bluuebunny/crossref_metadata_2025 huggingface dataset:
M.D. Anderson experience of immune checkpoint inhibitor therapy in classical Hodgkin lymphoma.
Authors: Nair Ranjit , Pinnix Chelsea Camille , Gunther Jillian Rebecca , Strati Paolo , Westin Jason , Fayad Luis , Hagemeister Fredrick B. , Iyer Swaminathan Padmanabhan , Nastoupil Loretta J. , Parmar Simrit , Rodriguez Maria Alma , Steiner Raphael , Dabaja Bouthaina Shbib , Fang Penny , Flowers Christopher , Noorani Mansoor , Feng Lei , Neelapu Sattva Swarup , Ahmed Sairah , Lee Hun Ju
Published: May 2020

e20013

Background: Nivolumab and Pembrolizumab are effective immune checkpoint inhibitor (ICI) therapies targeting PD-1/ PDL-1 immune axis. The drugs are currently approved for relapsed/ refractory classical Hodgkin lymphoma (cHL)based on phase I and II trial data. Methods: We conducted a retrospective study of patients (pts) with relapsed refractory cHL treated with ICI therapy at M.D. Anderson Cancer center from 4/2013 to 5/2019 to evaluate the efficacy of this treatment. The responses were assessed using revised response criteria according to the Lugano classification Results: Ninety-two pts treated with nivolumab (66) and pembrolizumab (26) were included. Fifty six pts (63%) were advanced stage at diagnosis, most treated initially with ABVD (88%) and BV-AVD (3%). Seventy percent pts had primary refractory disease or relapsed < 12 months after frontline therapy. At the time of ICI initiation, pts had the following characteristics: median age 35 (range 18-86), extranodal disease - 28 pts (37%), prior BV exposure in 81 pts (89%) with 66% considered BV refractory. Sixty one percent patients were refractory to the last prior line of salvage therapy. Median prior lines of therapy was of 3 (range 1-13) and 53 pts (58%) had a prior HSCT. At a median follow-up time of 20.2 months (range: 1.58 - 55.98 months), median progression free survival was 12.3 months and median overall survival was not reached. Among the 39 patients with no prior transplant, 11 patients who achieved CR with ICI were consolidated with HSCT (autologous - 7 and allogeneic - 4). Of this cohort, 2 pts (1 post auto, 1 post-allo) have relapsed. Five patients in our cohort were treated with an alternative ICI for subsequent relapse; of four patients with response assessment, 3 achieved CR and 1 experienced PD. Conclusions: In this cohort of cHL pts, ICI offered high response rates before and after HSCT supporting the possibility for using ICI earlier in the treatment course for refractory or early relapsed HL.
Risk-adapted therapy for advanced-stage natural killer/T-cell lymphoma: An analysis from the China Lymphoma Collaborative Group Study.
Authors: Liu Weiping , Yang Yong , Qi Shunan , Wang Ying , He Xia , Wu Gang , Qu Baolin , Qian Liting , Zhang Fuquan , Qiao Xueying , Hua Wang , Li Gaofeng , Zhang Yu-Jing , Zhu Yuan , Cao Jianzhong , Wu Junxin , Wu Tao , Zhu Jun , Li Ye-Xiong , Song Yuqin
Published: May 2020

