CHRONIC lymphocytic leukemia diagnosis, CHRONIC lymphocytic leukemia, MORTALITY, RESEARCH funding, SEX distribution, AGE distribution, DESCRIPTIVE statistics, CHRONIC diseases
Abstract
Simple Summary: Chronic lymphocytic leukemia (CLL) is a common leukemia characterized by an accumulation of lymphocytes in the blood and lymphoid organs. Disease presentation is highly variable as many patients do not initially require any treatment, and a watch and wait strategy remains the standard of care for up to 50% of patients. However, for those with a progressive disease, chemotherapy is the standard treatment and has improved over the years, increasing the survival of patients. We analyze here age-specific relative survival trends in CLL through 50 years up to 2020s in Denmark, Finland, Norway, and Sweden using the NORDCAN database. The large age-specific survival differences in 1972–76 almost disappeared by 2017–21. While 5-year survival in younger patients exceeded 90%, for those diagnosed at age 80–89-years, survival improved later, reaching 90% in Denmark and less in the other countries. Survival in Denmark is probably among the best in the world, which could be achieved by boosting survival even among the oldest patients. Most Nordic survival rates were better than those in the USA. Background: Chronic lymphocytic leukemia (CLL) is a common hematological malignancy with highly variable clinical presentation. Many patients never require any treatment but for the others, chemotherapy, immunochemotherapy, and newer targeted therapies have changed the treatment landscape. Diagnostic age influences the applied treatment, and we thus wanted to analyze age-specific survival trends through 50 years up to 2020s. Methods: We used 1- and 5-year relative survival from the NORDCAN database, with data from Denmark (DK), Finland (FI), Norway (NO), and Sweden (SE). Because of the variable presentation of CLL, we also considered incidence and mortality trends. For comparison, US SEER data were used. Results: The large age-specific survival differences in 1972–76 almost disappeared by 2017–21. While 5-year survival in younger patients exceeded 90%, for those diagnosed at age 80–89 years, survival reached 90% in DK and SE women, 80% in NO and SE men, but only 50% in FI. DK 5-year overall survival for men was 92.4%, and for women, it was 96.3%. These survival figures were higher than age-group-specific US survival data. Conclusions: The DK data are probably global top figures for national survival which could be achieved by boosting survival even among the oldest patients. The qualification to these figures and international comparisons is that survival needs to be considered in terms of incidence, which is high in DK and NO. Low survival of the FI 80–89-year-old patients, even in the first year after diagnosis, may suggest delayed diagnosis, which should call for a closer national scrutiny. [ABSTRACT FROM AUTHOR]
Background: The present study aimed to investigate physicians' perspectives on the diagnosis and treatment decisions for patients with non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutations in a real-world setting in China using an online questionnaire. Methods: This study was performed via the CAPTRA-Lung collaboration between December 9, 2022 and March 6, 2023. The questionnaire was distributed digitally to physicians around China and was comprised of three sections: basic characteristics of surveyed physicians, diagnosis and treatment status of NSCLC patients with the EGFR exon20ins-mutation, and physicians' perspectives on treatment options. Physicians who treat more than 10 patients with advanced NSCLC every month and who have treated patients with advanced EGFR exon20ins-mutant NSCLC in the past six months were involved in this study. Results: A total of 53,729 questionnaires were distributed and 390 valid ones were collected. The EGFR mutation test was performed in 80.9% and 59.9% of patients receiving first-line or second-line therapy and beyond (hereinafter "second-line")therapy, respectively. In terms of treatment options, chemotherapy plus antiangiogenic therapy was the most common treatment option (30.0% of patients in first-line settings; 25.0% of patients in second-line settings), and a certain proportion of patients received novel EGFR exon20ins-targeted agents (including tyrosine kinase inhibitors [TKIs] and bispecific antibodies) in first- or second-line settings, which accounted for 11.9% and 15.7% of all treated patients, respectively. Additionally, physicians reported the highest satisfaction score for the efficacy and safety of targeted agents. Most physicians believed that EGFR exon20ins-targeted TKIs represented the most promising treatment option (80.2% in first-line treatment and 73.3% in second-line treatment). Among several novel agents under study, sunvozertinib has received the highest recognition for efficacy and safety. Conclusions: This study investigated the current diagnosis and treatment status and physicians' perspective, of patients with EGFR exon20ins-mutant NSCLC. The results highlight significant unmet clinical needs in this subgroup of patients. EGFR exon20ins-targeted TKIs were recognized as the most promising treatment regimen and may benefit more patients considering their awareness and acceptance of targeted therapy. [ABSTRACT FROM AUTHOR]
Huipeng Fang, Qiao Ke, Shiji Wu, Qiang Tu, and Lei Wang
Subjects
ADVERSE health care events, HEPATOCELLULAR carcinoma, OVERALL survival, TREATMENT effectiveness, PREVENTIVE medicine
Abstract
Background: Transarterial chemo(embolization) is preferred for treating unresectable hepatocellular carcinoma (uHCC); however, because of emerging immune-targeted therapies, its efficacy is at stake. This systematic review pioneers to evaluate the clinical efficacy and safety of transarterial chemo (embolization) combined with immune-targeted therapy for uHCC patients. Methods: PubMed, Embase, and Cochrane Library were searched for studies comparing immune-targeted therapy with or without transarterial chemo (embolization) until 31 May 2024. The complete response (CR) rate, objective response rate (ORR), and disease control rate (DCR) were considered to be the primary outcomes calculated for the clinical outcomes of transarterial chemo (embolization) combined with immune-targeted therapy, along with progressionfree survival (PFS) and overall survival (OS). The incidence of treatment-related severe adverse events was set as the major measure for the safety outcome. Results: Sixteen studies, encompassing 1,789 patients receiving transarterial chemo(embolization) plus immune-targeted therapy and 1,215 patients receiving immune-targeted therapy alone, were considered eligible. The combination of transarterial chemo(embolization) and immune-targeted therapy demonstrated enhanced outcomes in CR (OR = 2.12, 95% CI = 1.35-3.31), ORR (OR = 2.78, 95% CI = 2.15-3.61), DCR (OR = 2.46, 95% CI = 1.72-3.52), PFS (HR = 0.59, 95% CI = 0.50-0.70), and OS (HR = 0.51, 95% CI = 0.44-0.59), albeit accompanied by a surge in ALT (OR = 2.17, 95% CI = 1.28-3.68) and AST (OR = 2.28, 95% CI = 1.42-3.65). The advantages of additional transarterial chemo(embolization) to immune-targeted therapy were also verified in subgroups of first-line treatment, intervention techniques, with or without extrahepatic metastasis, Child-Pugh grade A or B, and with or without tumor thrombus. Conclusion: The combination of transarterial chemo(embolization) and immune-targeted therapy seems to bolster local control and long-term efficacy in uHCC, albeit at the expense of hepatic complications. [ABSTRACT FROM AUTHOR]
Simple Summary: This review discusses the topic of prevention of brain metastases from the most frequent solid tumor types, i.e., lung cancer, breast cancer and melanoma. Within each tumor type, the issues of screening in asymptomatic patients, prophylactic strategies with radiation and secondary chemoprevention with targeted agents are discussed. This review discusses the topic of prevention of brain metastases from the most frequent solid tumor types, i.e., lung cancer, breast cancer and melanoma. Within each tumor type, the risk of brain metastasis is related to disease status and molecular subtype (i.e., EGFR-mutant non-small cell lung cancer, HER2-positive and triple-negative breast cancer, BRAF and NRAF-mutant melanoma). Prophylactic cranial irradiation is the standard of care in patients in small cell lung cancer responsive to chemotherapy but at the price of late neurocognitive decline. More recently, several molecular agents with the capability to target molecular alterations driving tumor growth have proven as effective in the prevention of secondary relapse into the brain in clinical trials. This is the case for EGFR-mutant or ALK-rearranged non-small cell lung cancer inhibitors, tucatinib and trastuzumab–deruxtecan for HER2-positive breast cancer and BRAF inhibitors for melanoma. The need for screening with an MRI in asymptomatic patients at risk of brain metastases is emphasized. [ABSTRACT FROM AUTHOR]
