Lung Cancer Survival with Current Therapies and New Targeted Treatments: A Comprehensive Update from the Srinagarind Hospital-Based Cancer Registry from (2013 to 2017).

BACKGROUND: Lung cancer (LC) is a common malignancy and leading cause of cancer death worldwide and in Thailand. An update on LC survival factors after diagnosis at Srinagarind Hospital is needed. METHODS: We conducted a retrospective cohort study, and the data were sourced from the Srinagarind Hospital-Based Cancer Registry. All LC cases were diagnosed between January 1, 2013, and December 31, 2017, and followed up until November 30, 2019. Cases of LC (ICD-O-3) numbered 2,149, but only those with coding C34.0-C34.9 were included. The survival rate was estimated using Kaplan-Meier, while the Log-rank test was used to estimate survival. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression models. RESULTS: The 2,149 patients had a total follow-up of 269.6 person-years. Overall, 1,867 patients died during the study, for a corresponding case-fatality mortality rate of 86.0 per 100 person-years. The respective 1-, 3-, and 5-year survival rate was 31.2 % (95% CI; 29.21 to 33.15%), 12.9 % (95%CI: 11.49 to 14.45), and 10.2% (95%CI: 8.74 to 11.70). After patient diagnosis, the median survival time was 0.46 years (5.51 months) (95% CI: 0.42 to 0.50). Targeted therapy was associated with longer survival than non-targeted therapy (p-value < 0.001). After adjusting for sex, TNM stage, and histologic type, multivariable analysis of the entire cohort identified chemotherapy as an independent predictor of improved survival (adjusted HR= 0.48; 95% CI: 0.42 to 0.55; P < 0.001), and that sex, TNM stage, and histologic type were associated with survival. CONCLUSION: The study confirmed that sex, stage of disease, histology, and chemotherapy are associated with survival of LC. Primary prevention and screening for early detection improve survival. Further investigations into factors affecting survival of LC in Northeast Thailand should focus on targeted therapy.
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Advances in Supportive Care for Acute Lymphoblastic Leukemia.

PURPOSE OF REVIEW: Tremendous advances have been made in the treatment armamentarium for acute lymphoblastic leukemia in recent years, which have substantially improved outcomes for these patients. At the same time, unique toxicities have emerged, and without early intervention, are life-threatening. This article will review the novel therapies in acute leukemias and highlight the clinically relevant supportive care advances. RECENT FINDINGS: The American Society for Transplantation and Cellular Therapy (ASTCT) has put forth the most recent recommendations in managing the cytokine release syndrome and neurotoxicity after chimeric antigen receptor T cells (CAR-T) and blinatumomab. The hepatic injury incurred by inotuzumab, and the vascular toxicity of tyrosine kinase inhibitors, other relatively novel agents, require subspecialist intervention and multidisciplinary care. Asparaginase, a long-established and key element of pediatric regimens, has made a comeback in the young adult leukemia population. Updated guidelines have been outlined for management of asparaginase thrombotic complications. Lastly, although there have been few changes in the applications of growth factor, antimicrobial prophylaxis, and management of neuropathy, these encompass exceedingly important aspects of care. While the rapidly changing treatment paradigms for acute lymphoblastic leukemia have transformed leukemia-specific outcomes, treatment emergent toxicities have forced much necessary attention to better definitions of these toxicities and on improving supportive care guidelines in acute lymphoblastic leukemia.

Survival outcomes in an older US population with advanced melanoma and central nervous system metastases: SEER-Medicare analysis.