e20041

Background: Few studies focused on the risk-adapted therapy for advanced-stage natural killer/T-cell lymphoma (NKTCL) due to poor prognosis. Methods: Data of 406 patients with advanced-stage NKTCL from 20 Chinese institutions between 2000 and 2015 were retrospectively analyzed. To develop a prognosis index model for advanced-stage NKTCL, all patients were divided into the primary cohort from South China (n = 198) and the validation cohort from North China (n = 208). Clinical factors related to survival in the primary cohort were identified to construct a new prognosis index model. An external validation for the prognosis index model was performed in the validation cohort. Stratified by the prognosis index model, survival benefit for treatment models was assessed. Results: The median age was 42 years with the ratio of male/female of 2.5:1. Extra-nodal involvement was observed in 72.4% of patients. More than one third of patients received asparaginase (Asp)–containing chemotherapy. In addition, radiotherapy was administrated in 135 (33.3%) patients. The overall response rate (ORR) and complete remission (CR) rate were 59.3% and 38.3% in 337 available patients. The expected 3-year progression-free survival (PFS) and overall survival (OS) rates were 26.9% and 37.3%, respectively. Based on 3 clinical variables including ECOG-PS > 1, elevated LDH and solid organs involvement, a new prognosis index model (ASPRIN) was developed and showed superior discrimination than current models including IPI, KPI and PINK in this particular population. The expected 3-year OS rates in the primary and validation cohort were 54.8% and 52.9% in the low risk group (with 0-1 risk factor), 34.4% and 38.0% in the intermediate risk group (with 2 risk factors), 13.8% and 10.6% in the high risk group (with 3-4 risk factors), respectively. Stratified by ASPRIN model, combined radio-chemotherapy provided better survival benefit than chemotherapy alone regardless of chemotherapy regimens in the low risk group (3-year PFS 52.6% vs. 22.6%, P < 0.001; 3-year OS 72.8% vs. 35.8%, P < 0.001), while Asp–containing chemotherapy improved survival with an increase of about 10%-15% in PFS and OS compared with non–Asp–containing chemotherapy in the intermediate and high risk groups. Conclusions: The outcome of advanced-stage NKTCL is still poor and heterogeneous even in the era of Asp–containing chemotherapy, which highlighted the need of establishing more effective risk-adapted therapeutic strategies.
Circulating nucleosomes in hematological malignancy.
Authors: Terrell Jason , Josseaux Eleonore , Latora Helene , Rommelaere Guillaume , Hardat Natalie , Herzog Marielle , Micallef Jake , Eccleston Mark
Published: May 2020

e20078

Background: There are over 700,000 new cases of non-Hodgkin lymphoma (NHL), acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL) diagnosed globally each year and approximately 415,000 deaths. The non-specific symptoms of lymphoma and leukemia often delay diagnosis. We investigated the circulating levels of intact nucleosomes containing the histone H3.1 isoform (Nu.Q-H3.1) in a variety of solid tumors, NHL, AML, ALL, and in healthy subjects. Methods: We measured levels of Nu.Q-H3.1 in plasma samples taken from 62 healthy volunteers (mean age = 45 yrs) and 329 patients diagnosed with cancer (mean age = 56 yrs), including 25 patients diagnosed with each of cancer of the bladder, bone, brain, oesophagus, cervix, skin, head & neck or melanoma, 21 patients diagnosed with uterine cancer as well as with NHL (n = 25), AML (n = 25) and ALL (n = 8). The cohort included samples taken from patients at diagnosis and at relapse. Whole blood samples were collected in EDTA plasma tubes, double-centrifuged at 1500 rcf for 15 minutes within 2 hrs of blood draw, after which plasma was transferred to a cryotube and frozen immediately until analysis. Plasma samples (20µl) were analyzed in duplicate for Nu.Q-H3.1 using an ELISA method developed and validated to CLSI guidelines. Results: We observed elevated levels of Nu.Q-H3.1 in the patients diagnosed with various cancers. Only 14 of 271 patients with a solid tumor had levels > 200ng/ml. In contrast the median Nu.Q-H3.1 levels observed for NHL, AML and ALL were 276, 284 and 585ng/ml respectively. The median nucleosome level in 62 healthy subjects was 40ng/ml; the highest level was 198ng/ml. The AUC for all patients diagnosed with NHL, AML or ALL (n = 54) vs healthy volunteers was 91% with a sensitivity of 74% at 95% specificity. The AUC for the subset of patients newly diagnosed with NHL, AML or ALL (n = 31) vs healthy volunteers was 92% with a sensitivity of 81% at 95% specificity. Conclusions: Elevated nucleosome levels have been reported for a number of diseases. Our early results indicate that levels of Nu.Q-H3.1 are particularly elevated in haematological malignancies and may be a useful diagnostic tool warranting further study.
T-cell receptor gene rearrangement clonality, flow cytometry status, and associated outcomes in early-stage CTCL.
Authors: Marks Jennifer Aline , Switchenko Jeffrey M. , Allen Pamela Blair , Lechowicz Mary Jo
Published: May 2020

