Era Of Targeted Therapy Research Articles

New horizons for uncommon mutations in non-small cell lung cancer: BRAF, KRAS, RET, MET, NTRK, HER2.

The 2004 discovery of EGFR mutations, followed by ALK rearrangements, ushered in a targeted therapy era for advanced non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors targeting gene alterations have substantially improved survival and quality of life for patients with NSCLC. In the last decade, rearrangements of the ROS1 oncogene have been incorporated into healthcare practice that are applicable to another small subgroup of patients who benefit from similar targeted strategies. Recent genome studies of lung adenocarcinoma have identified other possible therapeutic targets, including RET, NTRK fusions, c-MET alterations, and activating mutations in KRAS, BRAF, and HER2, all with frequencies greater than 1%. Lung cancers harbouring these genome changes can potentially be treated with agents approved for other indications or under clinical development. This review updates the therapeutic arsenal that especially targets those genes.

Impact of quality of response on survival outcomes among multiple myeloma patients treated with novel agents - a retrospective analysis.

In this era of target therapies, novel data on the correlation between response endpoints and survival outcomes in multiple myeloma have arisen. To determine the impact of quality of response on clinical outcomes, using first-line treatment, and identify risk factors influencing progression-free survival (PFS) and overall survival (OS) among myeloma patients. Retrospective analysis on myeloma patients who were treated at the Clinic of Hematology and Clinical Immunology, University Clinical Centre, Niš, Serbia, over a four-year period. A total of 108 newly diagnosed patients who received first-line therapy consisting of conventional chemotherapy or novel agent-based regimens were included in this analysis. The quality of response to first-line therapy for the whole cohort was classified as follows: complete response (CR) in 19%; very good partial response (VGPR) in 23%; partial response (PR) in 38%; and less than PR for the remaining patients. After a median follow-up of 25.4 months, the three-year PFS and OS for the entire study population were 47% and 70%, respectively. Achievement of CR was the main factor associated with significantly prolonged PFS and OS, in comparison with patients who reached VGPR and PR. Likewise, addition of the new drugs bortezomib and thalidomide to standard chemotherapy led to considerably extended PFS and OS, compared with conventional therapy alone. This analysis demonstrated that the quality of response after application of first-line treatment using novel agent-based regimens among multiple myeloma patients was a prognostic factor for PFS and OS, which are the most clinically relevant outcomes.

Characteristics and outcomes of patients with blastic plasmacytoid dendritic cell neoplasm treated with frontline HCVAD

AbstractBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive blood cancer, often involving the skin, bone marrow, lymph nodes, and central nervous system (CNS) in 20% to 30% of patients. Despite significant progress in CD123- and BCL-2–targeted therapy, most patients are not cured without hematopoietic stem cell transplant (HSCT), and CNS relapses occur quite frequently. Combination approaches with targeted and chemotherapy agents plus incorporation of prophylactic CNS-directed therapy are urgently needed. In this setting, we sought to analyze outcomes using the cytotoxic chemotherapy backbone regimen hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (HCVAD). We conducted a retrospective analysis of patients with BPDCN (n = 100), evaluating complete remission (CR) and median overall survival (OS) among 3 groups: those who received frontline HCVAD-based therapy (n = 35), SL-401 (n = 37), or other regimens (n = 28). HCVAD-based regimens yielded higher CR (80% vs 59% vs 43%; P = .01). There was no significant difference in OS (28.3 vs 13.7 vs 22.8 months; P = .41) or remission duration probability among treatment groups (38.6 vs not reached vs 10.2 months; P = .24). HSCT was performed in 51% vs 49% vs 38%, respectively (P = .455). These results suggest a continued important role for HCVAD-based chemotherapy in BPDCN, even in the modern targeted-therapy era, with high CR rates in the frontline setting. Further studies must establish the clinical activity, feasibility, and safety of doublet/triplet combinations of targeted therapies plus cytotoxic agents and the addition of CNS prophylaxis, with the ultimate goal of durable long-term remission for patients with BPDCN.