Su, Yi-Chia, Wu, Chih-Chien, Chen, Yu-Hsun, Su, Chien-Chou, Chang, Yu-Ching, Hsieh, Meng-Che, and Kao Yang, Yea-Huei
Abstract
Background: Primary tumor resection and metastasectomy may be beneficial for many patients with metastatic colorectal cancer (mCRC). Objective: To assess the differences in postoperative survival outcomes between adjuvant therapy with chemotherapy alone and chemotherapy plus targeted agents (TAs). Design: Retrospective cohort study. Methods: Patients with mCRC who underwent surgical resection for primary colorectal tumor and distant metastases and received adjuvant therapy from 1 January 2010 to 31 December 2017 were enrolled in the Taiwan Cancer Registry. We analyzed the overall survival of patients with resectable or initially unresectable mCRC who received adjuvant chemotherapy alone and chemotherapy plus TAs. Results: We enrolled 1124 and 542 patients with resectable and initially unresectable mCRC, respectively. Adjuvant chemotherapy plus TAs and chemotherapy alone resulted in similar mortality rates among patients with resectable mCRC [adjusted hazard ratio (aHR) = 1.13; 95% confidence interval (CI), 0.93–1.36]; however, it marginally reduced the mortality rate among patients with initially unresectable mCRC who underwent conversion surgery after neoadjuvant therapy (aHR = 0.81; 95% CI, 0.62–1.06). The subgroup analysis of patients who received more than nine cycles of TAs preoperatively and anti-epidermal growth factor receptor agents revealed aHRs of 0.48 (95% CI, 0.27–0.87) and 0.33 (95% CI, 0.18–0.60), respectively. Conclusion: Adjuvant chemotherapy plus TAs may improve survival in patients with initially unresectable tumors who underwent conversion surgery following neoadjuvant therapy with TAs, especially in those who respond well to the targeted therapy. Our study underscores the importance of stratifying patients with mCRC based on tumor resectability when selecting the adjuvant therapy regimen. [ABSTRACT FROM AUTHOR]
Molica, Stefano, Shanafelt, Tait D., Allsup, David, and Giannarelli, Diana
Subjects
CHRONIC lymphocytic leukemia, AMERICANS, IMMUNOTHERAPY, SEX distribution, LIFE expectancy, RITUXIMAB, AGE distribution, TREATMENT effectiveness, DESCRIPTIVE statistics, CANCER chemotherapy, SYSTEMATIC reviews, MEDLINE, ITALIANS, COMPARATIVE studies, CONFIDENCE intervals, FLUDARABINE, CYCLOPHOSPHAMIDE
Abstract
Simple Summary: In a comprehensive analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and the CLL13 trials, we assessed the impact of first-line treatments with targeted agents (TAs), or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT), on overall survival (OS) compared to age- and sex-matched individuals in the general population. TAs demonstrated a higher 5-year restricted mean survival time (RMST) (58.1 months; 95% CI: 57.4 to 58.8) compared to CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Moreover, the comparison with age- and gender-matched general populations (AGMGP) suggested that TAs may mitigate CLL's impact on OS during the first five years post-treatment initiation. In contrast, CLL patients treated with FCR exhibited sustained OS differences compared to both the Italian and US AGMGP cohorts. These results support TAs as the preferred first-line treatment for younger/fit CLL patients but imply the need for a careful interpretation due to variations in patient selection criteria and clinical profiles across trials. Longer follow-up is essential to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. To assess the impact of first-line treatment with targeted agents (TAs) or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT) on overall survival (OS) compared to age- and sex-matched individuals in the general population, we conducted an aggregated analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and CLL13 trials. The restricted mean survival time (RMST), an alternative measure in outcome analyses capturing OS changes over the entire history of the disease, was used to minimize biases associated with the short follow-up time of trials. Patients treated with TAs demonstrated a higher 5-year RMST (58.1 months; 95% CI: 57.4 to 58.8) compared to those treated with CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Furthermore, the OS comparison of treatment groups with the AGMGP suggests that TAs may mitigate the impact of CLL on OS during the first five years post-treatment initiation. In summary, the 5-year RMST difference was −0.4 months (95% CI: −0.8 to 0.2; p = 0.10) when comparing CLL patients treated with TAs to the Italian age- and gender-matched general population (AGMGP). A similar trend was observed when CLL patients treated with TAs were compared to the US AGMGP (5-year RMST difference, 0.3 months; 95% CI: −0.1 to 0.9; p = 0.12). In contrast, CLL patients treated with FCR exhibited sustained OS differences when compared to both the Italian cohort (5-year RMST difference: −1.6 months; 95% CI: −2.4 to −0.9; p < 0.0001) and the US AGMGP cohort (5-year RMST difference: −0.9 months; 95% CI: −1.7 to −0.2; p = 0.015). Although these results support TAs as the preferred first-line treatment for younger CLL patients, it is crucial to acknowledge that variations in patient selection criteria and clinical profiles across clinical trials necessitate a cautious interpretation of these findings that should be viewed as directional and hypothesis-generating. A longer follow-up is needed to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. [ABSTRACT FROM AUTHOR]
Simple Summary: Advancements in treating patients with metastatic colorectal cancer have shown remarkable progress in the last two decades. Enhanced comprehension of tumor biology via molecular profiling has broadened treatment avenues. The approach to treating patients with metastatic colorectal cancer has evolved from a uniform method to a more individualized one. It's now clear that colorectal cancer manifests in diverse forms, characterized by varied molecular subtypes and genetic mutations, demanding personalized treatment approaches. This review delves into the latest clinical findings concerning late-stage treatment options for patients with metastatic colorectal cancer, mainly focusing on randomized trials wherever available. We include recommendations for options in unselected patients and therapies that should only be offered in patients with distinct tumor profiles. Systemic treatment of metastatic colorectal cancer (mCRC) has improved considerably over the past 20 years. First- and second-line combinations of 5FU, oxaliplatin, and irinotecan, with or without anti-angiogenic and/or anti-EGFR antibodies, were approved shortly after the turn of the millennium. Further triumphs were not seen for almost 10 years, until the approval of initially regorafenib and shortly after trifluridine/tipiracil. A growing understanding of tumor biology through molecular profiling has led to further treatment options. Here, we review the most recent clinical data for late-line treatment options in mCRC, focusing on randomized trials if available. We include recommendations for options in unselected patients and therapies that should only be offered in patients with distinct tumor profiles (e.g., BRAF mutations, KRAS G12C mutations, HER2 amplification, deficient MMR, or NTRK gene fusions). [ABSTRACT FROM AUTHOR]
Bertin, Beatriz, Zugman, Miguel, and Schvartsman, Gustavo
Subjects
MESOTHELIOMA, IMMUNE checkpoint inhibitors, CANCER chemotherapy, EVIDENCE-based medicine, PLEURAL tumors, COMBINED modality therapy, CANCER vaccines, DISEASE management
Abstract
Simple Summary: Malignant pleural mesothelioma is an invasive and drug-resistant tumor related to asbestos exposure, with limited therapy options. It is associated with an unfavorable prognosis and a 5-year survival rate of only 12%. Current standard-of-care treatment based on platinum-pemetrexed chemotherapy has been in place for the past two decades, though survival is increased by just a few months. In this article, we aim to review the current chemotherapy and immunotherapy options for this malignancy and highlight recent developments with regard to chemoimmunotherapy, targeted agents and cellular therapy. The incidence of malignant pleural mesothelioma is expected to increase globally. New treatment options for this malignancy are eagerly awaited to improve the survival and quality of life of patients. The present article highlights the results of recent advances in this field, analyzing data from several relevant trials. The heterogeneous tumor microenvironment and biology, together with the low mutational burden, pose a challenge for treating such tumors. So far, no single biomarker has been soundly correlated with targeted therapy development; thus, combination strategies are often required to improve outcomes. Locally applied vaccines, the expansion of genetically engineered immune cell populations such as T cells, the blockage of immune checkpoints that inhibit anti-tumorigenic responses and chemoimmunotherapy are among the most promising options expected to change the mesothelioma treatment landscape. [ABSTRACT FROM AUTHOR]