e20087

Background: Cutaneous T-Cell Lymphoma (CTCL) is a monoclonal lymphoproliferative disease. Studies hypothesize T-cell receptor gene (TCR) rearrangement and flow cytometry as means of predicting those at risk of aggressive disease. We aimed to assess outcomes in early-stage disease by TCR clonality and flow cytometry in peripheral blood. Methods: We performed a retrospective analysis of 328 pts with early-stage (1-2A) CTCL using our internal CTCL database with protocol approved by our institutional review board (IRB00045798). Early-stage CTCL pts included were those with TCR clonality and/or flow cytometry in the peripheral blood obtained within 6 months of diagnosis and/or at initial check. Overall survival (OS) and time to next treatment (TTNT) were examined. Missing data or OS/ TTNT values larger than 25 years were excluded. Univariate/multivariate models and Kaplan-Meier analyses were run for both OS and TTNT. Results: In the cohort (n = 328) the median age was 53.2 years (8.6-87.5), with equal sex predominance, and distribution among stages. 261 pts had TCR clonality assessed. 78.5% (n = 205) were non-clonal and 21.5% (n = 56) were clonal. 284 pts had flow assessed (n = 44/328 with missing data). 89.8% (255/284) were flow (-), initially. Of those without clonality, 95.29% (n = 182 p < 0.001) were flow (-). 76% (38/56 p < 0.001) with TCR clonality were flow (-). TCR clonality in the blood was not associated with a survival nor TTNT by univariate or multivariate analyses. Age at diagnosis was significant contributing to OS and TTNT in multivariate analyses (HR 1.04,CI 1.01-1.06,p < 0.01;HR 1.01, CI 1.00-1.02,p = 0.033, respectively). Flow cytometry status was not associated with TTNT. Flow cytometry in the blood was associated with survival but was limited to stage 2A pts (n = 98, p = 0.0171). Median survival of those with flow negative results was 20.8 yrs (CI 11.8,NA, p = 0.0171) with a 5-year survival of 95.8%(CI 87.4%-98.6%) compared to those with positive results of 12 yrs (CI 1.3, NA), p = 0.0171) with a 5-yr survival of 80.8%(CI 42.3%-94.9%). Conclusions: We found no difference in OS or TTNT by TCR status in blood for stage 1-2A disease. Flow cytometry status and OS differed in stage 2A pts. Significance of TCR clonality or flow cytometry in early-stage disease remains unclear. Findings raise questions of needing to risk-stratify in early-stage disease by TCR gene rearrangement or flow cytometry. Those with stage 2A disease, flow cytometry status may confer some benefit. Larger cohorts needed to further investigate these findings.
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.
PD-L1 expression and progression risk of stage III NSCLC patients on durvalumab consolidation.
Authors: Jazieh Khalid , Gad Mohamed , Saad Anas M , Pennell Nathan A.
Published: May 2020

