bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel approaches in marginal zone lymphoma: Systematic review.
Authors: Durer Seren , Durer Ceren , Hoilat Gilles Jad , Khan Rashad , Duggan David B. , Babiker Hani M. , Anwer Faiz 
Published: May 2020

e20089 Background: Marginal zone lymphoma represents no more than 17% of NHLs and there is no standard of care. We reviewed the efficacy of novel drugs with main focus on ORR and PFS/OS (when available). Methods: Literature search was performed based on PRISMA guidelines in PubMed, Cochrane, EMBASE, Clinicaltrials.gov. Studies which did not give separate results for MZL were excluded. Results: 23 trials (n = 1491 patients) were included. 57% were refractory to previous line of therapy. 9 studies were conducted specifically in MZL (n = 440). The most common intervention was Rituximab and its combinations. PFS and OS were inconsistently reported. 1. Monotherapy in untreated MZL: In a phase III study, ORR was reported at 82.8% vs 81.3% with PFS of 75% vs 78% at 3 years in Obinutuzumab vs Rituximab. In Phase II Ibritumumumab tiuxetan showed 100% ORR in 11 patients with 5-year PFS of 82%. Most common grade 3-4 AE were hematological. Lenalidomide was studied in 18 EMZL patients, with 60% being untreated. In this study, ORR was reported at 61% with CR 33%. 2. Combination therapy in untreated MZL: Lenalidomide+Rituximab showed 93% ORR and median PFS 59.8 months with manageable toxicities. Ibrutinib in combination with Rituximab and Lenalidomide produced ORR of 90% with CR 60%. The addition of Bendamustine to Rituximab showed ORR and CR of 91% and 73% with 3-year PFS of 93% in a study of only SMZL (n = 56). 3. Monotherapy in R/R MZL: Ibrutinib demonstrated ORR of 50%, 54% and 41% in EMZL, SMZL and NMZL, respectively with median PFS of 14.2 months. Less hematologic toxicity was seen in MZL patients receiving Ibrutinib monotherapy compared to other regimens. In 30 patients receiving Everolimus, ORR was reported at 25%. Bortezomib has significant activity in EMZL with ORR of 48%. PI3Kδ inhibitors Idelalisib, Copanlisib and Duvelisib showed clinical activity. Umbrelisib and Ofatumumab demonstrated ORR > 50%. Vorinostat demonstrated an ORR of 22%. 4. Combination therapy in R/R MZL: Rituximab+Lenalidomide had a higher ORR (39.4 vs. 14.1%) and higher PFS (58 vs. 36% at 2-year) compared to Rituximab monotherapy. Combination of Tirabrutinib and Entospletinib showed 20% ORR in a small group of MZL patients. Addition of Idelalisib to Tirabrutinib demonstrated ORR 40%. Ibrutinib and Venetoclax combination demonstrated ORR > 50%. Ublituximab and Umbralisib showed clinical activity. Conclusions: With expanding armamentarium of targeted agents, our review has demonstrated positive results especially in terms of ORR in patients with MZL. Further studies are required to explore the role of these drugs and their impact on survival.
Prognostic role of beta-2 microglobulin in patients with light chain amyloidosis treated with autologous stem cell transplantation.
Authors: Al Saleh Abdullah S. , Dispenzieri Angela , Muchtar Eli , Wolf Robert C. , Dingli David , Lacy Martha , Warsame Rahma M. , Gonsalves Wilson I. , Kourelis Taxiarchis , Hogan William J. , Hayman Suzanne R. , Kapoor Prashant , Buadi Francis , Kumar Shaji , Gertz Morie A. 