Laface, Carmelo, Giuliani, Francesco, Melaccio, Assunta, Pappagallo, Maria Nicla, Santoro, Anna Natalizia, Perrone, Martina, De Santis, Pierluigi, Guarini, Chiara, Carrozzo, Daniela, and Fedele, Palma
Subjects
OLDER patients, BREAST cancer, OLDER women, CLINICAL trials, GERIATRIC assessment
Abstract
Breast cancer (BC) in elderly women is an increasing health issue due to demographic changes. BC tends to present later and may receive less than standard treatment options. More often, BC in elderly patients is endocrine-positive (HR+). The treatment of elderly patients with metastatic BC (mBC) represents a therapeutic challenge. In recent years, the treatment landscape of patients that are HR+/Her2-negative has changed due to the introduction in clinical practice of new targeted drugs, which have improved patient outcomes. Elderly patients are a small percentage of all patients enrolled in clinical trials and, to date, there are no standardized guidelines that define the best treatment option for this patient population. This can lead to undertreatment or overtreatment, impacting patient morbidity and mortality. Geriatric Assessment tools to tailor the treatment in elderly patients are underused because they are long and difficult to apply in a busy routine clinical practice. For all these reasons, there is an urgent need to produce data about the best treatment for elderly patients with HR+ mBC. Herein, we report data from randomized clinical trials and real-world evidence on the therapeutic options for HR+ Her2-negative mBC elderly patients and explore future treatment directions. [ABSTRACT FROM AUTHOR]
THYROID cancer, ADVERSE health care events, ANAPLASTIC thyroid cancer, MEDULLARY thyroid carcinoma, TASK forces
Abstract
Recently, targeted therapy has become the standard of care for advanced thyroid cancer. Although expert consensus on the management of adverse events in patients receiving targeted agents for radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) was formulated by Thyroid Cancer Committee of Chinese Society of Clinical Oncology in 2018, the tumor types which are eligible for targeted therapy have been extended to medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC), and targeted agents have been approved from multikinase inhibitors (MKIs) to BRAF inhibitors, MEK inhibitors, RET inhibitors and TRK inhibitors. Along with the widely used targeted agents with different mechanism, the management of adverse events for targeted agents needs to be standardized and improved, especially considering the specialties of the physicians who are involved in the targeted therapy for thyroid cancer are variable. Therefore, Thyroid Cancer Committee of Chinese Society of Clinical Oncology convened an expert task force charged with developing consensus to serves as a guidance to standardize utilization of targeted agents and to optimize clinical practice. [ABSTRACT FROM AUTHOR]
Arciero, Vanessa, McDonald, Erica, Nguyen, Vivian, Saluja, Ronak, Raphael, Michael, Parmar, Ambica, and Chan, Kelvin K. W.
Subjects
SEX (Biology), ONCOLOGY, MEDICAL research, SENSITIVITY analysis
Abstract
Purpose: The National Institutes of Health's policy for the inclusion of females in clinical research was a pivotal step towards the consideration of sex as a biological variable, which is of particular importance in oncology, given differential incidence and outcomes of cancer between the sexes, and known pharmacodynamic, pharmacokinetic, and immunological differences. Therefore, we aim to investigate if such biological sex-based differences translate to clinically meaningful outcome differences from recently approved systemic oncology therapies. Methods: A systematic review of randomized control trials (RCTs) cited in Food and Drug Administration, European Medicines Agency, and Health Canada approvals was conducted. Chemotherapy, targeted agents, and immunotherapy RCTs reporting sex-based sub-group analyses for overall/progression-free survival (OS/PFS) were considered. Hazard ratios (HRs) and 95% confidence intervals (CIs) were utilized. Sensitivity analyses for survival endpoints, drug type, and cancer site were conducted. Results: Ninety-nine RCTs were included, representing 62,384 patients (23,574 (38%) female). Pooled OS HRs [95% CIs] were 0.77 [0.72–0.81] and 0.76 [0.72–0.79] for females and males, respectively (P = 0.73), and 0.51 [0.47–0.56] and 0.57 [0.53–0.61] (P = 0.08) for PFS. Sensitivity analyses yielded similar results. No RCTs reported sex-based toxicity or quality-of-life (QOL) data. Conclusion: Female and male patients appear to derive comparable benefits from recently approved systemic oncology therapies. Future RCTs are encouraged to report sex-based toxicity and QOL data. [ABSTRACT FROM AUTHOR]
Scherm, Angelika, Ippen, Franziska Maria, Hau, Peter, Baurecht, Hansjörg, Wick, Wolfgang, Gempt, Jens, Knüttel, Helge, Leitzmann, Michael F., and Seliger, Corinna
Subjects
BRAIN tumors, CLINICAL trials, GLIOBLASTOMA multiforme, PROTEIN kinase inhibitors, HISTONE deacetylase inhibitors, ELECTRIC field therapy
Abstract
Glioblastoma (GB) is the most common malignant primary brain tumor in adults. The standard of care for newly diagnosed GB involves surgical resection followed by radiochemotherapy with temozolomide, with or without tumor‐treating fields. In recent years, various efforts have been made to identify suitable molecularly targeted treatment options for malignant brain tumors. This meta‐analysis provides an overview of recently published randomized controlled trials (RCTs) with and without molecular stratification, analyzing targeted agents in patients with newly diagnosed GB. The Cochrane Library, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform, and Google Scholar were searched for RCTs on targeted therapies in patients with newly diagnosed glioblastoma. Hazard ratios (HRs) for overall survival (OS) and progression‐free survival (PFS) were extracted and pooled in a random‐effects meta‐analysis. Twelve RCTs (n = 3941 patients) involving protein kinase inhibitors, proteasome and histone deacetylase inhibitors, anti‐angiogenic approaches and poly (ADP‐ribose) polymerase (PARP) inhibitors were included in the meta‐analysis. None of the targeted agents achieved a significant benefit with regard to OS (HR = 0.98 [95% confidence interval (CI) 0.86‐1.11, P =.7731]). By comparison, targeted therapy showed a benefit for PFS (HR = 0.83 [95% CI 0.74‐0.94, P =.0037]), especially for patients with an unmethylated O6‐methylguanine‐DNA‐methyltransferase (MGMT) promoter (0.75 [95% CI 0.56‐0.99, P =.0440]). Prolongation of PFS was largely driven by VEGF inhibition with bevacizumab (HR = 0.70 [95% CI 0.61‐0.80, P =.0000]). VEGF inhibition with bevacizumab prolonged PFS in patients with newly diagnosed glioblastoma compared to standard care. However, no improvement in OS was observed with any of the targeted agents. [ABSTRACT FROM AUTHOR]
Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular syndrome characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, which eventually leads to right heart failure and even death. Although the exact mechanism of PAH is not fully understood, pulmonary vasoconstriction, vascular remodeling, immune and inflammatory responses, and thrombosis are thought to be involved in the development and progression of PAH. In the era of non-targeted agents, PAH had a very dismal prognosis with a median survival time of only 2.8 years. With the deep understanding of the pathophysiological mechanism of PAH as well as advances in drug research, PAH-specific therapeutic drugs have developed rapidly in the past 30 years, but they primarily focus on the three classical signaling pathways, namely the endothelin pathway, nitric oxide pathway, and prostacyclin pathway. These drugs dramatically improved pulmonary hemodynamics, cardiac function, exercise tolerance, quality of life, and prognosis in PAH patients, but could only reduce pulmonary arterial pressure and right ventricular afterload to a limited extent. Current targeted agents delay the progression of PAH but cannot fundamentally reverse pulmonary vascular remodeling. Through unremitting efforts, new therapeutic drugs such as sotatercept have emerged, injecting new vitality into this field. This review comprehensively summarizes the general treatments for PAH, including inotropes and vasopressors, diuretics, anticoagulants, general vasodilators, and anemia management. Additionally, this review elaborates the pharmacological properties and recent research progress of twelve specific drugs targeting three classical signaling pathways, as well as dual-, sequential triple-, and initial triple-therapy strategies based on the aforementioned targeted agents. More crucially, the search for novel therapeutic targets for PAH has never stopped, with great progress in recent years, and this review outlines the potential PAH therapeutic agents currently in the exploratory stage to provide new directions for the treatment of PAH and improve the long-term prognosis of PAH patients. [ABSTRACT FROM AUTHOR]
Oberoi, Sapna, Choy, Edwin, Chen, Yen-Lin, Scharschmidt, Thomas, and Weiss, Aaron R.