BACKGROUND: Central nervous system (CNS) metastasis is common in advanced melanoma patients. New treatment options have improved overall prognosis, but information is lacking for patients with CNS metastases. We investigated treatment patterns and survival outcomes in older melanoma patients with and without CNS metastases. METHODS: A retrospective analysis of SEER-Medicare, a population-based linked database, was undertaken in patients aged > 65 years with advanced melanoma diagnosed from 2004 to 2011 and followed until 2013. RESULTS: A total of 2522 patients were included. CNS metastases were present in 24.8% of patients at initial metastatic diagnosis; 16.5% developed CNS metastases during follow-up. Chemotherapy was the most common treatment regardless of CNS metastases. Overall survival (OS) was better for patients without CNS metastases (median, 9.5 months; 95% confidence interval [CI], 8.8-10.2) vs patients with CNS metastases (3.63 months; 95% CI, 3.4-3.9). Among patients with CNS metastases, median OS for targeted therapy, immunotherapy, and chemotherapy was 6 (95% CI, 2.5-9.6), 5.5 (95% CI, 3.8-7.5), and 4.5 (95% CI, 3.8-5.4) months, respectively, vs 2.4 (95% CI, 2.1-2.7) and 2.1 (95% CI, 1.8-2.7) months for local radiotherapy and no treatment, respectively. Stereotactic radiosurgery demonstrated higher OS vs whole-brain radiation therapy (median, 4.98 [95% CI, 3.5-7.5] vs 2.4 [95% CI, 2.1-2.7] months). CONCLUSION: Patients with CNS metastases from melanoma remain a population with high unmet medical need despite recent advances in treatment. Systemic treatments (eg, BRAF-targeted therapy and immunotherapy) and stereotactic radiosurgery demonstrated meaningful but modest improvements in OS. Further explorations of combinations of radiotherapy, BRAF-targeted therapies, and immunotherapies are needed.

The Evolution of Targeted Therapies in Chronic Lymphocytic Leukaemia.

PURPOSE OF REVIEW: The treatment landscape for chronic lymphocytic leukaemia (CLL) is rapidly evolving, with several targeted agents recently approved. These compounds have dramatically changed the natural history of the disease. RECENT FINDINGS: However, with the array of effective therapies commercially available, the challenge is to define tailored treatment strategies able to realize a balance between treatment efficacy and toxicity or tolerance. New algorithms of treatment are being developed, and it appears that minimal residual disease (MRD) directed therapy will become the norm in the future. Clinical trials are looking at various combinations of novel therapies given with a defined, fixed-period of treatment based on MRD analysis. This approach enables patients to have a period of treatment-free remission instead of continuous therapy. In this review, we summarize this evolution of targeted therapies in CLL.

Frontline Therapy of Chronic Lymphocytic Leukemia: Changing Treatment Paradigm.

PURPOSE OF REVIEW: The treatment landscape of treatment-naive chronic lymphocytic leukemia (TN-CLL) is rapidly evolving. As more and more new drugs and combinations are becoming part of therapeutic armamentarium, it becomes highly pertinent to understand the evidence for each of the treatment options to select the right drug for the right patient. We summarize the recent data of the available frontline treatment options. RECENT FINDINGS: The novel agents can overcome adverse biological attributes and provide long-term disease control. MRD may become a reliable surrogate for survival in the evaluation of future therapies. FCR still remains one of the best options in a young fit CLL with mutated IGVH. Long-term follow-up data of ibrutinib confirm its efficacy and safety in both high-risk and elderly TN-CLL patients. A combination of venetoclax with obinutuzumab has provided the hope of fixed-duration therapy and the potential for functional cure in TN-CLL. Several other trials testing the efficacy of other targeted agents and the optimal sequencing approaches are underway. Chemoimmunotherapy holds its ground as an effective treatment in the IGVH-mutated CLL. The targeted agents either singly or in combination have become standard of care in many subsets of TN-CLL.

Novel Therapies in the Treatment of Adult Acute Lymphoblastic Leukemia.

PURPOSE OF REVIEW: Acute lymphoblastic leukemia (ALL) is a rare hematologic malignancy. Advances in multi-agent chemotherapy have resulted in dramatic improvements in the number of pediatric cases that result in a cure; however, until recently, treatment options for older adults or patients with relapsed and refractory disease were extremely limited. This review seeks to describe in greater detail a number of emerging novel treatment modalities recently approved for this cancer. RECENT FINDINGS: In this review, we discuss a number of recently approved novel therapies for ALL, including new approaches with targeted tyrosine kinase inhibitors, novel immune-based therapies including the bispecific antibody blinatumomab and the antibody-drug conjugate inotuzumab ozogamicin, and the role of cellular therapeutics such as chimeric antigen receptor (CAR) T cells. We also discuss the impact that advances in diagnostics and disease classification and monitoring have had on treatment. A number of advances in ALL have resulted in dramatic changes to the treatment landscape and therapeutic options both at the time of diagnosis and in salvage. These findings are reshaping our treatment paradigms throughout the course of disease.