e21070

Background: Durvalumab is an anti-PD-L1 agent used as consolidation for patients with stage III non-small cell lung cancer (NSCLC) following chemoradiation. In the PACIFIC trial similar progression-free survival (PFS) and overall survival (OS) benefits were seen whether patients had PD-L1 expression of ≥25% or <25%. In this study we sought to examine outcomes for patients with PD-L1 expression using the more commonly used <1%, 1-49%, and 50-100% cutoff points. Methods: This was a retrospective analysis of 52 patients with stage III NSCLC who underwent treatment with chemoradiation followed by durvalumab maintenance. Patients were divided into groups of PD-L1 Negative (<1% positivity), Low PD-L1 (1-49%), and High PD-L1 (50-100%) based on the percentage of tumor PD-L1 expression using local testing with the Dako 22C2 antibody. The primary endpoint was presence or absence of radiographic progression while on durvalumab or after completing therapy, while PFS and OS were also determined. Results: Of the 52 patients, 25% were in the High PD-L1 group, 21% in the Low PD-L1 group, 27% in the PD-L1 Negative group, and the remaining were not tested for PD-L1. The progression rates were 64.3%, 90.9%, and 23.1% for the PD-L1 Negative, Low PD-L1, and High PD-L1 groups respectively (Table). Using Chi-square analysis there was a significant association between the extent of PD-L1 expression and progression (p = 0.003). The odd’s ratio (OR) of progression in the High PD-L1 group compared to the PD-L1 Negative group was 0.167 (0.031-0.904, p = 0.038), and the OR of progression in the Low PD-L1 group compared to PD-L1 Negative was 5.556 (0.541-57.00, p = 0.149). There was a statistically significant difference in PFS between the groups (p = 0.019), but not OS. Conclusions: Our results show that PD-L1 expression may be useful in predicting the risk of cancer progression in stage III NSCLC patients undergoing durvalumab consolidation. Patients with high PD-L1 (50-100%) expression had significantly lower odds of disease progression and longer PFS compared to those who were negative for PD-L1. While the rate of progression was higher in the Low PD-L1 group, the OR was not statistically significant when compared to the PD-L1 Negative group. [Table: see text]
Trends in management of locally advanced large cell neuroendocrine carcinoma of the lung.
Authors: Limonnik Vladimir , Abel Stephen , Colonias Athanasios , Monga Dulabh K. , Finley Gene Grant , Wegner Rodney E.
Published: May 2020

e21073

Background: Large cell neuroendocrine carcinoma (LCNEC) is a rare pulmonary malignancy with clinicopathologic features of both non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). The optimal treatment approach for LCNEC is not well established, likely a result of the histology’s underrepresentation in randomized clinical trials. Given the paucity of available data regarding LCNEC management, we queried the National Cancer Database (NCDB) to describe trends in management, identify predictors of treatment receipt, and compare outcomes in patients receiving chemotherapy (ChT) and chemoradiotherapy (CRT). Methods: We identified patients with locally advanced (Stage III) LCNEC of the lung treated with definitive ChT or CRT between the years of 2004-2015. Odds ratios were calculated to determine predictors of CRT receipt. Multivariable cox regression was used to determine predictors of overall survival. Results: Using the above criteria, 6,802 patients were identified, 46% of whom received CRT (n = 3,153) while 39% (n = 2,644) received ChT alone. Median age of the entire cohort was 68 years old. Most patients had T4 (35%) and N2 (59%) disease. Median overall survival was 11.9 months (11.3-12.6) in patients receiving ChT compared to 16.1 months (15.4-16.9) in patients receiving CRT (p < 0.0001). Overall survival at 1, 3, and 5 years was 50%, 20%, and 13% versus 60%, 27%, and 18%, in patients receiving ChT and CRT, respectively. Older patients and those with higher comorbidity scores were less likely to receive CRT; whereas patients with higher education level, treatment receipt at an academic/research program facility, N2 disease, and later treatment year were more likely to receive CRT. On multivariable analysis, older age, greater comorbidity score, presence of N2 disease, and presence of T4 disease were all associated with decreased OS, whereby female sex, private insurance, higher income, lower T stage, and more recent treatment were associated with increased overall survival. CRT receipt was an independent predictor of increased overall survival. Conclusions: Definitive CRT was an independent predictor of increased overall survival in patients with locally advanced LCNEC of the lung. Findings from our study may help guide potential areas of future investigation to help define an ideal treatment approach for LCNEC.
Stereotactic body radiotherapy and systemic dose chemotherapy for locally advanced lung cancer, single-arm phase II study.
Authors: Kubicek Greg , Khrizman Polina , Squillante Christian Michael , Xu Qianyi , Abouzgheib Wissam , Boujaoude Ziad , Patel Ashish Bharat , Hageboutros Alexandre
Published: May 2020