Significance of upfront cytoreductive nephrectomy stratified by IMDC risk for metastatic renal cell carcinoma in targeted therapy era – a multi-institutional retrospective study

BackgroundThis retrospective multicenter study aimed to evaluate the survival benefit of upfront cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (RCC) patients stratified by International Metastatic RCC Database Consortium (IMDC) risk criteria.MethodsWe reviewed the medical records in the Michinoku Database between 2008 and 2019. Patients who received upfront CN, systemic therapy without CN (no CN) and CN after drug therapy (deferred CN) were analyzed. To exclude selection bias due to patient characteristics, baseline clinical data were adjusted by inverse probability of treatment weighting (IPTW). Overall survival (OS) was compared between upfront CN and non-upfront CN (no CN plus deferred CN). Associations between time-varying covariates including systemic therapies and OS stratified by IMDC risk criteria were analyzed by IPTW-adjusted Cox regression method.ResultsOf 259 patients who fulfilled the selection criteria, 107 were classified in upfront CN and 152 in non-upfront CN group. After IPTW-adjusted analysis, upfront CN showed survival benefit compared to non-upfront CN in patients with IMDC intermediate risk (median OS: 52.5 versus 31.3 months, p < 0.01) and in patients with IMDC poor risk (27.2 versus 11.4 months, p < 0.01). In IPTW-adjusted Cox regression analysis of time-varying covariates, upfront CN was independently associated with OS benefit in patients with IMDC intermediate risk (hazard ratio 0.52, 95% confidence interval 0.29–0.93, p = 0.03) and in patients with IMDC poor risk (0.26, 0.11–0.59, p < 0.01).ConclusionsUpfront CN may confer survival benefit in RCC patients with IMDC intermediate and poor risk.

Editorial: Novel therapeutic approaches in chronic kidney disease and kidney transplantation: the draw of evolving integrated multimodal approaches in the targeted therapy era.

Editorial: Novel therapeutic approaches in chronic kidney disease and kidney transplantation: the draw of evolving integrated multimodal approaches in the targeted therapy era.

Outcomes for Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Treated with Frontline HCVAD-Based Chemotherapy

Outcomes for Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Treated with Frontline HCVAD-Based Chemotherapy

Improvement of hematopoietic stem cell transplantation in the targeted therapy era

Improvement of hematopoietic stem cell transplantation in the targeted therapy era

Do Metastatic Kidney Cancer Patients Benefit From Cytoreductive Nephrectomy? A Real-World Retrospective Study From the SEER Database.

Introduction: The benefit of cytoreductive nephrectomy (CN) for metastatic kidney cancer has been challenged recently. The study aimed to evaluate the prognostic roles of surgical resection of primary tumor site for metastatic kidney cancer under a real-world setting.Methods: The Surveillance, Epidemiology, and End Results (SEER) database (2010–2015) and the overall survival (OS) and cancer-specific survival (CSS) were evaluated using the Cox proportional hazards regression model. One-to-one matching using the propensity score was used to estimate and compare the survival rates.Results: The SEER data contain records of 8,932 patients from 2010 to 2015. The data showed that 61.7% of the patients underwent CN while 38.2% did not receive any surgery. The median survival month for a patient without surgery was 4 months and for a patient with surgery was 19 months. The multivariate analysis showed that surgical resection of the primary tumor site was an independent favorable predictor for both OS and CSS (all p < 0.001) in the original and the matching cohort.Conclusions: In the era of target therapy, CN might still be a vital method to treat metastatic kidney cancer.