Published: May 2020

e20506 Background: Autologous stem cell transplantation (ASCT) prolongs survival in patients with light chain (AL) amyloidosis. Mayo 2012 stage and increased plasma cell percentage (%PC) are known predictors for survival. Increased beta-2 microglobulin (B2M) predicts survival in patients with multiple myeloma. However, its prognostic effect in patients with AL amyloidosis undergoing ASCT is not known. Methods: We retrospectively reviewed patients who had a diagnosis of AL amyloidosis and were treated with ASCT between July-1996 and September-2017. Patients with creatinine > 1.2 mg/dL were excluded, as that affects B2M levels. The receiver operator curve was used to determine the best cutoff for B2M in predicting survival and was 2.5 mcg/mL. Baseline characteristics were compared between patients with B2M > 2.5 and ≤2.5. Progression-free survival (PFS) was defined as time from ASCT to relapse or death, whichever occurred first. Overall survival (OS) was calculated from ASCT to death of any cause. Univariate and multivariate analysis were done for OS. Results: Five-hundred patients were identified and 222 (44%) had a B2M > 2.5. These patients were more likely to be > 65 years old (32% vs. 17%, P = 0.0001), have Mayo 2012 stage III/IV (33% vs. 8%, P < 0.0001), have ≥3 organs involved (25% vs. 14%, P = 0.001), and have ≥10% PCs (56% vs. 40%, P = 0.0002) compared to patients with B2M ≤2.5. The median PFS and OS were shorter in patients with B2M > 2.5 (median PFS: 64 vs. 80 months, P = 0.03); (median OS: 104.9 vs. 175.5 months, P < 0.0001). On univariate analysis, predictors for OS included age > 65 (HR: 1.6, P = 0.001), Mayo 2012 stage III/IV (HR: 3.3, P < 0.0001), ≥3 organs involved (HR: 1.3, P = 0.06), ≥10% PC (HR: 1.5, P = 0.004), melphalan conditioning 200mg/m2 (HR: 0.28, P < 0.0001), and B2M > 2.5 (HR: 1.8, P < 0.0001). In a multivariate analysis, only Mayo 2012 stage III/IV (HR: 1.8, P = 0.006), melphalan conditioning 200mg/m2 (HR: 0.35, P < 0.0001), and B2M > 2.5 (HR: 1.7, P = 0.01) remained independent predictive of OS. Conclusions: Beta-2 microglobulin > 2.5 is an independent predictor for OS in AL amyloidosis patients undergoing ASCT and should be routinely measured.
Outcomes of patients with primary plasma cell leukemia (pPCL) in the era of novel agent therapy.
Authors: Nandakumar Bharat Nayar , Kumar Shaji , Dispenzieri Angela , Buadi Francis , Dingli David , Lacy Martha , Kapoor Prashant , Lin Yi , Kourelis Taxiarchis , Muchtar Eli , Lust John Anthony , Go Ronald S. , Warsame Rahma M. , Hayman Suzanne R. , Leung Nelson , Jevremovic Dragan , Gertz Morie A. , Kyle Robert A. , Rajkumar S. Vincent , Gonsalves Wilson I. 
Published: May 2020

e20510 Background: pPCL is a rare and aggressive form of multiple myeloma (MM) with dismal survival outcomes compared to the remainder of MM patients. Several studies have validated the optimal cutoff for defining pPCL to be >5% circulating plasma cells (cPCs) on a peripheral blood smear due to equally poor outcomes in this less restrictive cohort. We evaluated the clinical outcomes and cytogenetic features of patients diagnosed with pPCL at our institution that were treated with novel agent induction therapies. Methods: We evaluated patients with pPCL diagnosed between 2000 – 2018 (using the 5% cut off) at Mayo Clinic, Minnesota. Data was extracted from a prospectively maintained database and from the review of electronic medical records. Patients were categorized as having high risk (HR) cytogenetics if any of the following abnormalities were present: del 17p, t(4;14), t(14;16) or t(14;20). Chi-square tests and Fisher exact tests were used to compare differences between sub-groups. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: This cohort consisted of 67 patients with pPCL with a median age of 62 years (range: 34-91) of which 33 (46%) were male. The median follow up was 46 months (95% CI: 41 – 90). The median bone marrow plasma cell involvement was 84% (Range: 10 – 100) and the median cPCs percentage on the peripheral blood was 23% (range: 5 - 93). Data on primary cytogenetic abnormalities were available in 60 (85%) patients and the distribution was as follows: t(11;14) – 27 (45%), t(4;14) – 5 (8%), t(14;16) – 8 (13%), t(14;20)- 3(5%) and del 17p- 15(25%). All patients received novel agent induction therapy with 36 (54%) having received autologous stem cell transplant and 4 undergoing an allogeneic stem cell transplant. The median time to next therapy (TTNT) and overall survival (OS) for all patients was 13 months (95% CI: 9 – 17) and 24 months (95% CI: 19 – 40) respectively; 16 months and 51 months for standard risk (SR) vs. 10 months and 19 months for HR (P = 0.005 for OS), when stratified by cytogenetic risk. There were only 17 (31%) patients who were alive for ≥48 months since diagnosis (i.e. twice the median OS of this cohort); The absence of high risk cytogenetics (P = 0.049) and non-elevated LDH level (P = 0.047) at diagnosis predicted for achieving this survival goal. Conclusions: The outcomes of patients diagnosed with pPCL remain poor despite the use of novel agent induction therapy. However, some patients appear to do better than expected and this phenomenon may be influenced by the presence of HR cytogenetics.