Treatment of Aggressive B Cell Lymphomas: Updates in 2019.

PURPOSE OF REVIEW: Recent years have seen the development of gene expression profiling and next-generation sequencing in diffuse large B cell lymphoma (DLBCL), leading to a more defined characterization of this disease into distinct subentities. The genomic era has ushered in the possibility of using precision guided therapy, in part based on targeting genes with somatic mutations. Such precision-targeted therapies will ultimately reduce the need for chemotherapy, induce fewer adverse events, and likely enhance the cure rate for these patients. Here, we discuss emerging therapeutic strategies that have been recently developed for the upfront and relapse setting of DLBCL. RECENT FINDINGS: Clinical trials exploring precision medicine have showed promising results; however, attempts to enhance frontline immunochemotherapy by adding targeted agents to the R-CHOP backbone did not confirm the expected benefit. The last decade has also seen a revolutionary development of immunotherapy in B cell lymphomas. While cellular immunotherapy demonstrated a striking success of CAR T cells in DLBCL, checkpoint inhibitors have lacked success in B cell lymphomas. A parallel therapeutic expansion has involved bispecific monoclonal antibodies as a powerful tool for redirected T cell therapy independently from costimulatory molecules and major-histocompatibility complex. The landscape of drugs for the treatment of DLBCL has become overwhelmed by the increasing number of targeted and immunological therapies; however, none have enhanced efficacy of frontline therapy. Future direction should focus to redefine therapeutic paradigm and develop mechanism-based combinatorial regimens specifically tailored for DLBCL genetic subgroups.

Cutaneous Melanoma - A Review of Systemic Therapies.

This decade has brought significantly improved outcomes for patients with advanced melanoma with immunotherapies and targeted treatments offering utility in a variety of settings. In 2020, we can hope for durable long-term responses, and complete remission in a subset of patients with metastatic disease. In the adjuvant setting, approximately 50% improvements in recurrence-free survival are seen both with targeted and immunotherapies. Early data from neoadjuvant immunotherapy clinical trials are very promising. However, responses to treatment are heterogeneous and not always durable; further advances are required, and several emerging strategies are of particular interest. We review the systemic treatment of melanoma, discussing the treatment of unresectable stage III-IV and recurrent disease, outlining curative treatment of cutaneous melanoma in the adjuvant setting and briefly discussing neoadjuvant systemic therapies for advanced melanoma.

The choice for the optimal therapy in advanced biliary tract cancers: Chemotherapy, targeted therapies or immunotherapy.

Biliary tract cancers (BTCs) represent a heterogeneous group that includes intrahepatic cholangiocarcinomas (CCAs), perihilar-CCAs or Klatskin tumors, extrahepatic-CCAs, and gallbladder adenocarcinoma. These entities have distinct demographics, risk factors, clinical presentation, and molecular characteristics. In advanced BTCs, the recommendations are mainly supporting a doublet chemotherapy regimen using cisplatin/gemcitabine (CisGem) with a 5-year overall survival rate close to 5% and median overall survival (mOS) of less than a year. The lack of overall efficacy stresses the need for personalized therapies. Recently, whole-genome and transcriptome sequencing highlighted the diversity of BTCs' subtypes. Distinct genetic alterations were retrieved according to the localization, with a high rate of potentially actionable alterations. Targeted therapies and immunotherapy have since then been tested for BTCs, trying to propose a more personalized treatment. This review describes the different therapeutic options, validated and in development, for patients with advanced BTCs.

Is There a Role for Chemotherapy in the Era of Targeted Therapies?