e21081

Background: The outcomes for locally advanced non-small cell lung cancer (NSCLC) are overall poor. This is a single arm phase 2 study (Clinical trials.gov NCT02568033) evaluating the role of stereotactic body radiosurgery (SBRT) along with full dose systemic chemotherapy in the treatment of unresectable stage 2 and stage 3 NSCLC. Methods: patients were treated with SBRT to all sites of gross disease. Dosing consisted of 60 Gy in 3 fractions for peripheral lung tumors, 50 Gy in 5 fractions for central lung tumors, and 40-50 Gy in 5 fractions for hilar and mediastinal lymph nodes. Chemotherapy was histology dependent and consisted of 4 cycles, there was a 7 days break between chemotherapy and SBRT. Quality of life was measured using FACT-L. Results: Twenty two patients were enrolled and analyzed. 17 (77 %) were stage III and 19 (86%) had lymph node involvement. Median follow-up for all patients was 23.1 months. Median overall survival is 27.2 months. Overall survival at one year was 82% and overall survival at two years was 53%. Two year regional failure rate 19%. Two year distant failure rate 47.2%. Quality of life scores at one year were available for 12 patients and were unchanged compared to baseline. Acute toxicity grade 3 or greater was seen in 6 patients and late toxicity grade 3 or higher was seen in 2 patients. Conclusions: A combination of SBRT and full dose chemotherapy appears to be a safe and effective treatment for locally advanced NSCLC and warrants further investigation. Clinical trial information: NCT02568033 .
Mutational distinction between adenocarcinoma in situ, minimally invasive adenocarcinoma and invasive adenocarcinoma in lung cancer patients with multiple tumors.
Authors: Liu Jixian , Li Yingmei , Xie Yuancai , Luan Xinyu , Peng Xuxing , Mu Tianhao , Chen Shifu , Wu Da
Published: May 2020

e21089

Background: Lung adenocarcinoma is the most popular lung cancer type, and it can be classified as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA) based on histology. The mutational similarities and differences have not been discussed in these subtypes. Methods: Targeted deep sequencing was performed on 31 lung adenocarcinomas with matched blood samples from 15 patients with multiple tumors. We compared mutations among each subtype. Results: The 31 tumors consisted of 10 AIS, 6 MIA and 15 IA subtypes; the median mutation number in each type was 1, 1 and 3 respectively. Eleven, six and fifty-three mutations were identified in AIS, MIA, and IA respectively. Among all the 67 mutations, only EGFR_p.L858R was found in all three types; BRAF_p.K601E was found in AIS and IA. Conclusions: AIS, MIA and IA harbor distinct mutational signatures, except for several popular driver mutations, suggesting their distinct origin and evolution path.
A single-center retrospective cohort study evaluating the role of neoadjuvant chemotherapy in malignant peritoneal mesothelioma.
Authors: Wang Xiao , Katz Sharyn I. , Roshkovan Leonid , Walker Suzanne , McNulty Sally , Ciunci Christine Agnes , Muira John , Karakousis Giorgos , Cengel Keith A. , Langer Corey J. , Marmarelis Melina Elpi
Published: May 2020