Abstract
Opinion statement: Extremity soft tissue sarcoma (ESTS) constitutes the majority of patients with soft tissue sarcoma (STS). Patients with localized high-grade ESTS > 5 cm in size carry a substantial risk of developing distant metastasis on follow-up. A neoadjuvant chemoradiotherapy approach can enhance local control by facilitating resection of the large and deep locally advanced tumors while trying to address distant spread by treating the micrometastasis for these high-risk ESTS. Preoperative chemoradiotherapy and adjuvant chemotherapy are often used for children with intermediate- or high-risk non-rhabdomyosarcoma soft tissue tumors in North America and Europe. In adults, the cumulative evidence supporting preoperative chemoradiotherapy or adjuvant chemotherapy remains controversial. However, some studies support a possible benefit of 10% in overall survival (OS) for high-risk localized ESTS, especially for those with a probability of 10-year OS < 60% using validated nomograms. Opponents of neoadjuvant chemotherapy argue that it delays curative surgery, compromises local control, and increases the rate of wound complications and treatment-related mortality; however, the published trials do not support these arguments. Most treatment-related side effects can be managed with adequate supportive care. A coordinated multidisciplinary approach involving sarcoma expertise in surgery, radiation, and chemotherapy is required to achieve better outcomes for ESTS. The next generation of clinical trials will shed light on how comprehensive molecular characterization, targeted agents and/or immunotherapy can be integrated into the upfront trimodality treatment to improve outcomes. To that end, every effort should be made to enroll these patients on clinical trials, when available. [ABSTRACT FROM AUTHOR]
Objective: For patients with advanced or metastatic renal cell carcinoma (RCC), the dose of targeted agents was recommended in combination with immune checkpoint inhibitors. We performed a network meta‐analysis to describe a categorized safety ranking profile and assess the adaptability of the combination options of targeted agents. Methods: The targeted agents refer to vascular endothelial growth factor tyrosine kinase inhibitors (VEGF‐TKIs) and mammalian target of rapamycin (mTOR) inhibitors. Randomized controlled trials comparing these drugs were enrolled in a Bayesian model network meta‐analysis. Results: Nineteen clinical trials with 11 treatments and 10,615 patients were included. For grade ≥ 3 adverse events (AEs), compared with placebo, lenvatinib plus everolimus showed worse safety than all other treatments except for lenvatinib (placebo vs. OR 0.23, 95% CI 0.07–0.78). Everolimus was generally the safest agent (OR 1.23, 95% CI 0.50–3.14). Sorafenib arose the least renal AEs (placebo vs. OR 0.85, 95% CI 0.06–11.64), whereas lenvatinib plus everolimus had the highest risk of renal toxicity (placebo vs. 0.17 95% CI 0.01–1.02). For gastrointestinal symptoms, everolimus was related to much lower toxicity than other agents. In the respiratory safety analysis, tivozanib (placebo vs. OR 0.15, 95% CI 0.07–0.31) and axitinib (OR 5.43, 95% CI 3.26–9.22) were the riskiest agents. In terms of hepatobiliary (placebo vs. OR 0.44, 95% CI 0.09–2.10) and hemotoxicity (placebo vs. OR 1.03, 95% CI 0.14–7.68) related AEs, lenvatinib was found to be the safest treatment compared to placebo. Conclusions: Everolimus, with the best safety of grade ≥ 3, gastrointestinal, and respiratory AEs, was more likely to be considered for combination therapies. Lenvatinib appears to be the safest for blood/lymphatic and hepatobiliary AEs. For patients with renal disorders, sorafenib arises the least renal toxicity AEs. This study will guide treatment options and optimize the trial design for advanced or metastatic RCC. [ABSTRACT FROM AUTHOR]
Esteban-Villarrubia, Jorge, Torres-Jiménez, Javier, Bueno-Bravo, Carolina, García-Mondaray, Rebeca, Subiela, José Daniel, and Gajate, Pablo
Subjects
THERAPEUTIC use of antineoplastic agents, PERIOPERATIVE care, BLADDER tumors, ADJUVANT chemotherapy, CYSTECTOMY, IMMUNE checkpoint inhibitors, CANCER invasiveness, CANCER relapse, METASTASIS, COMBINED modality therapy, IMMUNOTHERAPY
Abstract
Simple Summary: The risk of recurrence of patients with localized muscle-invasive bladder carcinoma (MIBC) is still high. The outcomes of surgery and perioperative therapy are limited, and several patients are not candidates for neoadjuvant chemotherapy and have no further alternatives available. In recent years, many drugs have been evaluated in the metastatic setting. This review summarizes the evidence of perioperative treatment with these new drugs for MIBC, emphasizing immunotherapy and targeted agents. Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy is the current standard of care for muscle-invasive bladder cancer (MIBC). However, less than half of patients are candidates for this treatment, and 50% will develop metastatic disease. Adjuvant chemotherapy could be offered if neoadjuvant treatment has not been administered for suitable patients. It is important to reduce the risk of systemic recurrence and improve the prognosis of localized MIBC. Systemic therapy for metastatic urothelial carcinoma has evolved in recent years. Immune checkpoint inhibitors and targeted agents, such as antibody-drug conjugates or FGFR inhibitors, are new therapeutic alternatives and have shown their benefit in advanced disease. Currently, several clinical trials are investigating the role of these drugs, as monotherapy and in combination with chemotherapy, in the neoadjuvant and adjuvant settings with promising outcomes. In addition, the development of predictive biomarkers could predict responses to neoadjuvant therapies. [ABSTRACT FROM AUTHOR]
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by polyarticular, symmetric, and aggressive inflammation of the small joints in the hands and feet, resulting in dysfunction. With progress and development in medicine, treatment of RA is constantly evolving, making several drugs available for the treatment of RA. From the nonsteroidal anti-inflammatory drugs (NSAIDs) at the start of illness to glucocorticoids and then to conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs), therapeutic-use drugs for RA have been keeping pace with scientific research. However, various types of drugs have additional side effects when used over the long-term. New and emerging biological and targeted agents have been widely applied in recent years; however, the side effects have not been thoroughly investigated. In this paper, we review the research progress on liver damage caused by novel biological and targeted agents available for RA treatment. The aim is to provide a reference for rational clinical administration of such drugs. [ABSTRACT FROM AUTHOR]
Keywords: chemo-immunotherapy; chronic lymphocytic leukemia; targeted agents EN chemo-immunotherapy chronic lymphocytic leukemia targeted agents 201 204 4 02/03/23 20230201 NES 230201 PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1002/hon.3047. 1 TABLE Management of chronic lymphocytic leukemia (CLL) patients: Staging, criteria for starting treatment, response assessment and follow up HT
2020 (before first line)
2021 (before second line)
N = 35 (%)
N = 42 (%)
(1) What do you perform before starting first/second-line therapy? Dear Editor, different clinical trials on Chronic Lymphocytic Leukemia (CLL) indicate the superiority of targeted agents (TA), as ibrutinib, acalabrutinib and venetoclax, respect to chemo-immunotherapy (CIT). [Extracted from the article]
Bewersdorf, Jan Philipp, Shallis, Rory M., Derkach, Andriy, Goldberg, Aaron D., Stein, Anthony, Stein, Eytan M., Marcucci, Guido, Zeidan, Amer M., Shimony, Shai, DeAngelo, Daniel J., Stone, Richard M., Aldoss, Ibrahim, Ball, Brian J., and Stahl, Maximilian
FLT3, IDH1 and IDH2 inhibitors as well as venetoclax in combination with hypomethylating agents or low-dose cytarabine have expanded treatment options for patients with acute myeloid leukemia (AML). However, little data exist on the efficacy of venetoclax-based therapies in AML patients previously treated with FLT3 or IDH1/2 inhibitors. In this multicenter, retrospective cohort study, we included 44 patients who received venetoclax-based therapy after FLT3, IDH1 or IDH2 inhibitors. The overall response rate (ORR; composite of complete remission [CR]/CR with incomplete count recovery, partial remission, and morphologic leukemia free state) was 56.8% (18.2% CR) and a median overall survival of 9.2 months. While 6 out of 7 patients with IDH1 mutations who had previously been treated with ivosidenib responded to venetoclax-based therapy, FLT3-ITD mutations were associated with a lower response rate. Our data suggest that venetoclax can be an effective salvage therapy in patients previously treated with IDH1/2 or FLT3 inhibitors. [ABSTRACT FROM AUTHOR]
