bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pneumocystis infection during first-line chemotherapy for solid tumours: Increased virulence or better diagnosis?
Authors: James Alena Talia , James Alex , Pinto do Nascimento Marcela , Higgs Domenic , Rogers-Seeley Madeline , Dean Andrew Peter 
Published: September 2018

e18277 Background: Pneumocystis Jirovecii (PJP, previously Pneumocystis Carinii) infection is typically seen in those with advanced immunodeficiency such as Acquired Immunodeficiency Syndrome, haematological malignancies, sustained chemotherapy with temozolomide or patients heavily pretreated with multiple lines of chemotherapy. PJP rarely presents early in the natural history of solid tumour malignancy. We observed a cluster of cases of PJP at our institution in patients undergoing first-line chemotherapy for solid tumours. Methods: An electronic database search was conducted to identify occurrences of PJP over a 3 month period. 4 patients were identified who developed Pneumocystis Jirovecii. The patients’ records, laboratory, radiology and pathology results were examined. Results: All 4 patients identified had developed PJP during first line chemotherapy for GI malignancy. In each case, the patient presented with dyspnoea, fever and hypoxia. All were noted to be lymphopenic with lymphocyte counts of 0.2 to 0.9 x10^9/L. All were HIV negative. Chest CT revealed new bilateral ground-glass changes associated with cyst formation. All cases were found to have positive PJP PCR on testing of induced sputum. On the basis of clinical presentation, positive PCR sputum cultures and CT findings, the patients were diagnosed with PJP and treated with high-dose sulphamethoxazole and trimethoprim. 3 patients recovered and 1 died despite best ICU management. Conclusions: The relatively high number of cases of PJP early in treatment is noteworthy. It raises the question as to whether PJP is becoming more potent or that better awareness leads to earlier and more accurate diagnosis. Coincidental clustering is also a possibility. Clinicians should be aware that pneumocystis infection can occur during first-line therapy in solid tumour malignancy. It should be considered as a differential in any patient on chemotherapy (regardless of line of therapy) presenting with acute respiratory illness.
Phase IB/II study of lirilumab with azacytidine (AZA) in relapsed AML.
Authors: Daver Naval Guastad , Garcia-Manero Guillermo , Cortes Jorge E. , Basu Sreyashi , Ravandi Farhad , Kadia Tapan M. , Borthakur Gautam , Jabbour Elias , Dinardo Courtney Denton , Pemmaraju Naveen , Brandt Mark , Pierce Sherry , Hussin Nawar , Kornblau Steven Mitchell , Andreeff Michael , Konopleva Marina , Ning Jing , Allison James Patrick , Sharma Padmanee , Kantarjian Hagop M. 
Published: September 2018

e18505 Background: Lack of KIR-HLA class I interactions has been associated with NK-mediated antitumor efficacy in AML patients (pts) in remission upon KIR-mismatched haploidentical stem cell transplantation (SCT) (Ruggeri L et al., Science 2002). Blockade of KIR2DL1, 2 and 3 receptors induced augmented NK-cell mediated lysis of tumor cells (Romagne F et al., Blood 2009). Hypomethylating agents possess anti-leukemia activity, increase MHC II expression, and interferon-gamma signature. Methods: Pts with AML who failed prior therapy, have adequate performance status (ECOG ≤ 2) and organ function are eligible. AZA 75mg/m2 Days 1-7 was given with lirilumab on Day 8 at the dosage of 1 and 3 mg/kg in 2 consecutive cohorts of 6 pts each. Courses were repeated every 4-5 weeks. Lirilumab 3mg/kg established as recommended phase 2-dose with AZA. 13 additional pts treated at the RP2D. Responses evaluated at the end of 3 courses. Results: To date, 25 pts (16 de novo, 9 secondary AML), median age 64 years (range, 30 – 89), 52% adverse cytogenetics, median prior therapies 3 (range, 1-8), and