RADI-07. Individualized Nomogram for Predicting Survival of Patients with Brain Metastases after Stereotactic Radiosurgery

BackgroundGiven the increasing use of stereotactic radiosurgery (SRS) for brain metastases (BM), there is an emerging need for more precise assessment of survival outcomes after SRS, especially in the modern targeted therapy era.MethodsPatients with BM and treated by SRS were eligible in this study. Primary endpoint was overall survival (OS). Cox models were used to identify independent prognostic factors. Survival predictive nomogram was developed and evaluated by Concordance-index (C-index), area under the curve (AUC) and calibration curve.ResultsFrom January 2016 to December 2019, a total of 356 BM patients were eligible. Median OS was 17.7 months (95%CI 15.5–19.9) and actual OS at 1- and 2-year measured 63.2% and 37.6%, respectively. Nomogram for OS was developed by incorporating four independent prognostic factors: Karnofsky Performance Score, cumulative tumor volume, driver gene mutation status and serum lactate dehydrogenase. The nomogram was validated in a separate cohort demonstrated a well calibration and good discriminative ability (C-index=0.780, AUC=0.784). The prognostic accuracy of the nomogram (0.792) was considerably enhanced compared with classical prognostic indices, i.e., GPA (0.708), RPA (0.587) and SIR (0.536). Kaplan-Meier curves showed significant difference of OS among stratified low-, median- and high-risk groups (P < .001).ConclusionIn conclusion, we developed and validated an individualized prognostic nomogram by integrating physiological, volumetric, clinical chemistry and molecular biological surrogates. This nomogram, should be validated by independent external study, has a potential to facilitate more precise risk-stratifications to guide personalized treatment for BM.

Prognosis of Japanese metastatic renal cell carcinoma patients in the targeted therapy era.

The aims of this study were to investigate prognosis and validate prognostic models [Memorial Sloan-Kettering Cancer Center (MSKCC), International Metastatic Renal Cell Carcinoma Data Consortium (IMDC), and Japanese metastatic renal cancer (JMRC) models] in the targeted therapy era in Japanese patients with metastatic renal cell carcinoma. We retrospectively analyzed 692 patients who were diagnosed with mRCC from January 2008 to August 2018 in the Michinoku Japan Urological Cancer Study Group database. Nivolumab as sequential therapy was widely used. Other immune checkpoint inhibitors were excluded from this study. The median overall survival (95% confident interval) in all, MSKCC favorable, intermediate, and poor risk patients was 41.0months (33.9-46.8), not reached (63.5 to not estimable), 46.8months (37.1-52.9), and 10.4months (8.9-14.4), respectively. The median overall survival (95% confident interval) in IMDC favorable, intermediate, and poor risk patients was not reached (61.6 to not estimable), 47.4months (41.4-56.5), and 11.5 (9.9-16.3), respectively. The c-index of the MSKCC, IMDC, and JMRC models calculated at mRCC diagnosis was 0.680, 0.689, and 0.700, respectively. No statistical differences were found in the c-index among the models. While the real-world overall survival in Japanese patients with mRCC in the targeted therapy era improved compared to that previously reported in the cytokine era, there was no clear difference in the survival of poor risk patients between these eras. There were no differences in the superiority among the models.

Radiomics in Oncology, Part 1: Technical Principles and Gastrointestinal Application in CT and MRI.

Radiomics has been playing a pivotal role in oncological translational imaging, particularly in cancer diagnosis, prediction prognosis, and therapy response assessment. Recently, promising results were achieved in management of cancer patients by extracting mineable high-dimensional data from medical images, supporting clinicians in decision-making process in the new era of target therapy and personalized medicine. Radiomics could provide quantitative data, extracted from medical images, that could reflect microenvironmental tumor heterogeneity, which might be a useful information for treatment tailoring. Thus, it could be helpful to overcome the main limitations of traditional tumor biopsy, often affected by bias in tumor sampling, lack of repeatability and possible procedure complications. This quantitative approach has been widely investigated as a non-invasive and an objective imaging biomarker in cancer patients; however, it is not applied as a clinical routine due to several limitations related to lack of standardization and validation of images acquisition protocols, features segmentation, extraction, processing, and data analysis. This field is in continuous evolution in each type of cancer, and results support the idea that in the future Radiomics might be a reliable application in oncologic imaging. The first part of this review aimed to describe some radiomic technical principles and clinical applications to gastrointestinal oncologic imaging (CT and MRI) with a focus on diagnosis, prediction prognosis, and assessment of response to therapy.

CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma.

9506 Background: In the phase 3 CheckMate 067 trial, a durable and sustained clinical benefit was achieved with nivolumab (NIVO) + ipilimumab (IPI) and NIVO alone vs IPI at 5-y of follow-up (overall survival [OS] and progression-free survival [PFS] rates: 52%, 44%, 26% and 36%, 29%, 8%, respectively). Here we report 6.5-y efficacy and safety outcomes. Methods: Eligible pts with previously untreated unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio and stratified by PD-L1 status, BRAF mutation status, and metastasis stage. Pts received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W followed by NIVO 3 mg/kg Q2W (n = 314), NIVO 3 mg/kg Q2W + placebo (n = 316), or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were PFS and OS with NIVO + IPI or NIVO vs IPI. Secondary endpoints included objective response rate (ORR), descriptive efficacy assessments of NIVO + IPI vs NIVO alone, and safety. Results: With a minimum follow-up of 6.5 y, median OS was 72.1 mo with NIVO + IPI, 36.9 mo with NIVO, and 19.9 mo with IPI (table). Median time from randomization to subsequent systemic therapy was not reached (NR; 95% CI, 59.6–NR) with NIVO + IPI, 25.2 mo (95% CI, 16.0–43.2) with NIVO, and 8.0 mo (95% CI, 6.5–8.7) with IPI; 36%, 49%, and 66% of pts, respectively, received any subsequent systemic therapy. Median treatment-free interval (which excluded pts who discontinued follow-up prior to initiation of subsequent systemic therapy) was 27.6 mo (range, 0–83.0), 2.3 mo (range, 0.2–81.6), and 1.9 mo (range, 0.1–81.9) with NIVO + IPI, NIVO, and IPI, respectively. Of the pts alive and in follow-up, 112/138 (81%; NIVO + IPI), 84/114 (74%; NIVO), and 27/63 (43%; IPI) were off treatment and never received subsequent systemic therapy; 7, 8, and 0 pts, respectively, were still on treatment. Grade 3/4 treatment-related adverse events were reported in 59% of NIVO + IPI-treated pts, 24% of NIVO-treated pts, and 28% of IPI-treated pts. Since the 5-y analysis, no new safety signals were observed and no additional treatment-related deaths occurred. Conclusions: This 6.5-y analysis represents the longest follow-up from a phase 3 melanoma trial in the modern checkpoint inhibitor combination therapy and targeted therapy era. The results show durable improved outcomes with NIVO + IPI and NIVO vs IPI in pts with advanced melanoma. We observed improvement in OS, PFS, and ORR with NIVO + IPI over NIVO alone. Clinical trial information: NCT01844505. [Table: see text]

Large Cell Neuro-Endocrine Carcinoma of the Lung: Current Treatment Options and Potential Future Opportunities.

Large-cell neuroendocrine carcinomas of the lung (LCNECs) are rare tumors representing 1–3% of all primary lung cancers. Patients with LCNEC are predominantly male, older, and heavy smokers. Histologically, these tumors are characterized by large cells with abundant cytoplasm, high mitotic rate, and neuroendocrine immunohistochemistry-detected markers (chromogranin-A, synaptophysin, and CD56). In 2015 the World Health Organization classified LCNEC as a distinct subtype of pulmonary large-cell carcinoma and, therefore, as a subtype of non-small cell lung carcinoma (NSCLC). Because of the small-sized tissue samples and the likeness to other neuroendocrine tumors, the histological diagnosis of LCNEC remains difficult. Clinically, the prognosis of metastatic LCNECs is poor, with high rates of recurrence after surgery alone and overall survival of approximately 35% at 5 years, even for patients with early stage disease that is dramatically shorter compared with other NSCLC subtypes. First-line treatment options have been largely discussed but with limited data based on phase II studies with small sample sizes, and there are no second-line well defined treatments. To date, no standard treatment regimen has been developed, and how to treat LCNEC is still on debate. In the immunotherapy and targeted therapy era, in which NSCLC treatment strategies have been radically reshaped, a few data are available regarding these opportunities in LCNEC. Due to lack of knowledge in this field, many efforts have been done for a deeper understanding of the biological and molecular characteristics of LCNEC. Next generation sequencing analyses have identified subtypes of LCNEC that may be relevant for prognosis and response to therapy, but further studies are needed to better define the clinical impact of these results. Moreover, scarce data exist about PD-L1 expression in LCNEC and its predictive value in this histotype with regard to immunotherapy efficacy. In the literature some cases are reported concerning LCNEC metastatic patients carrying driver mutations, especially EGFR alterations, showing targeted therapy efficacy in this setting of disease. Due to the rarity and the challenging understanding of LCNEC, in this review we aim to summarize the management options currently available for treatment of LCNEC.