Second-line treatments are standard care for advanced hepatocellular carcinoma (HCC) patients with preserved liver function who are intolerant of or progress on first-line therapy. However, determinants of treatment benefit and post-treatment survival (PTS) remain unknown. HCC patients previously treated with sorafenib and enrolled in second-line clinical trials were pooled according to the investigational treatment received and the subsequent regulatory approval: approved targeted agents and immune checkpoint inhibitors (AT) or other agents (OT) not subsequently approved. Univariate and multivariate analyses using Cox proportional hazards models established relationships among treatments received, clinical variables, and overall survival (OS) or PTS. For 174 patients (80 AT; 94 OT) analyzed, baseline factors for longer OS in multivariate analysis were second-line AT, absence of both portal vein thrombosis and extrahepatic spread (EHS). Treatment with AT (versus OT) was associated with significantly longer OS among patients with EHS (pinteraction = 0.005) and patients with low neutrophil-to-lymphocyte ratio (NLR; pinteraction = 0.032). Median PTS was 4.0 months (95% CI 2.8–5.3). At second-line treatment discontinuation, alpha-fetoprotein (AFP) levels <400 ng/dl, albumin-bilirubin (ALBI) grade 1, and enrolment onto subsequent trials independently predicted longer PTS. Treatment with AT, PVT, and EHS were prognostic factors for OS, while AFP, ALBI grade and enrolment onto a third-line trial were prognostic for PTS. Presence of EHS and low NLR were predictors of greater OS benefit from AT. [ABSTRACT FROM AUTHOR]
Triarico, Silvia, Rivetti, Serena, Capozza, Michele Antonio, Romano, Alberto, Maurizi, Palma, Mastrangelo, Stefano, Attinà, Giorgio, and Ruggiero, Antonio
Subjects
CANCER chemotherapy, THERAPEUTIC use of antineoplastic agents, DACTINOMYCIN, ANTHRACYCLINES, ANTINEOPLASTIC agents, FETAL development, ANTIMETABOLITES, PREGNANCY complications, BLEOMYCIN, ENZYME inhibitors, PREGNANCY, FETUS
Abstract
Simple Summary: In this paper we perform an introduction about pregnancy-associated cancer (PAC) and transplacental passage of antineoplastic agents. Furthermore, we describe therapeutic use and potential toxic effects of chemotherapeutic drug (alkylating agents, antimetabolites agents, anthracyclines, topoisomerase inhibitors, antimitotic agents, actinomycin-D, bleomycin) and targeted agents during pregnancy. This manuscript may be a useful and practical guide for the management of PAC, which is a challenge for clinicians that have to consider alike maternal benefits and fetal potential risks correlated to the antineoplastic treatment. The incidence of PAC is relatively infrequent among pregnant women. However, it has gradually increased in recent years, becoming a challenging area for clinicians that should take into account in the same way maternal benefits and fetal potential risks correlated to the antineoplastic treatment. None of the antineoplastic drugs is completely risk-free during the pregnancy, the timing of exposure and transplacental transfer properties influence the toxicity of the fetus. Despite the lack of guidelines about the management of PAC, several studies have described the use and the potential fetal and neonatal adverse events of antineoplastic drugs during pregnancy. We provide a review of the available literature about the transplacental passage and fetal effects of chemotherapy and targeted agents, to guide the clinicians in the most appropriate choices for the management of PAC. [ABSTRACT FROM AUTHOR]
Lambertini, Matteo, Marrocco, Camilla, Spinaci, Stefano, Demeestere, Isabelle, and Anderson, Richard A.
Subjects
AMENORRHEA, IMMUNOTHERAPY, DRUG side effects, HORMONE receptor positive breast cancer, HER2 positive breast cancer, TRIPLE-negative breast cancer, IMMUNE checkpoint inhibitors
Abstract
Two other analyses have reported on post-treatment amenorrhoea rates in premenopausal women receiving anti-HER2 therapies without prior exposure to anthracycline- and cyclophosphamide-based chemotherapy. Keywords: breast cancer; immunotherapy; oncofertility; targeted agents EN breast cancer immunotherapy oncofertility targeted agents 1 4 4 06/16/22 20220701 NES 220701 In recent years, survivorship has become an area of crucial importance in the care of cancer patients. In addition, T-DM1 is now approved as post-neoadjuvant treatment in patients with HER2-positive breast cancer without pathological complete response following chemotherapy and trastuzumab-based anti-HER2 therapy, and several newer antibody drug conjugates alone or in combination with other targeted agents are currently being investigated in the early setting. Adjuvant anti-HER2 therapy, treatment-related amenorrhea, and survival in premenopausal HER2-positive early breast cancer patients. [Extracted from the article]
Simple Summary: Tumor cells are highly resistant to oxidative stress, but beyond a certain threshold, it may lead to apoptosis/necrosis. Thus, induced loss of redox balance can be a strategy used in anticancer therapies. However, the effectiveness of drugs contrasts with unknown mechanisms involved in the loss of fertility. Considering that cancer patients' life expectancy is increasing, it raises concerns about the unknown adverse effects. Therefore, new strategies should be pursued alongside explaining to the patients their options regarding the reproduction side effects. Tumor cells are highly resistant to oxidative stress resulting from the imbalance between high reactive oxygen species (ROS) production and insufficient antioxidant defenses. However, when intracellular levels of ROS rise beyond a certain threshold, largely above cancer cells' capacity to reduce it, they may ultimately lead to apoptosis or necrosis. This is, in fact, one of the molecular mechanisms of anticancer drugs, as most chemotherapeutic treatments alter redox homeostasis by further elevation of intracellular ROS levels or inhibition of antioxidant pathways. In traditional chemotherapy, it is widely accepted that most therapeutic effects are due to ROS-mediated cell damage, but in targeted therapies, ROS-mediated effects are mostly unknown and data are still emerging. The increasing effectiveness of anticancer treatments has raised new challenges, especially in the field of reproduction. With cancer patients' life expectancy increasing, many aiming to become parents will be confronted with the adverse effects of treatments. Consequently, concerns about the impact of anticancer therapies on reproductive capacity are of particular interest. In this review, we begin with a short introduction on anticancer therapies, then address ROS physiological/pathophysiological roles in both male and female reproductive systems, and finish with ROS-mediated adverse effects of anticancer treatments in reproduction. [ABSTRACT FROM AUTHOR]
ESOPHAGEAL cancer, CANCER treatment, NIVOLUMAB, OVERALL survival, CHEMORADIOTHERAPY
Abstract
Background: Concurrent chemoradiotherapy (CRT) is the preferred treatment strategy for inoperable esophageal cancer (EC). However, the effect of CRT needs to be improved. Methods: This study comprehensively analyzed targeted agents combined with CRT for the treatment of EC by a network meta-analysis. The search was performed in public databases from incipient to 5 August 2021. Randomized controlled trials comparing the effect of targeted agents combined with CRT and CRT alone on EC patients were included. Results: Ten studies were included. For progression-free survival (PFS), nivolumab (67.4%) and erlotinib (64.6%) had advantages based on Cox analysis. Regarding the frequency of PFS, cetuximab (OR: 1.39; 95% CI: 1.01, 1.91; p=0.042) and nivolumab (OR: 1.81; 95% CI: 1.34, 2.44; p<0.01) were significantly superior to the control. For overall survival (OS), nivolumab (71.6%) in Cox analysis and nimotuzumab (69.7%) in frequency analysis were found to have relative advantages. Nimotuzumab combined with CRT was significantly better than the control with regard to endoscopic and the pathologic complete response (epCR; OR: 2.81; 95% CI: 1.28, 6.14; p=0.011) and objective response rate (ORR; 4.71; 95% CI: 1.45, 15.29; p=0.008). The targeted drugs were not associated with significant SEA risk. Conclusion: In conclusion, compared to CRT alone, cetuximab and nivolumab combined with CRT were found to significantly improve the PFS rate only based on the frequency results. However, there was no benefit in terms of OS. For epCR and ORR, nimotuzumab was better than the blank control. Considering the limitations in this study, more well-designed RCTs are needed in the future to validate the results. [ABSTRACT FROM AUTHOR]