PURPOSE OF REVIEW: The treatment landscape of chronic lymphocytic leukemia has been rapidly evolving over the past few years. The prior standard of care, chemoimmunotherapy, is being replaced by targeted agents, and the utility of chemotherapy has come under question. In this review, we examine recent data comparing chemoimmunotherapy to targeted agents, how these data impact clinical management, and whether there are potential future roles for cytotoxic chemotherapy. RECENT FINDINGS: Clinical trials have shown improved clinical outcomes with targeted agents compared to traditional chemoimmunotherapy. Based on these data, the current treatment paradigm primarily favors targeted agents over chemoimmunotherapy, with a few exceptions. However, targeted agents have notable limitations, and thus, there may be a future role of cytotoxic chemotherapy when administered in combination with targeted agents. Although targeted agents have nearly replaced chemoimmunotherapy in the treatment of chronic lymphocytic leukemia, novel combinations utilizing chemotherapy are being developed that may lead to better outcomes.

Salvage surgery for advanced non-small cell lung cancer after targeted therapy: A case series.

BACKGROUND: Tumor recurrence or residual tumor after targeted therapy is common in patients with advanced non-small cell lung cancer (NSCLC). There is a lack of high-level evidence on which type of treatment should be employed for these patients and the role of salvage surgery has not been well reported in the literature. METHODS: A retrospective analysis of patients who underwent salvage surgery in our center between January 2016 and June 2019 for advanced NSCLC after targeted therapy was performed. RESULTS: A total number of nine patients were identified, including five males and four females, with a median age of 56 years (range, 40-65 years), all diagnosed with lung adenocarcinoma stage IIIa-IVb. All patients had received targeted therapy according to individual positive mutation of driver gene(s). Salvage surgery was performed for tumor recurrence or residual tumor after a duration of 2-46 months of targeted therapy. A negative surgical margin was achieved in all cases. Postoperative complication rate was 11.1% (1/9). All patients were alive at the time of this analysis and two patients had disease progression. After a median follow-up of 17 months (range: 5-44 months), the median event-free survival and postoperative survival was 14 months (range: 2-44 months) and 17 months (range: 5-44 months) respectively. CONCLUSIONS: Salvage surgery may be a feasible and promising therapeutic option for tumor recurrence or residual tumor in advanced NSCLC in selective patients after targeted therapy. KEY POINTS: Salvage surgery is feasible in selected patients with advanced NSCLC and provides promising survival outcomes after targeted therapy failure. Salvage surgery provides precise molecular and pathological information which is most important for subsequent therapy.

Advances and Perspectives in the Treatment of T-PLL.

PURPOSE OF REVIEW: T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell tumor. Available treatment options in this aggressive disease are largely inefficient and patient outcomes are highly dissatisfactory. Current therapeutic strategies mainly employ the CD52-antibody alemtuzumab as the most active single agent. However, sustained remissions after sole alemtuzumab-based induction are exceptions. Responses after available second-line strategies are even less durable. More profound disease control or rare curative outcomes can currently only be expected after a consolidating allogeneic hematopoietic stem cell transplantation (allo-HSCT) in best first response. However, only 30-50% of patients are eligible for this procedure. Major advances in the molecular characterization of T-PLL during recent years have stimulated translational studies on potential vulnerabilities of the T-PLL cell. We summarize here the current state of "classical" treatments and critically appraise novel (pre)clinical strategies. RECENT FINDINGS: Alemtuzumab-induced first remissions, accomplished in ≈ 90% of patients, last at median ≈ 12 months. Series on allo-HSCT in T-PLL, although of very heterogeneous character, suggest a slight improvement in outcomes among transplanted patients within the past decade. Dual-action nucleosides such as bendamustine or cladribine show moderate clinical activity as single agents in the setting of relapsed or refractory disease. Induction of apoptosis via reactivation of p53 (e.g., by inhibitors of HDAC or MDM2) and targeting of its downstream pathways (i.e., BCL2 family antagonists, CDK inhibitors) are promising new approaches. Novel strategies also focus on inhibition of the JAK/STAT pathway with the first clinical data. Implementations of immune-checkpoint blockades or CAR-T cell therapy are at the stage of pre-clinical assessments of activity and feasibility. The recommended treatment strategy in T-PLL remains a successful induction by infusional alemtuzumab followed by a consolidating allo-HSCT in eligible patients. Nevertheless, long-term survivors after this "standard" comprise only 10-20%. The increasingly revealed molecular make-up of T-PLL and the tremendous expansion of approved targeted compounds in oncology represent a "never-before" opportunity to successfully tackle the voids in T-PLL. Approaches, e.g., those reinstating deficient cell death execution, show encouraging pre-clinical and first-in-human results in T-PLL, and urgently have to be transferred to systematic clinical testing.