Long-Term Survival Outcomes of Cytoreductive Nephrectomy Combined with Targeted Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review and Individual Patient Data Meta-Analysis.

Simple SummaryCytoreductive nephrectomy (CN) refers to the removal of the primary renal tumor in the setting of metastatic renal cell carcinoma. In the past, the combination of CN with cytokine-based immunotherapy was considered the standard of care. However, CN’s role during the targeted treatment era remains controversial. We attempted to address this issue by performing a systematic review and meta-analysis of the literature. We synthesized data from 15 studies comparing CN and targeted therapy to targeted therapy alone. Our results show that CN combined with targeted therapy was associated with increased survival compared to targeted therapy only. Careful patient selection is required to take full advantage of any survival benefit that CN may offer. Future research endeavors should focus on developing appropriate prognostic models to guide appropriate patient selection for CN.The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains controversial during the targeted therapy era. To reconcile the current literature, we analyzed the reported survival data at the individual patient level and compared the long-term survival outcomes of CN combined with targeted therapy vs. targeted therapy alone in patients with mRCC. We performed a systematic review of the literature using the MEDLINE, Scopus, and Cochrane Library databases (end-of-search date: 21 July 2020). We recuperated individual patient data from the Kaplan–Meier curves for overall (OS), progression-free (PFS), and cancer-specific survival (CSS) from each study. We subsequently performed one-stage frequentist and Bayesian random-effects meta-analyses using both Cox proportional hazards and restricted mean survival time (RMST) models. Two-stage random-effects meta-analyses were also performed as sensitivity analyses. A subgroup analysis was also performed to determine the effect of CN timing. Fifteen studies fulfilling our inclusion criteria were identified, including fourteen retrospective cohort studies and one randomized controlled trial. In the one-stage frequentist meta-analysis, the CN group had superior OS (hazard ratio [HR]: 0.58, 95% confidence interval [CI]: 0.54–0.62, p < 0.0001) and CSS (HR: 0.63, 95% CI: 0.53–0.75, p < 0.0001). No meaningful clinical difference was observed in PFS (HR: 0.90, 95% CI: 0.80–1.02, p = 0.09). One-stage Bayesian meta-analysis also revealed superior OS (HR: 0.59, 95% credibility interval [CrI]: 0.55–0.63) and CSS (HR: 0.63, 95% CrI: 0.53–0.75) in the CN group, while no meaningful clinical difference was detected in PFS (HR: 0.91, 95% CrI: 0.80–1.02). Similar results were obtained with the RMST models. The OS benefit was also noted in the two-stage meta-analyses models, and in the subgroup of patients who received upfront CN. The combination of CN and targeted therapy for mRCC may lead to superior long-term survival outcomes compared to targeted therapy alone. Careful patient selection based on prognostic factors is required to optimize outcomes.

Comparison of Outcomes of Transplant and Nontransplant High-Risk Chronic Lymphocytic Leukemia Patients in the Novel Targeted Therapy Era.