Cuneo, Antonio, Rigolin, Gian Matteo, Coscia, Marta, Quaresmini, Giulia, Scarfò, Lydia, Mauro, Francesca Romana, Motta, Marina, Quaglia, Francesca Maria, Trentin, Livio, Ferrario, Andrea, Laurenti, Luca, Reda, Gianluigi, Ferrari, Angela, Pietrasanta, Daniela, Sportoletti, Paolo, Re, Francesca, De Paoli, Lorenzo, Foglietta, Myriam, Giordano, Annamaria, and Marchetti, Monia
Subjects
COVID-19 pandemic, CHRONIC lymphocytic leukemia
Abstract
Interestingly, the percentage of patients treated with chemo-immunotherapy (CIT) at the time of the COVID-19 infection did not change in the phase 1 (15%) compared to the phase 3 (15.7%), suggesting that this treatment modality maintained its role in a distinct minority of CLL patients. COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus. Keywords: chronic lymphocytic leukemia; COVID-19; targeted agents; vaccination EN chronic lymphocytic leukemia COVID-19 targeted agents vaccination 570 574 5 10/08/21 20211001 NES 211001 TRANSPARENT PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2899. [Extracted from the article]
In the era of personalized medicine, systemic treatment with chemotherapy in combination with targeted drugs, tailored according to RAS and BRAF status, has improved the survival of patients with metastatic colorectal cancer (mCRC), but curative resection of metastases provides the only chance of cure. Here, we present a 40-year-old male with rectal adenocarcinoma and multiple bilateral synchronous liver metastases who has achieved long-term remission with multimodal treatment without resection of all metastatic lesions. This case emphasizes the need of repeated multidisciplinary team assessments and change of treatment intent if extraordinary responses are seen. The initial therapy consisted of short-course radiotherapy and surgery of the primary tumor followed by oxaliplatin-based combination chemotherapy and panitumumab with disease control intent. A complete radiologic response in >20 liver metastases in segments II–VIII was obtained. A biopsy-verified relapse of 3 liver metastases occurred at 9 months of treatment pause. Subsequently, major liver resection of 8 lesions was performed (4 with adenocarcinoma and 4 with cicatrix showing the challenge of disappearing lesions), followed by 6 months of adjuvant-like therapy. No relapse in MRI, PET, or CT has been noted since liver resection 6 years ago. Comprehensive genomic profiling of the primary tumor and liver metastases had similar driver mutations representing a low level of gene alteration and low diversity, possibly explaining the exceptional treatment response. [ABSTRACT FROM AUTHOR]
Recently approved therapies have contributed to a significant progress in the management of ovarian cancer; yet, more options are needed to further improve outcomes in patients with advanced disease. Here we review the rationale and ongoing clinical trials of novel combination strategies involving chemotherapy, poly ADP ribose polymerase, programmed death 1 (PD-1)/PD-ligand 1 immune checkpoint and/or vascular endothelial growth factor receptor inhibitors. Further, we discuss novel agents aimed at targets associated with ovarian cancer growth or progression that are emerging as potential new treatment approaches. Among them, agents targeted to folate receptor α, tissue factor, and protein kinase-mediated pathways (WEE1 kinase, phosphatidylinositol-3 kinase α, cell cycle checkpoint kinase 1/2, ATR kinase) are currently in clinical development as mono- or combination therapies. If successful, findings from these extensive development efforts may further transform treatment of patients with advanced ovarian cancer. [ABSTRACT FROM AUTHOR]
Spetsieris, Nicholas, Boukovala, Myrto, Weldon, Justin A., Tsikkinis, Alexandros, Anh Hoang, Aparicio, Ana, Shi-Ming Tu, Araujo, John C., Zurita, Amado J., Corn, Paul G., Pagliaro, Lance, Kim, Jeri, Wang, Jennifer, Subudhi, Sumit K., Tannir, Nizar M., Logothetis, Christopher J., Troncoso, Patricia, Xuemei Wang, Sijin Wen, and Efstathiou, Eleni
Subjects
CLINICAL trials, ABIRATERONE acetate, DASATINIB, SUNITINIB, CASTRATION-resistant prostate cancer
Abstract
The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. In an open-label randomized phase 2 study, no difference was reported in overall survival or time to treatment failure between dasatinib and sunitinib combined with abiraterone after disease progression while receiving abiraterone monotherapy in patients with bone metastatic castration-resistant prostate cancer. Background: Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC. Patients and Methods: In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety. Results: From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years. Conclusion: There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC. [ABSTRACT FROM AUTHOR]
ACUTE myeloid leukemia, MOLECULAR pathology, MYELOID leukemia, THERAPEUTIC use of antineoplastic agents, MYELODYSPLASTIC syndromes, ONLINE information services, RESEARCH, SEQUENCE analysis, HETEROCYCLIC compounds, RESEARCH methodology, PROGNOSIS, EVALUATION research, MEDICAL cooperation, BLOOD cells, COMPARATIVE studies, AMINOPYRIDINES, DISEASE susceptibility, CHROMOSOME abnormalities, MEDLINE, DAUNOMYCIN, CYTARABINE, CYTOGENETICS, BONE marrow, BONE marrow examination
Abstract
Objectives: Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) represents a high-risk and somewhat diverse subtype of AML, and substantial confusion exists about the pathologic evaluation needed for diagnosis, which can include the patient's clinical history, cytogenetic analysis, mutational analysis, and/or morphologic evaluation. Treatment decisions based on incomplete or untimely pathology reports may result in the suboptimal treatment of patients with AML-MRC.Methods: Using a PubMed search, diagnosis of and treatment options for AML-MRC were investigated.Results: This article reviews the current diagnostic criteria for AML-MRC, provides guidance on assessments necessary for an AML-MRC diagnosis, summarizes clinical and prognostic features of AML-MRC, and discusses potential therapies for patients with AML-MRC. In addition to conventional chemotherapy, treatment options include CPX-351, a liposomal encapsulation of daunorubicin/cytarabine approved for treatment of adults with AML-MRC; targeted agents for patients with certain mutations/disease characteristics; and lower-intensity therapies for less fit patients.Conclusions: Given the evolving and complex treatment landscape and the high-risk nature of the AML-MRC population, a clear understanding of the pathology information necessary for AML-MRC diagnosis has become increasingly important to help guide treatment decisions and thereby improve patient outcomes. [ABSTRACT FROM AUTHOR]
Primary liver cancer is a rapidly progressing neoplasm with high morbidity and mortality rates. The present study aimed to identify potential diagnostic and prognostic biomarkers, and candidate targeted agents for hepatitis B virus (HBV)-associated early stage hepatocellular carcinoma (HCC). The gene expression profiles were extracted from the Gene Expression Omnibus database. Differentially expressed genes (DEGs), hub genes and the enrichment of signaling pathways were filtered out via a high-throughput sequencing method. The association between hub genes and the effects of the abnormal expression of hub genes on the rate of genetic variation, overall survival (OS), relapse-free survival (RFS), progression-free survival (PFS) and disease-free survival (DSS) of patients with HCC, as well as pathological stage and grade, were analyzed using different databases. A total of 1,582 DEGs were identified. Gene Ontology analysis revealed that the DEGs were mainly involved in the 'oxidation-reduction process', 'steroid metabolic process', 'metabolic process' and 'fatty acid beta-oxidation'. Enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways revealed that the DEGs were mainly associated with 'metabolic pathways', 'PPAR signaling pathway', 'fatty acid degradation' and the 'cell cycle'. A total of 8 hub genes were extracted. Additionally, the abnormal expression levels of hub genes were closely associated with the OS, RFS, PFS and DSS of patients, the pathological stage and the grade. Furthermore, abnormal expression levels of the 8 hub genes were found in >30% of all samples. Several small molecular compounds that may reverse the altered DEGs were identified based on Connectivity Map analysis, including phenoxybenzamine, GW-8510, resveratrol, 0175029-0000 and daunorubicin. In conclusion, the dysfunction of fat metabolic pathways, the cell cycle, oxidation-reduction processes and viral carcinogenesis may serve critical roles in the occurrence of HBV-associated early stage HCC. The identified 8 hub genes may act as robust biomarkers for diagnosis and prognosis. Some small molecular compounds may be promising targeted agents against HBV-associated early stage HCC. [ABSTRACT FROM AUTHOR]
Hsu, Jessica C., Nieves, Lenitza M., Betzer, Oshra, Sadan, Tamar, Noël, Peter B., Popovtzer, Rachela, and Cormode, David P.