prior alloSCT in 6 (28%) have been enrolled. All 25 pts had baseline next generation sequencing, common mutations included ASXL1 (n = 9), TP53 (n = 7), RAS (n = 4), TET2 (n = 4), and RUNX1 (n = 3). Two (8%) achieved CR/CRi (1 CR, 1 CRi) and 3 (12%) achieved hematologic improvement for an overall response rate of 20%. The median cycles to response was 3 (range, 1-11). The 8-week mortality is 12%, respectively. The median duration of response and overall survival were 2.0 months and 4.0 months, respectively (med f/u = 5.1 months). Grade 3/4 toxicities were similar to those seen with AZA based therapies in salvage including bloodstream infections in 15 (60%), 6 pneumonia, 1 UTI, 1 skin infection, 2 abdominal pain, and 1 mucositis. Immune mediated toxicities were observed in 4 (16%) pts (1 pneumonitis Grade 3, 2 colitis Grade 3, 1 colitis Grade 2). The immune mediated toxicities responded rapidly to steroids and 3 pts could be rechallenged safely with lirilumab. Six pts were postSCT and no Grade 3/4 GVHD flares were noted. Conclusions: Full doses of AZA and lirilumab were well tolerated in heavily pretreated pts with relapsed AML. The efficacy data are still preliminary and the study is ongoing. Clinical trial information: NCT02399917.
Ten-year follow-up of pentostatin combined with cyclophosphamide, and rituximab in previously untreated indolent B-cell lymphoma.
Authors: Khashab Tamer , Niaz Muhammad Obaid , Hagemeister Fredrick B. , Romaguera Jorge Enrique , Fanale Michelle A. , Pro Barbara , McLaughlin Peter , Rodriguez Maria Alma , Neelapu Sattva Swarup , Fayad Luis , Younes Anas , Feng Lei , Berkova Zuzana , Jain Neeraj , Sehgal Lalit , Vega Francisco , Kwak Larry W. , Samaniego Felipe 
Published: September 2018

e19040 Background: Frontline regimens for indolent lymphoma are effective, but patients still suffer from relapse. From 2005 to 2007 we enrolled previously untreated patients on a phase II trial to investigate response rate and efficacy of pentostatin combined with cyclophosphamide and rituximab (PCR). PCR is an effective frontline therapy in chronic lymphocytic leukemia. We report the final analysis with a median follow up of nearly ten years. Methods: Patients were treated with 6 cycles of therapy with additional 3 cycles in case of not attaining a CR/CRu. All patients received Pentostatin (4 mg/m2), Cyclophosphamide (600 mg/m2), and Rituximab (375 mg/m2) on day one and every 21 days. Results: Of the 83 patients, five were considered unevaluable for response, but are included as non-responders in our intent-to-treat analysis. Diagnoses included FL (43.4%), SLL (38.5%), and MZL (18.1%). 78.3% had Ann Arbor stage IV lymphoma and 63.9% had bone marrow (BM) involvement. For all 83 patients, the overall response was 92%, and most toxicity events were hematologic, with grade ≥3 neutropenia in 68 of 509 cycles of chemotherapy administered. Long term toxicity includes secondary malignancies in 14 patients. Two patients developed treatment related MDS/AML and both occurred after additional lines of therapy. PFS at 10 years for FL, MZL, and SLL was 71%, 67% and 15%, respectively. PFS was affected by clinicopathologic characteristics. 10-year PFS rates for those with pretreatment β2M < 2.2 and > 2.2 mg/l were 71 % and 21 % respectively. Patients without BM involvement had 10-year PFS of 72% versus 29% for those with BM involvement. The median OS has not been reached. The overall survival rate was 87% at 5 years and 64% at 10 years. The difference in OS rate was statistically significant based on histology, 94% for FL, 66% for MZL, and 39 % for SLL. Conclusions: Long term follow up confirms that PCR is an effective, robust and tolerable treatment regimen for indolent B-cell lymphomas with 34 of 36 patients with FL alive at 10 years with 27 remaining in remission. Clinical Trial Information NCT00496873 Clinical trial information: NCT00496873.