Advances in precision therapy with venetoclax in multiple myeloma with t(11;14) and high BCL2 expression: A systematic review.
Authors: Ahmed Zahoor , Nabeel Shaha , Farooqui Arafat Ali , Imtiaz Hassan , Ashraf Aqsa , Farooq Umer , Ammad Ud Din Mohammad , Wahab Ahsan , Rehman Saif ur , Anwer Faiz 
Published: May 2020

e20535 Background: In multiple myeloma (MM), translocation t(11;14) has shown higher expression of B Cell Lymphoma 2 protein (BCL2)- a target for Venetoclax (VEN). This review highlights the role of precision therapy with VEN in t(11;14) MM. Methods: A systematic search of PubMed, Cochrane, Web of Science and Clinicaltrials.gov was performed for use of VEN in MM from inception to 1/2/20. 5 out of 183 studies were finalized (N = 512). Results: Out of 500 relapsed refractory (R/R) MM patients, 97 had t(11;14) and 168 had high BCL2. VEN as monotherapy had encouraging responses in t(11;14) MM patients with high BCL2:BCL2L1 (Kumar 2017). VEN when combined with proteasome inhibitors (PIs) achieved promising results. VEN achieved superior results with carfilzomib and dexamethasone (d) (ORR 100%) in t(11;14) MM patients (Costa 2018) as compared to bortezomib (B) and d (ORR 94%) (Moreau 2017). With high BCL2, VEN-Bd achieved ORR of 84% (CR 35%, VGPR 73%) versus placebo (ORR 83%; VGPR 33%) (Bellini 2019). Conclusions: Venetoclax achieved superior responses in RRMM pts with t(11;14) and high BCL2 expression. Further studies are warranted. [Table: see text]
Biological correlates to support a clinical role for tagraxofusp, a novel targeted therapy directed to CD123, in combination with pomalidomide and dexamethasone, to target plasmacytoid dendritic cells in poor-risk patients with multiple myeloma.