Abstract
X‐ray imaging is the most widely used diagnostic imaging method in modern medicine and several advanced forms of this technology have recently emerged. Iodinated molecules and barium sulfate suspensions are clinically approved X‐ray contrast agents and are widely used. However, these existing contrast agents provide limited information, are suboptimal for new X‐ray imaging techniques and are developing safety concerns. Thus, over the past 15 years, there has been a rapid growth in the development of nanoparticles as X‐ray contrast agents. Nanoparticles have several desirable features such as high contrast payloads, the potential for long circulation times, and tunable physicochemical properties. Nanoparticles have also been used in a range of biomedical applications such as disease treatment, targeted imaging, and cell tracking. In this review, we discuss the principles behind X‐ray contrast generation and introduce new types of X‐ray imaging modalities, as well as potential elements and chemical compositions that are suitable for novel contrast agent development. We focus on the progress in nanoparticle X‐ray contrast agents developed to be renally clearable, long circulating, theranostic, targeted, or for cell tracking. We feature agents that are used in conjunction with the newly developed multi‐energy computed tomography and mammographic imaging technologies. Finally, we offer perspectives on current limitations and emerging research topics as well as expectations for the future development of the field. This article is categorized under:Diagnostic Tools > in vivo Nanodiagnostics and ImagingNanotechnology Approaches to Biology > Nanoscale Systems in Biology [ABSTRACT FROM AUTHOR]
Taghizadeh, Hossein, Müllauer, Leonhard, Mader, Robert M., Schindl, Martin, and Prager, Gerald W.
Abstract
Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) bears a dismal prognosis due to the limited activity of systemic chemotherapy. In our platform for precision medicine, we aim to offer molecular-guided treatments to patients without further standard therapy options. Methods: In this single center, real-world retrospective analysis of our platform, we describe the molecular-based therapy approaches used in all 50 patients diagnosed with therapy-refractory mPDAC. A molecular portrait of the tumor specimens was created by next-generation sequencing, immunohistochemistry (IHC), microsatellite instability (MSI) testing, and fluorescence in situ hybridization. Results: In total, we detected 123 mutations in 50 patients. The five most frequent mutations were KRAS (n = 40; 80%), TP53 (n = 29; 58%), CDKN2A (n = 8; 16%), SMAD4 (n = 4; 8%), and NOTCH1 (n = 4; 8%), which together accounted for 40.2% of all mutations. Two patients had gene fusions, namely, TBL1XR1–PIK3CA and EIF3E–RSPO2. IHC detected expression of EGFR, phosphorylated mTOR, and PTEN in 36 (72%), 33 (66%), and 17 patients (34%), respectively. For 14 (28%) of the 50 patients, a targeted therapy was suggested based on the identified molecular targets. The recommended treatments included the mTOR inhibitor everolimus (n = 3), pembrolizumab (n = 3), palbociclib (n = 2), nintedanib (n = 2), and cetuximab, crizotinib, tamoxifen, and the combination of lapatinib and trastuzumab, in one patient each. Finally, five patients received the recommended therapy. Four patients died due to disease progression before radiological assessment. One patient was treated with nintedanib and achieved stable disease for 6 months. Conclusion: Based on our observations, precision medicine approaches are feasible and implementable in clinical routine and may provide molecular-based therapy recommendations for mPDAC. [ABSTRACT FROM AUTHOR]
Taghizadeh, Hossein, Mader, Robert M., Müllauer, Leonhard, Aust, Stefanie, Polterauer, Stephan, Kölbl, Heinz, Seebacher, Veronika, Grimm, Christoph, Reinthaller, Alexander, and Prager, Gerald W.
Subjects
BIOMARKERS, COLLECTION & preservation of biological specimens, FEMALE reproductive organ tumors, HEALTH care teams, IMMUNOHISTOCHEMISTRY, MOLECULAR diagnosis, MOLECULAR pathology, PHOSPHORYLATION, TUMOR classification, GENETIC markers, RETROSPECTIVE studies, INDIVIDUALIZED medicine, DESCRIPTIVE statistics
Abstract
Introduction: Advanced gynecologic cancers have a poor prognosis and constitute a major challenge for adequate treatment strategies. By analyzing and targeting molecular alterations, molecular guided treatments may be a viable option for the treatment of advanced gynecologic cancers. Patients and Methods: In this single‐center, real‐world retrospective analysis of our platform for precision cancer medicine (PCM), we describe the molecular profiling of 72 patients diagnosed with different types of advanced gynecologic malignancies. Tumor samples of the patients were examined by next‐generation sequencing panel and immunohistochemistry (IHC). Results: In total, we identified 209 genetic aberrations in 72 patients. The ten most frequent alterations were TP53 (n = 42, 20%), KRAS (n = 14, 6.6%), PIK3CA (n = 11, 5.2%), PIK3R1 (n = 9, 4.3%), ATR (n = 8, 3.8%), PTEN (n = 8, 3.8%), BRCA1 (n = 6, 2.8%), NF1 (n = 4, 1.9%), NOTCH1 (n = 4, 1.9%), and POLE (n = 4, 1.9%), which account for more than half of all molecular alterations (52.6%). In 21 (29.1%) patients only one mutation could be detected, and 44 (61.1%) patients had more than one mutation. No molecular alterations were detected in seven (9.7%) patients. IHC detected expression of phosphorylated mammalian target of rapamycin and epidermal growth factor receptor in 58 (80.6%) and 53 (73.6%) patients, respectively. In over two thirds (n = 49, 68.1%), a targeted therapy was suggested, based on the identified genetic aberrations. The most frequently recommended specific treatment was the combination of everolimus with exemestane (n = 18, 25 %). Conclusion: Based on our observations, it seems that PCM might be a feasible approach for advanced gynecologic cancers with limited treatment options. Implications for Practice: Nowadays molecular profiling of advanced gynecologic malignancies is feasible in the clinical routine. A molecular portrait should be done for every patient with an advanced therapy‐refractory gynecologic malignancy to offer molecular‐based treatment concepts. To determine the feasibility of precision cancer medicine (PCM) in gynecologic cancers, this retrospective study analyzed patients with advanced gynecologic cancers enrolled and profiled in a PCM platform, MONDTI, focusing on the technical feasibility to map the molecular profiles of advanced, pretreated, and mainly relapsed gynecologic cancers and to subsequently target the detected molecular alterations [ABSTRACT FROM AUTHOR]
Until recently, the treatment of bladder cancer, for several years, was limited to surgery and to immunotherapy or chemotherapy. Currently, the extensive analysis of molecular alterations has led to novel treatment approaches. The advent of polymerase chain reaction and genomic hybridization techniques has allowed to investigate alterations involved in bladder cancer at DNA level. By this way, bladder cancers can be classified as papillary or non-papillary based on genetic alterations with activation or mutations in FGFR3 papillary tumors and with inactivation or mutations involving TP53 and RB1 in non-papillary tumors. Recently, the patterns of gene expression allow to differentiate basal and luminal subtypes as reported in breast cancer. In particular, basal cancers are composed of squamous and sarcomatoid pathological findings, while luminal cancers are composed of papillary finding features and genetic mutations (FGFR3). In particular, specific investigative studies demonstrated that luminal cancers are associated with secondary muscle invasive cancer while basal tumors are related to advanced disease since they are often metastatic at diagnosis. Moreover, from therapeutic point of view, different researchers showed that mutations of DNA are related to the sensitivity of bladder cancer while performing cisplatin chemotherapy. In this prospective, the bladder cancer molecular subtyping classification might allow identifying the set of patients who can safely avoid neoadjuvant chemotherapy likely because of the low response to systemic chemotherapy (chemoresistant tumors). In this context, the Cancer Genome Atlas (TCGA) project has improved the knowledge of the molecular targets of invasive urothelial cancers allowing the researchers to propose hypothesis suggesting that agents targeting the genomic alterations may be an effective strategy in managing these cancers, which occur in about 68% of muscle invasive cancers. A future goal will be to combine treatment strategies of invasive bladder cancers according to their genetic mutational load defined by molecular pathology. [ABSTRACT FROM AUTHOR]