PTLD: Survival and analysis of prognostic factors in a cohort of 138 patients from a single institution.
Authors: Bishnoi Rohit , Bajwa Ravneet , Franke Aaron J , Patel Niraj , Skelton William Paul , Slayton William Birdsall , Zou Fei , Xiong Sican , Dang Nam H. 
Published: September 2018

e19048 Background: The outcome and prognostic factors of post-transplant lymphoproliferative disorder (PTLD) varies in currently reported literature. We present one of the largest single institution retrospective analysis from University of Florida. Methods: Patient population was identified from EMR and charts were reviewed to collect data. Primary outcome was Overall survival (OS) and secondary outcome was identification of prognostic factors. Results: We identified 138 patients with PTLD from Sept 1994 to Feb 2016 (liver 34%, Kidney 23%, heart 21%, lungs 12%, kidney-pancreas 2% and BMT 6%). After survival analysis, 131 patients were further followed for secondary outcomes. 36% (n = 47) were less than 18 years of age, 60% (n = 83) were males. The median age of PTLD diagnosis was 44 years and the median duration from transplant to PTLD was 4.4 years. Pathology was early lesion 6% (n = 8), polymorphic 17% (n = 23), Monomorphic 71% (n = 93), Hodgkin/like 4.5% (n = 6). Extra-nodal site involvement was 61% (n = 80), most common being GI tract. Ann-Arbor stage distribution was stage I/II 50% (n = 65), stage III/IV 46% (n = 60). Initial treatment was immunosuppression (IS) reduction alone in 24% (n = 31), Rituximab (R) 24% (n = 31), chemotherapy (+/- R) 46% (n = 60). Most common chemo regimen was CHOP (+/-R) 27% (N = 36). After first line, 48% patients had complete remission (CR), 18% partial remission (PR) and 15% progressive disease (PD). Second line treatment was required in 33% (n = 44) and 10% (n = 13) patients required 3rdline treatment. Final analysis showed 61% (n = 80) achieved CR, 17% (n = 22) had PD, 56% (n = 74) patients were alive and 49% (n = 64) are alive without PTLD. Median OS was 14.99 years. Multivariate analysis identified transplant age, organ transplant recipients, PTLD diagnosis age, performance status, IPI score, graft rejection, history of malignancy and recipient EBV status as prognostic factors (p < .05). Conclusions: This study from a leading regional transplant center shows notable OS which is likely from improved immunosuppressive regimens, treatment modalities and large pediatric population. We identified various prognostic factors affecting survival and propose validation to generate prognostic score.
Conditional survival estimates for patients with plasma cell leukemia: An analysis of the SEER database.
Authors: Iyer Veena , Bagchi Arindam , Hamouda Danae , Nai Qiang , Hakim Hosam , Verghese Cherian 
Published: September 2018

e19533 Background: Plasma cell leukemia (PCL) is an aggressive malignancy with poor prognosis. Retrospective studies have suggested improved outcomes with stem cell transplant and use of novel agents. Methods: We used the Surveillance, Epidemiology, and End Results database to identify 480 patients with PCL from 1973 to 2009. Kaplan Meier method was used to calculate 3-year Cancer Specific Survival (CSS) estimates, conditional on 1 to 3 years of survival (CS3). Covariates included age, sex, race and geographic location. The cohort was divided into three time frames, 1973-95, 1996-2005 and 2006-2009, to account for use of transplant from 1995 and novel agents from 2005. Results: 398 patients were selected for analysis from the initial cohort. Median age was 65. 50.75% were female and 65.8% were white. The 3-year CSS for patients with PCL was 19.6% and conditional probability of surviving additional 3 years (CS3) at 1, 2, 3 and 5 years from diagnosis was 36.9%, 51.5%, 58.5% and 71.2% respectively. CSS rates at 3 years during 1973-95, 1995-2005 and 2006-2009 were 14.7%, 12.4% and 32.9% respectively and the CS3 improved from 37.4% / 27.9% / 44.5% at 1 year to 72.7% / 46.3% / 57.5% at 3 years. 3-year CSS rates of patients aged < 50, 50-59, > 70 years was 19.9%, 19.7% and 18.7% respectively. The CS3 with each year survived increased for all age groups, with the most dramatic increase for those > 70 years (45.8% at 1 year to 80.5% at 3 years). Hispanics had the lowest 3-year CSS rate (5.5%). Improvement in CS3 from 1 to 3 years for races was as follows – Whites: 35.8% to 57.9%, Blacks: 41.9% to 50.10%, Asians: 28.6% to 67% and Hispanics: 18.7% to 33.3%. 3-year CSS rate for patients from metropolitan/non-metropolitan areas was 19.5%/18%. CS3 for metropolitan/non-metropolitan areas increased from 38.2%/27.3% at 1 year to 63%/33.3% at 3 years. Conclusions: The risk profile of patients with PCL changes as they survive past the diagnosis. Improvements in survival are more substantial in older patients and patients from metropolitan areas.
