventional dendritic cells 1 (cDC1s) and promoted cytotoxic CD8+ T cell responses, resulting in efficient clearing of FVC-infected cells. Accordingly, CD169 blockade led to higher viral loads and accelerated death in susceptible mouse strains. Thus, CD169 plays a protective role during FVC pathogenesis by reducing viral dissemination to erythroblasts and eliciting an effective cytotoxic T lymphocyte response via cDC1s.Graphical abstract
Obinutuzumab Plus Gemcitabine, Dexamethasone and Cisplatin (O-GDP) As Salvage Chemotherapy Prior to Autologous Stem Cell Transplant in Aggressive B Cell Lymphoma
Authors: Michael D. Jain, Ryan D. Morin, Anca Prica, Vishal Kukreti, Robert Kridel, Rob C. Laister, Li Meng, Christopher Rushton, Miguel Alcaide, Rashmi S. Goswami, Jan M.A. Delabie, Jessica Weiss, Tony Panzarella, Michael Crump, David W. Scott, John Kuruvilla
Journal: Blood (2018)
Insomnia disorder subtypes derived from life history and traits of affect and personality
Authors: Tessa F Blanken, Jeroen S Benjamins, Denny Borsboom, Jeroen K Vermunt, Casey Paquola, Jennifer Ramautar, Kim Dekker, Diederick Stoffers, Rick Wassing, Yishul Wei, Eus J W Van Someren
Journal: The Lancet Psychiatry (2019)
Integration of Nanostring Profiling and Functional Characterization of Oxidative and Replicative Stress Biomarkers Identifies Poor Prognosis MYC/BCL-2 Positive Diffuse Large B-Cell Lymphoma Subsets, Providing Opportunities for Precision Therapies
Authors: Enrico Derenzini, Alessandra Rossi, Claudio Agostinelli, Maura Rossi, Federica Melle, Giovanna Motta, Marco Fabbri, Tommaso Radice, Safaa Ramadan, Anna Vanazzi, Valentina Tabanelli, Stefano Fiori, Annalisa Chiappella, Alberto Agazzi, Pier Luigi Zinzani, Umberto Vitolo, Corrado Tarella, Stefano A. Pileri
Journal: Blood (2018)
The condition of systemic status of hormones in lung cancer patients depending on sex.
Authors: Oleg Babenkov, Vladislav Legostayev, Elena Frantsiyants, Svetlana Dmitriyeva, Ekaterina Komarova
Journal: Journal of Clinical Oncology (2014)

e22205 Background: A higher percentage of lung cancer (LC) incidence among men gives grounds to suppose the presence of relation between the development of LC and disorder of sex hormones synthesis. Methods: The levels of ACTH (adrenocorticotropic hormone), FSH (follicle stimulating hormone), LH (luteinizing hormone), TTH (thyrotropic hormone), T4 (thyroxin), T3 (triiodothyronine), F (cortisole), T (testosterone), E1 (estrone), E2 (estradiol), and E3 (estriol) were determined by ELISA in blood of 56 women and 564 men having the LC T2N0-1M0. The control was peripheral blood of healthy donors. Results: In 80% of female patients, 1.5 times increase of the level of F and almost 2 times increase of ACTH was marked as compared to the healthy ones. Lowered production of T was found against the background of higher quantity of E1 and E2. The level of FSH and LH was validly lower (3 and 1.6 times, respectively) than in healthy donors. The decrease of quantity of T3 (almost 2 times lower) and a 1.8 times higher TTH level (in 65% of female patients), with T4 concentration within the norm, were discovered. As for male LC patients, the concentration of F and ACTH was 1.7 times and 2.8 times higher than the norm. The reduction of production of T was marked (1.8 times lower), as well as that of E1 (1.3 times) and E2 (1.7 times lower) as compared to the norm. The level of FSH was 2.8 times higher than that in healthy men against the LH level remaining unchanged. The condition of pituitary-thyroid system in men is characterized by 1.3 times lower content of TTH and inhibited synthesis of T4 and T3. Conclusions: The common features in condition of the hormonal status of female and male LC patients are the increase of level of F and ACTH and disorder of androgens and estrogens balance. The distinctions consist in the manner E1 and E2, T4 and TTH change, the direction of gonadotropins deviation from the norm.
Brain metastases in patients with testicular germ cell tumors: Toward optimization of diagnostics and treatment.
Authors: Marija Gamulin, Mislav Grgic, Ines Tomaskovic, Fedor Santek
Journal: Journal of Clinical Oncology (2014)

e15538 Background: Treatment of brain metastases (BM) in testicular germ cell tumors (TGCT) is still not fully resolved. There are conflicting data concerning the modalities of treatment in inoperable BM patients (pts) (radiotherapy (RT)+chemotherapy (CT) or CT, radiation doses, cisplatin-refractory pts). For diagnostics relevant information is possible association between testicular tumor histology, value of tumor markers (HCG, AFP) and incidence of BM. Methods: 601 TGCT pts were analyzed during the 10 years period (2003-2013). 15 pts (stage III) had BM. All pts with BM were in intermediate or poor risk group usually with a relapsed disease. Results: In TGCT pts the mean period of time between orchiectomy and BM was 9.9 months (range 0-130 months). All pts had mixed TGCT. The most represented type in testicular histology was teratoma (T) 9/15 (60 %) pts, CC 8/15 pts (53.3 %), and yolc sac (YS) in the 5/15 pts (33.3 %). At diagnosis of BM in 12/15 pts (80 %) levels of HCG were >20000 IU/L, while 3/15 pts (20 %) had elevated AFP levels (>1000ug/L). Since 2013 after introduction of brain MRI to those pts in relapse who had levels of HCG >140 000 IU/L, in 4 pts was diagnosed BM of which 2 were asymptomatic contrary to previous 9 years during which MRI was not performed thus not a single asymptomatic patient with BM was recognized. By concomitant CT (cisplatin based) and RT, (2/10 30Gy/10fr; 8/10 50Gy/25fr) were treated 8 pts. 7/15 pts died (46.6%), and 8 are alive(53.3%). Mean survival period from diagnosis of BM patients in this study was 29.7 months (0-121 months). Conclusions: Brain MRI is suggested in stage III relapsed pts with AFP values >1000ug/L and/or HCG >10000 IU/L with histological testicular components T, CC or YS. To define the CT schedule ± RT (doses/fractionation) especially in cis-refractory pts international collaborative study is suggested.