e21093

Background: Malignant peritoneal mesothelioma (MPM) is a rare variant of malignant mesothelioma, representing < 30% of cases. Standard of care is cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) when feasible. The benefit of systemic chemotherapy (chemo) (Neoadjuvant- N, Adjuvant- A, or 1st-line metastatic –M) is not well established and some retrospective studies report worse outcomes with N chemo. However, our institution has favored use of N chemo prior to surgery for symptom relief and surgical optimization. We conducted a single-center retrospective cohort study of MPM patients treated at our institution to evaluate the effect of N vs. A chemo on outcomes. Methods: We identified non-papillary MPM patients via ICD9/10 codes seen at our institution between 1/1/2009 and 9/1/2019. Pts were followed until 1/1/2020. Patients without pathologic diagnosis were excluded. We explored the effect of receipt of CRS, type of systemic therapy, and histology on overall survival. Median overall survival (mOS) from diagnosis was estimated from Kaplan-Meier curves. A Cox proportional hazard model computed hazard ratios (HR) to assess the effect of the exposure on OS. Results: We identified 47 patients with non-papillary MPM: median age 62 years, 77% epithelioid histology, 74.5% white, 55.3% known asbestos exposure. CRS was performed in 24 (51%) and 18/24 (75%) received HIPEC. The majority received systemic therapy (34/47 (72%)). Among those that received chemo and surgery, N chemo was more common than A chemo (N:12 (all platinum/pemetrexed), A:7). Median OS was 52.7 months (mo) overall and 77.2 mo with surgery vs 20.2 mo without (log rank p = 0.006). Toxicity from N chemo did not prevent surgery with 8/12 successfully receiving surgery (1 surgery scheduled, 2 lost to follow up). Of the 10 pts with evaluable scans: 5 had radiographic reduction of disease (2 complete responses by RECIST 1.1), 4 stable disease and 1 with disease growth. N chemo reduced ascites in 3 out of 4 pts with baseline ascites. N chemo was not associated with worse mOS compared to A chemo (HR 0.64, 95% CI 0.1-3.0, p = 0.62). Non-epithelioid histology was not associated with a worse OS compared to epithelioid (HR 1.5, 95% CI 0.6-4.1, p = 0.4). Conclusions: N chemo was not associated with worse outcomes compared to A chemo and toxicity from N chemo did not preclude surgery. In addition, N chemo resulted in reduction of disease burden and ascites in pts with MPM.
Identifying genomic alterations in small cell lung cancer using the liquid biopsy of bronchial washing fluid.
Authors: Zhai Jinfang , Han Songyan , Guo Qinxiang , Shan Binbin , Wang Jing , Guo Yanrong , Tong Guoping , Zhao Chang , Li Yuan , Han Qiao , An Xiaoqin , Yue Ruiqing , Wang Li , Guo Tingting , Yang Weihua
Published: May 2020

e21098

Background: With the rapid development of cancer genomics, the precision medicine of small cell lung cancer (SCLC) is emerging. However, there are limitations to the clinical use of tumor tissue and peripheral blood biopsies. The main purpose of this study was to evaluate the potential use of bronchial washing fluid (BWF) in the liquid biopsy of SCLC. Methods: Twenty-one SCLC patients diagnosed in 2019 were enrolled in this study. BWF (separated as supernatant and precipitate), treatment-naive plasma and tumor tissue samples were collected from all of patients and subjected to next-generation sequencing (NGS) using a 1021-gene panel. The concordance rates of genomic profiling using NGS in these four types of samples were evaluated. Results: Of these 21 patients, 20 BWF supernatant (BWFs) samples, 21 BWF precipitate (BWFp) samples, 21 tumor tissue samples and 20 plasma samples were successfully tested. The detectability of somatic mutations was 100% for BWFs, BWFp and tumor tissues, and only one plasma was absent with any mutation. Matched tumor tissue, BWFs, BWFp and plasma samples were subsistent for 19 patients. For these patients, 204 genomic alterations were identified in tissue samples, of which 189 (92.6%), 175 (85.5%) and 163 (79.9%) alterations were detected in the matched BWFs, BWFp and plasma samples, respectively. Moreover, tumor mutation burden (TMB) was also calculated. Compared with the proportion of TMB-H samples in tissue samples counting 61.9% (13/21), 60% (12/20) of BWFs samples and 52.38 % (11/21) of BWFp samples were TMB-H (defined as more than or equal to 9 mutations per megabase), which was a molecular biomarker that can be used in immunotherapy efficacy prediction. The TMBs of BWFs, BWFp and treatment-naive plasma samples all had strong correlation with that of tissue samples. The TMB of BWFs had the strongest correlation (Pearson r = 0.9512, p < 0.0001), and the TMB of treatment-naive plasma had relatively lower correlation (Pearson r = 0.8782, p < 0.0001) compared with those of BWFs (Pearson r = 0.936, p < 0.0001) and BWFp (Pearson r = 0.8782, p < 0.0001). Conclusions: For SCLC patients, the liquid biopsy of BWF showed high potential to identify DNA alterations and calculate TMB grades, which suggested that genomic analysis of BWF liquid biopsy may have clinical value in predicting the effectiveness of targeted therapy and immunotherapy. It can be widely used in routine clinical practice.