A phase 1b study of napabucasin plus weekly paclitaxel in patients with advanced thymoma and thymic carcinoma.
Authors: Hitron Matthew , Spittler Aaron John , Cote Gregory Michael , Heist Rebecca Suk , Kossler Kimiko , Li Wei , Li Youzhi , Li Chiang , Loehrer Patrick J. 
Published: September 2018

e20001 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Synergistic anti-tumor activity of napabucasin plus paclitaxel was observed in pre-clinical and early clinical testing. The STAT3 pathway is considered important in thymic carcinoma and thymoma, rare cancers with few treatment options. In 1st line, the objective response rate (ORR, partial response [PR] + complete response [CR] per RECIST) with carboplatin-paclitaxel was 22% in thymic carcinoma and 43% in thymoma (Gemma, 2011). A phase 1b cohort was established to evaluate safety and preliminary signs of activity of napabucasin plus paclitaxel in these patients (pts). Methods: Pts with previously-treated advanced thymoma or thymic carcinoma were enrolled with napabucasin (240 - 480 mg orally twice daily) plus paclitaxel (80 mg/m2 IV weekly for 3 of every 4 weeks). Adverse events were evaluated using CTCAE v4.03 and tumor assessments were obtained every 8 wks per RECIST 1.1. Results: A total of 9 pts (thymic carcinoma = 5, thymoma = 4) with a median 3 prior lines of systemic therapy were enrolled. In thymic carcinoma, the starting napabucasin dose was 480 mg BID (n = 2), and 240 mg BID (n = 3). Treatment was well tolerated and 1 pt required dose-reduction. There were no grade 3 AEs reported. As of data cut-off, 3 pts are off-study with progression and 2 remain on treatment. PRs were observed in 4 of 5 pts (ORR = 80%) and the median time on treatment is > 7.0 mo. In thymoma, 4 pts received napabucasin 240 mg BID. AEs included grade 3 diarrhea and dehydration in 1 pt. As of data cut-off, 1 pt was off-study with progression, 2 died (perforated bowel; autoimmune myocarditis secondary to Issac’s syndrome), and 1 pt remains on treatment. PR was observed in 1 pt (ORR 25%). Conclusions: Napabucasin plus weekly paclitaxel has demonstrated clinical safety and encouraging signs of anti-tumor activity in patients with advanced thymic carcinoma and thymoma. Further clinical evaluation of the combination regimen is warranted in this population. Clinical trial information: NCT01325441.
Cetuximab plus platinum-based chemotherapy in patients with malignant pleural mesothelioma: A single arm phase II trial.