The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.

BACKGROUND: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS. METHODS: We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018. RESULTS: We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels ≥ 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04). CONCLUSIONS: The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.

Evidence That Established Lung Cancer Mortality Disparities in American Indians Are Not Due to Lung Cancer Genetic Testing and Targeted Therapy Disparities.

BACKGROUND: American Indians and Alaska Natives (AI/AN) continue to experience extreme lung cancer health disparities. The state of Minnesota is home to over 70,000 AI/AN, and this population has a 2-fold increase in lung cancer mortality compared to other races within Minnesota. Genetic mutation testing in lung cancer is now a standard of high-quality lung cancer care, and EGFR mutation testing has been recommended for all adenocarcinoma lung cases, regardless of smoking status. However, genetic testing is a controversial topic for some AI/AN. PATIENTS AND METHODS: We performed a multisite retrospective chart review funded by the Minnesota Precision Medicine Grand Challenge as a demonstration project to examine lung cancer health disparities in AI/AN. We sought to measure epidemiology of lung cancer among AI receiving diagnosis or treatment in Minnesota cancer referral centers as well as rate of EGFR testing. The primary outcome was the rate of EGFR mutational analysis testing among cases and controls with nonsquamous, non-small-cell lung cancer. We secured collaborations with 5 health care systems covering a diverse geographic and demographic population. RESULTS: We identified 200 cases and 164 matched controls from these sites. Controls were matched on histology, smoking status, sex, and age. In both groups, about one third of subjects with adenocarcinoma received genetic mutation testing. CONCLUSION: There was no significant difference in mutation testing in AI compared to non-AI controls at large health care systems in Minnesota. These data indicate that other factors are likely contributing to the higher mortality in this group.

Extending the platinum-free interval: The impact of omitting 2nd line platinum chemotherapy in intermediate platinum-sensitive ovarian cancer.

OBJECTIVES: Patients with epithelial ovarian cancer (EOC) recurring between 6 and 12 months after primary platinum chemotherapy have worse prognosis than those recurring in >12 months. Artificially prolonging the platinum-free interval (PFI) with cytotoxic chemotherapy was tested in MITO-8 with poor outcomes. This study aimed to determine the impact of using non-platinum or targeted therapy in 2nd line treatment of EOC patients recurring 6-12 months after completion of primary platinum-based chemotherapy. METHODS: A multi-institutional retrospective review of 177 patients with recurrent EOC and PFI of 6-12 months following primary chemotherapy was performed comparing platinum versus non-platinum chemotherapy or targeted therapy for 2nd line treatment. PFI1 was defined as the date of last chemotherapy to date of recurrence. PFS2/3 were defined as start of 2nd or 3rd line chemotherapy to start of subsequent line. RESULTS: Of 177 patients, the majority of patients were Caucasian, had serous histology, and underwent primary cytoreductive surgery. Median PFI1 was 8.2 months (95% CI 8-9 months). Second line platinum was omitted in 28% of patients. Bevacizumab was used in 2nd line in 16% of patients; 19% received other targeted therapies. Median PFS2 for platinum chemotherapy was longer than non-platinum (7.1 vs 3 months, p = 0.0114). Median PFS2 was significantly longer for platinum vs. targeted therapy (7.1 vs. 3 months p = 0.0431). Median OS for platinum in 2nd line vs. no platinum was 43.6 vs. 37.6 months (p = 0.0174). CONCLUSIONS: Use of non-platinum chemotherapy and even targeted therapy to prolong PFI in patients with EOC recurring between 6 and 12 months leads to worse survival.