Our aim was to compare patients with high-risk chronic lymphocytic leukemia referred to our transplant center who underwent allogeneic stem cell transplant with those who did not receive this treatment. Factors compared included demographics, clinical characteristics, and survival rates in the novel targeted therapy era. All 33 patients with high-risk chronic lymphocytic leukemia who were referred to the hematopoietic stem cell transplant center were enrolled in this retrospective, single-center nonrandomized study. Outcomes of patients who received allogeneic stem cell transplant were compared with those of nontransplant patients. Chemoimmunotherapy and ibrutinib were given when indicated. Factors related to overall and progression-free survival were assessed. Thirteen patients underwent allotransplant, and transplant was not done in 20 patients for various reasons. Demographic and clinical features of the transplant and nontransplant groups were similar. The estimated cumulative overall survival was 72.6 ± 15 and 84.3 ± 13 months in the nontransplant and transplant groups, respectively. The 5-year overall and progression-free survival rates in the transplant and nontransplant groups were 57.3%/36.0% and 40%/20.6%, respectively. In the nontransplant group, overall survival of those who used ibrutinib was longer than overall survival in patients in the transplant group who used the same drug, but the difference was not statistically significant. Although not significant, overall survival in patients who did not use ibrutinib was longer in the transplant group than in the nontransplant group. Cox regression analyses showed that transplant, relapse, and Binet stage were independent predictors of overall survival. In patients who do not use ibrutinib, allogeneic stem cell transplant improved survival compared with nontransplant patients. Addition of ibrutinib provided comparable life expectancies, showing that allogeneic stem cell transplant and ibrutinib may have complementary roles. Transplant is still an independent predictor of overall survival.

Risk Factors for Overall and Disease Free Survival in Those Patients with Multiple Colorectal Liver Metastases in the Era of Target Therapy

Purpose: Although,the number of colorectal liver metastases (CRLM) is decreasingly considered as contraindication to surgery, most of the scores still include the number of lesions (GAME score, Tumor Burden Score) as one of main predictors of worst overall survival.This study aimed to evaluate the outcome after liver surgery of those patients with 5 or more lesions and to identify prognostic factors for survival in such group of patients. Methods: The study population consisted of an european unicentre cohort of patients with CRLM operated from January 2010 to December 2019 and whose data were prospectively collected in the LivermetSurvey registry after Ethics Committee aproval. An univariate and multivariate analyses was performed to identify the risk factors associated with overall and disease free survival in those patients with ≥5 lesions at diagnoses. Results: We included 250 patients of whom 54 patients had ≥5 lesions.The main characteristics of this group: right side primary tumor in 22%, stage N positive of primary tumor in 65%, CEA level at diagnoses in 16.8ng/mL (0.5-2,933), synchronous disease in 78%, KRAS and BRAF mutation 43% and 4%, GAME Score≥4 in 22% and preoperative chemotherapy 91% of whom targeted therapy was administered in 50% of the patients. The median overall survival (OS) and disease free survival (DFS) in this group was 25 months (4-108) and 10 months (0-103) respectively. Multivariate analyses showed that the primary tumor stage N positive (HR=3.41) and right side primary tumor (HR= 1.93) emerged as the strongest risk factor for OS. Regarding DFS, R1 resection (HR=3.09), right side primary tumor (HR=1.88) and KRAS mutation (HR= 1.56) were the main risk factors. The model demonstrated that a median of 30 months of OS could be achieved in selected cases and more than 16 months of DSF was possible providing R0 resection associated with at least an more additional favorable factor. Conclusions: Multiple CRLM is an important factor with impact in long-term survival however longer OS and DFS could be achieved in selected cases.

Discovery of Dysimmunity in Large Granular Lymphocytic Leukemia (LGLL) using Bioinformatic Analysis.