Authors: De Paepe Annelies , Vermaelen Karim Y , Cornelissen Robin , Germonpre Paul Richard , Janssens Annelies , Lambrechts Marc , Bootsma Gerben , Van Meerbeeck Jan P. , Surmont Veerle 
Published: September 2018

e20030 Background: Cetuximab is a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Previous studies suggested that cetuximab enhances chemotherapy activity in the presence of EGFR overexpression, which is present in a majority of MPM specimens. We investigated the activity and safety of the combination of platinum-based chemotherapy and cetuximab in EGFR immunohistochemical positive (IHC+) MPM patients (pts). Methods: This is an open, single arm multicenter phase II study according to a Simon 2-step design with progression-free survival (PFS) rate at 18 weeks as primary endpoint. PFS rate at 18 weeks in MPM pts with cisplatin-pemetrexed is 0.67. We hypothesized that the combination of cetuximab and chemotherapy would increase the PFS rate with 30% to 0.87 (alpha = 0.05, power 90%). 18 chemotherapy-naïve pts with epithelioid MPM and PS 0-1, EGFR IHC+ (assessed by DAKO kit with at least 1% of cells showing staining), were included in step 1 of in the study. If ≥14 were alive and free of progression at 18 weeks, sample size was to be increased to 43 pts. Treatment consisted of cisplatin (75 mg/m², day 1 of each 3-week cycle) or carboplatin AUC 5 (day 1 of each 3-week cycle) and pemetrexed (500mg/m2, day 1 of each 3-week cycle) and cetuximab (loading dose of 400 mg/m² followed by 250 mg/m² weekly) during chemotherapy until disease progression. Chemotherapy was given up to 6 cycles. Secondary end points were overall survival (OS), toxicity and response rate. Results: We enrolled 18 eligible pts between June 2010 and June 2013; 89% males, median age 68 years (range 57-80), 83% PS 1. Median number of cycles was 4 (range 2-6). Median number of weekly administrations of cetuximab was 25 (range 8-51). 13 pts were alive and without progression at 18 weeks, median PFS was 24 weeks (95% CI 18.5-29.5), median OS 49 weeks (95% CI 38.6-59.4). 44% (8/18) of patients obtained a partial response. The treatment was well tolerated; the most common adverse event was skin rash (89%), mainly grade 1-2. Conclusions: As platinum-based chemotherapy in combination with cetuximab in pts with epithelioid MPM did not reach the predefined threshold, the study was not continued. No new safety signal was observed. Clinical trial information: NCT00996567.
Whole body PD-1 and PD-L1 PET with 89Zr-nivolumab and 18F- BMS-986192 in pts with NSCLC.
Authors: Niemeijer Anna-Larissa N. , Smit Egbert F. , Dongen G.a.M.S. van , Windhorst A.D. , Huisman Marc C. , Hendrikse N. Harry , Leung David K. , Smith Ralph Adam , Hayes Wendy , Velasquez Linda M. , Bonacorsi Samuel J. , Donnelly David J. , Morin Paul E. , Thunnissen Erik , Poot Alex J. , Vugts Danielle J. , De Langen Joop 
Published: September 2018

e20047 Background: Tumor PD-L1 IHC relates moderately with treatment outcome following anti-PD-(L)1 monotherapy in pts with NSCLC. Aim: 1. To assess safety of the PET procedures. 2. To quantify PD-1 and PD-L1 expression in tumors with 89Zirconium-labeled nivolumab (89Zr-nivo) and 18F-labeled BMS-986192 (18F-PD-L1) PET. 3. To assess intra- and inter-patient tracer uptake differences in tumors. 