Clinical outcomes of non-small-cell lung cancer patients with BRAF mutations: results from the French Cooperative Thoracic Intergroup biomarkers France study.

INTRODUCTION: Patients with stage IV non-small-cell lung cancer (NSCLC) and BRAF V600 mutations may benefit from targeted therapies. Chemotherapy outcomes are little known in this population. METHODS: The French Cooperative Thoracic Intergroup (IFCT) Biomarkers France study was a national prospective cohort study aiming to describe the molecular characteristics and clinical outcome of all consecutive NSCLC patients (N = 17,664) screened for molecular alterations. We used this data set to set up a case-control analysis. Cases had stage IV BRAF-mutated (BRAF-MT) NSCLC, whereas controls had NSCLC that was wild-type for EGFR, KRAS, HER2, BRAF, PIK3CA and ALK. Each case was matched for sex, age at diagnosis and smoking status to two controls randomly selected. RESULTS: Overall, 83 cases with BRAF mutant disease (66.3% V600E) were matched to 166 controls. Five cases received tyrosine kinase inhibition in the first-line and 16 in the second-line. All others were treated with standard chemotherapy. There was no significant difference in first-line and second-line progression-free survival (PFS) between the groups, as well as in the disease control rate, BRAF mutation was not found to be prognostic of overall survival. We found no significant difference in outcome between the treatment types used in first-line or second-line in patients with BRAF-MT disease compared with controls nor between BRAF V600E or non-V600E compared with controls. CONCLUSIONS: BRAF mutation is not a strong prognostic factor in NSCLC. Although taxan-based therapy shows poorest PFS in first-line, no chemotherapy regimen was associated with prognosis.

Clinical and Histopathologic Features of Immune Checkpoint Inhibitor-related Pneumonitis.

Immune checkpoint inhibitors (ICIs) have revolutionized oncology, but are associated with immune-related adverse events. Clinically, pneumonitis is a well-recognized complication, but its histopathologic features are poorly understood. Institutional archives were searched for patients having ICI therapy and subsequent lung tissue sampling. After excluding infectious cases, 9 patients (5 women, median: 59 y) were identified with clinically suspected ICI-related pneumonitis. Clinical history, imaging, and pathology slides were reviewed. Patients received pembrolizumab (6 cases), nivolumab (1), ipilimumab followed by pembrolizumab (1), or pembrolizumab followed by nivolumab (1); the latter experienced pneumonitis with both agents. Treatment duration ranged from 1 to 33 cycles (median: 8). Three patients received concurrent chemotherapy and 1 received radiation; the remainder received ICI monotherapy. Symptoms were nonspecific; 2 patients were asymptomatic. Thoracic imaging showed bilateral ground glass or nodular opacities in all cases, often with pleural effusion. Histologically, organizing pneumonia was seen in 7 patients, all with subclinical or mild disease, admixed with vague non-necrotizing airspace granulomas in 3 cases; all 6 patients with follow-up did well. One patient had acute fibrinous pneumonitis and 1 had diffuse alveolar damage; both died. All 9 cases showed foamy macrophages and pneumocyte vacuolization; 6 had rare eosinophils. ICI-related pneumonitis presents as bilateral ground-glass opacities or nodules, and usually manifests as organizing pneumonia histopathologically, often with vague non-necrotizing airspace granulomas. Foamy macrophages and pneumocyte vacuolization are characteristic and rare eosinophils are often seen. Less commonly, acute fibrinous pneumonitis or diffuse alveolar damage can occur, which may be fatal.

NGS-based oncogenic mutations analysis in advanced colorectal cancer patients improves targeted therapy prediction.