Authors: Chauhan Dharminder , Ray Arghya , Song Yan , Olguin Arturo , Chen Janice , Brooks Christopher , Mughal Tariq I. , Richardson Paul G. , Anderson Kenneth Carl 
Published: May 2020

e20537 Background: We have previously described the pivotal pathogenetic role of plasmacytoid dendritic cells (pDCs; CD123/IL-3Ra+) in multiple myeloma (MM) (Chauhan et al Cancer Cell, 2009,16:309). In preclinical MM models, we demonstrated that tagraxofusp, a novel targeted therapy directed to CD123, triggers anti-MM activity by reducing the viability of MM-promoting pDCs. These observations led to an ongoing phase 1/2 clinical trial of tagraxofusp in MM patients (NCT02661022). The treatment regimen demonstrated safety and efficacy, with 5 of 9 heavily pretreated patients achieving durable partial response (PR). Here, we report the initial results of our translational exploratory studies using bone marrow (BM), peripheral blood (PB), and serum from the study cohort. Methods: pDCs and MM tumor cells were purified from BM/PB samples and quantified using FACS, as described ( Ray et al Leukemia, 2018,32:843). A high-throughput seroproteomics platform SOMAscan was utilized to analyze 1,310 protein analytes in serum samples from MM patients (N = 9). SOMAscan data were subjected to meta-analysis to generate heatmaps, followed by hierarchical cluster analysis. SOMAscan results were validated with ELISA using supernatants from MM patient pDCs cultured with or without tagraxofusp. Results: Analysis of BM/PB samples from MM patients receiving tagraxofusp therapy showed a marked reduction in the frequency of viable pDCs [average 2% at screen vs 0.75% post-tagraxofusp; N = 6; p = 0.036]. pDCs isolated from tagraxofusp-treated patients showed decreased ability to trigger MM cell growth. Seroproteomics analysis of MM patient serum before and after tagraxofusp therapy showed alterations in the levels of 100 proteins [Median Fold Change in expression: 0.39 to 4.5; n = 6; 3 each; p < 0.05]. Importantly, we found that tagraxofusp treatment reduced pDC-related soluble proteins, in particular, IFN-a and IL-3Rα. Additionally, our earlier study showed that pDC-MM interactions triggered secretion of MM cell growth including IL-3, which serves a dual role of promoting pDC survival and MM cell growth. Importantly, tagraxofusp decreased serum IL-3, suggesting that tagraxofusp attenuates survival mechanisms for tumor-promoting pDCs. Conclusions: Our current correlative studies validate target specificity of tagraxofusp and support further evaluation for this novel therapeutic to improve the clinical outcome of patients with MM.
Association of postoperative radiotherapy with survival in patients with completely resected pathologic N2 non-small cell lung cancer treated with chemotherapy.
Authors: Zeng Yuan , Liang Wenhua , He Jian 
Published: May 2020

e21008 Background: The current staging system for completely resected pathological N2 non-small-cell lung cancer (NSCLC) treated with chemotherapy is not suitable for predicting those patients most likely to benefit or not from post-operative radiotherapy (PORT). This study aimed to construct a survival prediction model that will enable individualized predictions of the net survival of PORT. Methods: A total of 3094 cases between 2002 and 2014 were extracted from the Surveillance, Epidemiology, and End Results databases. Patient characteristics were included as covariates, and their association for overall survival (OS) with and witout PORT was assessed. Externally validate data of 602 patients were included from China. Results: A total of 3696 patients were included for analysis. Age, gender, examined lymph node, positive lymph node, tumor size, extent of surgery, and visceral pleural invasion were significantly associated with OS, with P < .05. The calibration curve for OS showed great agreement between prediction by survival prediction model and actual observation.In the training cohort, the C-index for OS was 0.619 (95% CI, 0.598-0.641) in the PORT group and 0.627 (95% CI, 0.605-0.648) in the non-PORT group. In the externally validation cohort, the C-index for OS was 0.599 (95% CI, 0.485- 0.713) in the PORT group and 0.595 (95% CI, 0.544-0.646) in non-PORT group. The two survival prediction models were developed based on clinical variables to estimate an individual's net survival gain or not attributable to PORT. We found that PORT could improve OS (HR, 0.861; P = 0.044) for patients with a positive PORT net survival benefit. Conclusions: We established a practical survival prediction model that can be used to make individualized predictions about the expected survival of PORT or without PORT in patients with completely resected pathological N2 NSCLC, treated with chemotherapy.
Expression level of ACE2 in lung adenocarcinoma.