4. To correlate PET results with IHC and treatment outcome. Methods: NSCLC pts eligible for treatment with nivolumab were included. Pts received a dynamic and static whole body 18F-PD-L1 and a static 89Zr-nivo PET scan. A baseline tumor biopsy was required and up to two additional biopsies were allowed in case PET showed heterogeneous tumor uptake. SUVpeak was calculated for all delineable tumor lesions and related to PD-(L)1 IHC (28.8 assay) and response after 6 wks of nivolumab treatment. Results: 7 pts (5 ≥1%, 2 ≥50% and 2 negative by PD-L1 IHC) were enrolled and 11 lesions analyzed. No toxicity related to radiotracer administration was identified. Tumor uptake of both tracers was visualized in all pts. There was substantial variability among pts for 18F-PD-L1 (mean SUV 5.4, range 2.2 - 14.4) and 89Zr-nivo (mean SUV 5.0, range 1.6 - 9.7). Intra-patient tracer uptake heterogeneity was also seen: mean 2.5-fold (±0.96) and 2.3-fold (±0.86) differences between lesions for 18F-PD-L1 and 89Zr-nivo SUV, respectively. For lesions with < 50% PD-L1 IHC mean 18F-PD-L1 SUV was 3.4 (±2.9) as compared to 7.1 (±6.0) for lesions with ≥50% PD-L1 IHC (p = 0.22). For lesions with low PD-1 expression mean 89Zr-nivo SUV was 6.9 (±2.7) as compared to 8.1 (±2.0) for lesions with high PD-1 expression (p = 0.44). Five pts were evaluable for response evaluation: 1 PR, 2 SD and 2 PD with 18F-PD-L1 SUV values (most PET avid lesion) of 14.4 (PR), 2.0 and 5.4 (SD) and 6.4 and 6.6 (PD). Conclusion: 1.PET-imaging with both tracers is safe and feasible, with good tumor-to-normal tissue contrast. 2. Tumor uptake demonstrated substantial heterogeneity among pts and among tumors within the same pts. 3. Although higher 18F-PD-L1 tumor uptake was seen in pts with ≥50% tumor PD-L1 IHC and the highest 18F-PD-L1 SUV was measured in the responding pt, the dataset is still very small. Clinical trial information: 2015-004760-11.
KRAS mutants to regulate PD-L1 expression through NF-ƘB and HIF-1α pathways in non-small cell lung cancer cells.
Authors: Guo Rong , Li Yong , Bai Hua , Wang Jie 
Published: September 2018

e20049 Background: PD-L1 (programmed death ligand 1) is expressed in various kinds of human tumors including non-small cell lung cancer (NSCLC) and is of critical importance for the immune escape of tumor cells by inhibiting T cell function via its coinhibitory receptor, programmed death 1 (PD-1). Some driver gene mutations including KRAS have been reported to be involved in intrinsic regulation of PD-L1 expression. However, the potential role and precise mechanism of KRAS mutants in regulation of PD-L1 expression in NSCLC cells remain obscure. Methods: We first examined the expression of PD-L1 and key molecules of KRAS signaling pathway in a panel of NSCLC cells with wild-type or mutant KRAS gene. Additionally, KRAS mutant transfection and pharmacological inhibitors of MEK/ERK, PI3K/AKT, and NF-κB were employed to elucidate the regulation mechanism of PD-L1 expression by KRAS mutant in NSCLC cells. We further analyzed KRAS status and protein levels of PD-L1 and hypoxia inducible factor 1 alpha (HIF-1α) in 82 cases of NSCLC tissue. Results: Examination of the KRAS signaling cascades in NSCLC cells revealed an apparent association of PD-L1 overexpression with activation of MEK/ERK and PI3K/AKT pathways. Moreover, NSCLC cells transfected with KRAS mutants and subsequently treated with pharmacological inhibitors showed strong accordance between PD-L1 expression and two transcription factors, NF-κB and HIF-1α. Further transfection or depletion of HIF-1α increased or decreased PD-L1 expression in NSCLC cells accompanied by enhanced or reduced p-IκBα level, respectively, indicating the central role of HIF-1α in upregulating PD-L1 expression in a mechanism parallel to and partially dependent on activation of the NF-κB pathway. Moreover , PD-L1 expression was detected in 31.7% of 82 NSCLC tissues and showed positive correlation with the rate of HIF-1α expression (52.4%). Conclusions: Taken together, KRAS mutants were identified to regulate PD-L1 expression by activating PI3K/AKT and MEK/ERK pathways via NF-κB and HIF-1α, suggesting the correlation between driver gene mutation and tumor immune escape in NSCLC.