BACKGROUND: Characterization of genetic alterations has been revealed to be important to predict the outcomes of targeted therapy in cancer. We here aimed to assess the mutation profiling of 526 colorectal cancer (CRC) patients by next-generation sequencing (NGS) to enable a more personalized anti-EGFR treatment. METHODS: Tumors were analyzed using NGS to determine hotspot mutations in 22 cancer-related genes. RESULTS: Mutations were observed in 13 genes in 436 of 526 (82.9%) tumors, and the most common mutations occurred in TP53 and KRAS. PIK3CA mutations usually coexisted with KRAS, NRAS or BRAF mutations. A higher frequency of concomitant PIK3CA mutations was observed in tumors with KRAS outside codon 13 mutations, with NRAS codon 61 mutations and with BRAF kinase-activated mutations. Moreover, KRAS, PIK3CA, AKT1 and FBXW7 mutations were statistically associated with some clinicopathological features, including location, age or metastasis of CRC patients. For RAS wild-type patients treated with cetuximab, longer progression-free survival (PFS) was observed in patients identified as wild type in all 22 genes compared with patients with mutations in one or more genes. CONCLUSIONS: A wild-type result in all 22 cancer-related genes detected by NGS is associated with a better outcome of cetuximab treatment. Determining mutation patterns by NGS may aid to understand the molecular mechanisms of CRC and improve targeted therapy prediction.

Management of Acute Complications of Targeted Therapy in Patients With Cancer: A Review of Cases Managed in ICU.

INTRODUCTION: Targeted therapies, molecules in full expansion, are not free of side effects that can lead patients to intensive care. We performed an extensive review of the published evidence and propose a management strategy for acute complications of targeted therapy in critically ill patients with cancer. METHODS: The literature search was performed in August 2017 using the Ovid Medline system by a scientific librarian and physicians. We made a review of cases admitted in intensive care unit (ICU) and a review of toxicities of grades greater or equal to 3. RESULTS: Our search selected 59 articles. The main cardiovascular side effects requiring ICU are heart failure, which is generally reversible, severe hypertension, thrombotic and ischemic events, and rhythm disturbances. The main pulmonary side effects are interstitial lung disease essentially caused by crizotinib, respiratory infections, pneumothorax, and alveolar hemorrhage. The main gastrointestinal side effects are fulminant hepatitis that may be fatal, colitis that may be complicated by hemorrhage, and perforation. The main neurological side effect is posterior reversible encephalopathy syndrome essentially caused by bevacizumab. The main other side effects are Steven-Johnson syndrome, necrotizing fasciitis, and anaphylactic reactions. CONCLUSIONS: The side effects induced by targeted therapies may be fatal but are generally potentially reversible. The main treatment includes stopping current therapy and symptomatic management. Treatment rechallenge should be discussed on a case-by-case basis.

Patterns of treatment and BRAF testing with immune checkpoint inhibitors and targeted therapy in patients with metastatic melanoma presumed to be BRAF positive.

Patients with BRAF V600 (BRAF) mutated metastatic melanoma are eligible for therapy with both immune checkpoint inhibitors and targeted therapies, making treatment choice a complex decision. The present study aimed to describe patterns of treatment with immunotherapy and targeted therapy and BRAF testing in patients with metastatic melanoma presumed to have BRAF mutations (BRAF+) in the years following the approval of the newer generation of immune checkpoint inhibitors and targeted therapies (2014-2016). Two large US commercial claims databases [Truven Health Analytics MarketScan and IQVIA Real-World Data Adjudicated Claims - USA (IQVIA RWD Adjudicated Claims - USA)] were used. Patients were presumed BRAF+ if they received at least 2 lines of therapy of which at least 1 included targeted therapy. Sequence of lines of therapy and regimens used in first (1L), second (2L), and third (3L), as well as timing of BRAF testing by sequence of therapy were described. In the Truven sample (n=162), targeted therapy was used by 66% in 1L and by 54% in 2L, and 62% had a BRAF test; in the IQVIA RWD Adjudicated Claims - USA sample (n=247), targeted therapy was used by 62% in 1L and by 50% in 2L, and 68% had a BRAF test. Among those with a claim for a BRAF test prior to 1L, over two-thirds were initiated on targeted therapy. These findings suggest that the rate of BRAF testing remained low in the years following the approval of BRAF-targeted regimens for metastatic disease. Given the recently approved adjuvant treatment options for stage III melanoma, improving the rates of BRAF testing becomes increasingly important.