Large granular lymphocytic leukemia (LGLL) is a chronic lymphoproliferative disorder characterized by the clonal proliferation of large granular lymphocytes (LGL), classified as T and NK subtypes. Although JAK/STAT pathway gene mutation, such as STAT3/STAT5B, is the dominant driver in the proliferation of LGLL, immune abnormality remains an unsolved puzzle in the pathogenesis. By means of bioinformatic method through the GEO dataset GSE39838, we performed the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, as well as protein-protein interaction network (PPI) module calculation. As a consequence, differentially expressed genes (DEGs) involved in immune regulation were detected to be related with LGLL, including C1QA, C1QC and CD163 etc. Among all the DEGs, 147 genes were up-regulated, while the number of down-regulated genes was 1,296. In the KEGG pathway of LGLL, infection and immunity were the primary alteration, including tuberculosis and rheumatoid arthritis (RA). However, meticulous experiments are required to validate. To sum up, dysimmunity might be another internal anomaly of LGLL, thus it is a reminder that immune regulation of LGLL should be paid more attention. Moreover, immune microenvironment studies in LGLL covering T, B, and NK cells probably contribute to the molecular pathology, aiming to contribute to the molecular pathology of the LGLL. Additionally, pharmaceutical development directed at immune molecules might be pre-dictive of targeted therapy era in LGLL.

The current role of cytoreductive nephrectomy for metastatic renal cell carcinoma.

The management of metastatic renal cell carcinoma (mRCC) continues to be a therapeutic challenge; however, the options for systemic therapy in this setting have exploded over the past 20 years. From the advent of toxic cytokine therapy to the subsequent discovery of targeted therapy (TT) and immune checkpoint inhibitors, the landscape of viable treatment options continues to progress. With the arrival of cytokine therapy, two randomized trials demonstrated a survival benefit for upfront cytoreductive nephrectomy (CN) plus interferon therapy and this approach became the standard for surgical candidates. However, it was difficult to establish the role and the timing of CN with the subsequent advent of TT, just a few years later. More recently, two randomized phase III studies completed in the TT era questioned the use of CN and brought to light the role of risk stratification while selecting patients for CN. Careful identification of the mRCC patients who are likely to have a rapid progression of the disease is essential, as these patients need prompt systemic therapy. With the continued advancement of systemic therapy using the immune checkpoint inhibitors as a first line therapy, the role of CN will continue to evolve.

Impact of Whole Brain Radiotherapy on Leptomeningeal Metastasis from Non-Small Cell Lung Cancer in Targeted Therapy Era

Impact of Whole Brain Radiotherapy on Leptomeningeal Metastasis from Non-Small Cell Lung Cancer in Targeted Therapy Era

Survival Trends in Patients Under Age 65 Years With Mantle Cell Lymphoma, 1995-2016: A SEER-Based Analysis.

Purpose: The treatment paradigm for mantle cell lymphoma (MCL), a B-cell malignancy, has shifted considerably during the past decades. This study aimed to evaluate time trends in overall survival (OS) and disease-specific mortality (DSM) of younger (age ≤ 65 years) patients with MCL from 1995 to 2016.Methods: We used the Surveillance, Epidemiology, and End Results database. Year of diagnosis was divided into three eras: the chemotherapy-alone era (1995–2000), intensified-immunochemotherapy era (2001–2012), and targeted-therapy era (2013–2016). We used the Kaplan–Meier method, log-rank test, and subdistribution proportional hazard regression in the analysis.Results: A total 4,892 patients were identified. Median OS increased from 67 months in the chemotherapy-alone era to 107 months in the intensified-immunochemotherapy era (P < 0.001). The DSM rate decreased significantly from 1995 to 2016 (P < 0.001); the adjusted hazard ratios of MCL-specific death were 0.589 (P < 0.001) for the intensified-immunochemotherapy era and 0.459 (P < 0.001) for targeted-therapy era, as compared with the chemotherapy-alone era. Patients with advanced-stage MCL exhibited lowering risk of death across the three eras (P < 0.001).Conclusions: During 1995–2016, survival in younger patients with MCL increased significantly, especially those with advanced-stage disease, potentially reflecting the impact of advancement in treatment modalities on MCL outcome.