Authors: Liu Danni , Mu Tianhao , Chen Shifu 
Published: May 2020

e21022 Background: 2019-nCoV, a novel coronavirus (2019-nCoV), has infected tens of thousands of people in Wuhan, Hubei Province, China. This new coronavirus has led to hundreds of deaths, and especially threatened people with underlying diseases. ACE2 was reported as the 2019-nCoV putative receptor. The expression abundance of ACE2 may cause different disease progressions. Here, we evaluated the expression profile of ACE2 from 283 samples in lung adenocarcinoma . Methods: 283 samples from the public datasets (GEO: GSE31210 and GEO: GSE2109) were grouped by tissue, ethnicity and gender. The data was normalized by the RMA algorithm. Student 's t-test was used to compare the expression of ACE2 in different groups . Results: The expression level of ACE2 of primary lung tumor was significantly higher than normal lung tissue ( p < 0.0001). ACE2 was significantly differential-expressed between Asian and Caucasian lung adenocarcinoma patients ( p < 0.0001). However, no significant difference of the expression of ACE2 was observed by gender ( p = 0.33). Conclusions: ACE2 was highly expressed in primary lung adenocarcinoma , compared with normal lung tissues. The expression level of ACE2 was higher in Asian lung adenocarcinoma patients than Caucasian’s. These conclusions imply that Asian people with lung adenocarcinoma may be more vulnerable to 2019-nCoV.
Phase II prospective trial of primary lung tumor stereotactic body radiation therapy (SBRT) followed by concurrent mediastinal chemoradiation and adjuvant immunotherapy for locally-advanced non-small cell lung cancer (NSCLC): Planned toxicity analysis.
Authors: Heinzerling John H , Mileham Kathryn Finch , Robinson Myra M. , Symanowski James Thomas , Induru Raghava Reddy , Prabhu Roshan Sudhir , Gant Dean A. , Pal Sridhar E. , Haggstrom Daniel Ernest , Kim Edward S. , Burri Stuart , Simone Charles B. 
Published: May 2020

e21047 Background: The care of pts with locally-advanced NSCLC has continued to evolve. Dose escalation with conventional radiation and concurrent chemotherapy has failed to improve outcomes and is associated with low primary tumor control rates and high toxicity rates. We initiated a phase II study to evaluate full dose SBRT to the primary tumor followed by conventional chemoradiation to the involved lymph nodes followed by adjuvant immunotherapy in patients (pts) with unresectable locally-advanced NSCLC. Methods: Eligible pts included peripheral primary tumors ≤ 7cm or centrally based tumors that had at least 2 cm separation from involved nodal disease. Pts received SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by standard radiation to 60 Gy in 30 fractions with concurrent chemotherapy (physician choice of carboplatin/paclitaxel or cisplatin/etoposide). Pts without disease progression after chemoradiation then received adjuvant durvalumab (PACIFIC trial). Planned analysis of early toxicity was performed given this is the first prospective trial to replace conventional fractionation and deliver full dose SBRT to the primary tumor in the locally advanced setting. Results: From May 2017 to January 2020, 35pts were enrolled. Median follow up is 7.9 months (range 0-27 months). Toxicity related to either SBRT or mediastinal radiation was lower than previous published prospective trials with a grade 2 radiation pneumonitis incidence of only 17%. There was no ≥grade 3 pneumonitis. Grade 3 esophagitis was observed in 1 pt (3%) with grade 2 esophagitis in 37%. No grade ≥3 toxicity has been attributed to SBRT with 26% of pts experiencing a grade 2 toxicity from SBRT. Overall incidence of grade ≥3 pulmonary toxicity attributed to any therapy was 9%. One pt died of neutropenic sepsis due to legionella while on therapy attributed to chemotherapy. No major cardiac events were reported to date. Conclusions: Full dose SBRT to the primary tumor followed by standard chemoradiation to the involved lymph nodes appears to have a favorable toxicity profile when compared with conventional dose escalation and to previously published experiences with SBRT boost following chemoradiation in the treatment of locally advanced NSCLC. Our trial continues to enroll with a target of 56 pts. Clinical trial information: NCT03141359 .
Epidemiology, treatment, and outcomes in locally advanced spindle cell lung cancer.
Authors: Sterpi Michelle , Handa Shivani , Mehta Kathan , Kasi Anup 
Published: May 2020

e21048 Background: Spindle cell lung cancer (SpCC) is a rare type of NSCLC which portends a poor prognosis. Due to the rarity of diagnosis, there is a dearth of information about the epidemiology and overall survival for these patients. Methods: We performed a retrospective analysis using the SEER database from 1975-2016 to study the demographics, treatment modalities and outcomes for patients with locally advanced SpCC. Data regarding age, sex, race, pathological grade, staging, treatment, overall and disease specific survival was extracted. Hazards ratios were calculated to identify any difference in mortality between patients who received surgery alone versus those who received adjuvant chemotherapy or radiation. Results: A total of 936 cases of SpCC were identified, out of which 367 (39%) patients had locally advanced disease. 84% cases were diagnosed after the age of 60, with peak incidence occurring in the 70-74 age group. 87% were Caucasians, and 56% were males. 68% of the tumors were poorly differentiated. In terms of the treatment modalities for locally advanced SpCC, surgical resection was performed only in 58.5% cases. 27% patients received systemic chemotherapy, out of which 50% was in the adjuvant setting after surgery. 32 % patients received radiation therapy, only 38.5% of which was in the adjuvant setting. No statistically significant difference in mortality was seen in patients who received surgery alone vs adjuvant RT vs adjuvant chemotherapy. However, pts who did not receive surgery had a higher odds of mortality (OR = 4.2, p value 0.0001). Similarly, pts who only received chemotherapy alone had a higher odds of mortality vs those who received chemotherapy along with surgery (OR = 3.4, p-0.045), Overall survival was 25% for patients with localized disease, 9.5% for regional and only 2.6% for distant metastatic disease. For locally advanced SpCC, the observed cumulative 1-year survival was 54.8 % and declined to 29.2% after 5 years. Conclusions: Majority of the spindle cell carcinoma cases are poorly differentiated and present at an advanced stage at the time of diagnosis. For locally advanced SpCC, surgical resection can improve survival. Randomized trials are needed to test efficacy of adjuvant therapies.
Variant allele frequency of circulating tumor DNA mutations detected in preoperative blood is indicator for lymph node metastasis in early stage lung cancer.
Authors: Zhang Rusi , Liu Xinyi , Xie Wenzhuan , Huang Mengli , Zhang Lanjun 
Published: May 2020

e21057 Background: The advances in deep sequencing technologies makes circulating tumor DNA (ctDNA) detection in preoperative plasma a more and more significant indicator in early stage cancers. In particular, it allows us to learn a lot about tumor progression before surgery. Plasma variant allele frequency (VAF) of preoperative ctDNA mutations had been verified to correlate with tumor sizes in early lung cancers. Identification of lymph node (LN) metastasis status before surgery in patients with lung cancer is valuable for prognosis and treatment strategy decisions. To evaluate whether ctDNA predict the LN metastasis status, we conducted this analysis. Methods: Preoperative plasma and the matched leukocyte before treatment were collected from 38 early stage lung cancer patients, in which 8 cases with lymph node metastasis. 150-gene panel sequencing were performed on the specimens and the sequencing data were used as primary cohort. Multivariable logistic regression analysis was used to develop a prediction model based on the DNA and other clinical characteristics. The performance of the model was assessed by its calibration, discrimination and clinical usefulness in the public TRACERx 100 early lung cancers cohort. Results: The proportion of high variant allele frequency (HAF proportion) of mutations was significantly associated with LN status (p < 0.05, for both primary and validation cohorts). A prediction model was developed and predictors included the HAF proportion, smoking status and tumor size. The C-index of the model was 0.419 in primary cohort. In external validation cohort, the AUCs for LN positive was 0.678. Conclusions: Based on pan-gene panel deep sequencing, a big proportion of high variant allele frequency mutations in a single patient indicates advanced disease progression, which may reflect in LN involvement status. A logistic regression model was constructed using ctDNA and clinical characteristics. It showed considerable performance in the prediction of LN metastasis in early lung cancers.