Thekkudan, Shinto F., Lima, Marcos, and Metheny, Leland
Subjects
ACUTE myeloid leukemia treatment, STEM cell transplantation, CANCER relapse
Abstract
Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is a potentially curative treatment for acute myeloid leukemia (AML). Reduced intensity regimens, alternative graft sources, advances in HLA‐matching, improved supportive care, and tailored graft versus host disease (GVHD) prophylaxis have led to a wider application of allo‐HSCT to eligible patients. Unfortunately, 30‐40% of patients with AML will relapse after transplant and this is the major cause of treatment failure. Careful consideration should be paid in choosing the type of graft, graft source, and conditioning regimen to minimize the risk of disease recurrence. In addition, maintenance therapy following allo‐HSCT is a potential method to keep the disease in remission, especially in those with high‐risk disease characteristics. Pharmacological targeted agents with low side effect profile such as tyrosine kinase inhibitors, hypomethylating agents (HMAs), HDAC inhibitors, antibody drug conjugates (ADCs), isocitrate dehydrogenase inhibitors, and hedgehog inhibitors may prevent relapse in posttransplant setting and are under investigation. Immunological therapies including donor lymphocyte infusions (DLIs), natural killer (NK) cell therapy, peptide vaccine targeting tumor antigens, and adoptive T‐cell therapies all hold promises in this area as well. As targeted agents and immunotherapies continue to be developed, patients at high risk of recurrence may benefit from prophylactic maintenance therapy. Here we review the current landscape in this rapidly evolving clinical setting. [ABSTRACT FROM AUTHOR]
OLDER patients, METASTASIS, META-analysis, CANCER patients, PUBLICATION bias
Abstract
Introduction: The aim of the present study was to assess the efficacy of molecularly targeted agents (MTAs) in the treatment of elderly patients with metastatic oesophago-gastric cancer (mOGC).Material and Methods: We systematically searched electronic databases and abstracts presented at American Society of Clinical Oncology (ASCO) meetings up to January 31, 2017. Hazard ratios (HRs) were used to estimate overall survival (OS) and progression-free survival (PFS). Subgroup analysis and publication bias were also evaluated. All statistical analysis was conducted using Comprehensive Meta Analysis software (Version 2.0).Results: A total of 2,149 elderly patients with mOGC from thirteen trials were included. Compared to non-MTA-containing regimens, OS was significantly improved in the MTA-containing regimens (HR = 0.86, 95% CI: 0.75-0.99, p = 0.037), but not for PFS (HR = 1.05, 95% CI: 0.85-1.30, p = 0.67). In addition, subgroup analysis indicated that MTA-containing regimens as second-line therapy in elderly mOGC patients significantly improved PFS (HR = 0.58; 95% CI: 0.39-0.85, p = 0.005) and OS (HR = 0.82, 95% CI: 0.70-0.96, p = 0.016), but did not significantly improve PFS (HR = 1.36; 95% CI: 1.06-1.76, p = 0.017) and OS (HR = 0.98, 95% CI: 0.77-1.27, p = 0.90) for MTA-containing regimens as first-line therapy in these patients. No publication bias was detected by Begg's and Egger's tests for OS and PFS.Conclusions: Our results indicate that the MTA-containing therapies significantly improve OS but not for PFS in elderly mOGC patients. Sub-group analysis shows that improved efficacy is only observed in the second-line setting and not in the first-line setting. Our findings support the use of angiogenesis as second-line treatment for elderly mOGC patients. [ABSTRACT FROM AUTHOR]
Hauser, Haley, Gerson, Daniela Shveid, Reidy-Lagunes, Diane, and Raj, Nitya
Abstract
Opinion Statement: Over the years, there have been significant advances in systemic treatments for metastatic pancreatic neuroendocrine tumors (panNETs). Despite these advancements, uncertainty remains regarding how to best sequence available therapies. For well-differentiated and metastatic panNETs that are somatostatin receptor (SSTR) avid on functional imaging, first-line therapy typically consists of somatostatin analogs (SSAs), given their favorable toxicity profile and overall low burden for patients. When progression of disease is observed on an SSA, multiple treatment options are available, including the targeted agents everolimus and sunitinib, peptide receptor radionuclide therapy (PRRT), as well as chemotherapy, with the latter often preferred for those panNETs of heavy tumor burden, higher grade, and/or more aggressive behavior clinically and/or radiographically. Here, we review panNET classification, currently available systemic treatments, therapy sequencing, and areas of active investigation to further our treatments for the disease. [ABSTRACT FROM AUTHOR]
ANTINEOPLASTIC agents, COMPARATIVE studies, META-analysis, METASTASIS, NEUROENDOCRINE tumors, OCTREOTIDE acetate, PLACEBOS, SURVIVAL analysis (Biometry), TIME, EARLY medical intervention, DESCRIPTIVE statistics, EVEROLIMUS
Abstract
Background: Most guidelines still recommend active surveillance for patients with asymptomatic, unresectable neuroendocrine tumors (NETs). However, recent findings from several randomized placebo‐controlled trials suggest that most patients would benefit from active treatment. We conducted a meta‐analysis of pooled outcomes from clinical trials in which an active treatment arm was compared with placebo to determine whether active treatment provides a survival advantage. Materials and Methods: This meta‐analysis evaluated six trials that compared a medication with placebo in patients with an asymptomatic, metastatic NET. The trials were heterogenous with regard to the active medication (octreotide, lanreotide, sunitinib, everolimus, Lu‐Dotatate) and tumor localizations (gastrointestinal, pancreas, lung). Overall survival (OS) and progression‐free survival (PFS) for the placebo and active treatment arms were obtained from individual trial data and combined to obtain pooled outcomes. Results: The individual trials all reported significantly better PFS outcomes for active treatment. The pooled data confirmed this advantage. At months 3, 6, 12, 18, and 24, pooled PFS rates for the placebo and treatment arms, respectively, were 92.9% versus 96.9%; 54.3% versus 83.7%; 35.5% versus 68.5%; 25.1% versus 54.7%; and 17.7% versus 61.0%. OS was also higher in the active treatment groups. At months 6, 12, 24, 36, 48, and 60, OS rates (placebo vs. active treatment), respectively, were 88.1% versus 93.4%; 84.1% versus 86.2%; 67.4% versus 76%; 56.6% versus 64.4%; 49.9% versus 61.0%; and 41.7% versus 45.9%. Conclusion: This meta‐analysis confirms findings from recent clinical trials indicating that active treatment yields better survival outcomes than placebo. Importantly, these findings were obtained across a wide range of patient profiles and diverse medical treatments for metastatic NETs. Given the lack of reliable prognostic factors to determine a priori which patients are unlikely to benefit from active treatment, these findings support early treatment in most patients. Implications for Practice: Although most guidelines still recommend active surveillance for patients diagnosed with metastatic neuroendocrine tumors, the results of this meta‐analysis, together with recent data from key clinical trials, suggest that most patients could benefit from upfront active treatment. However, more data are needed to confirm this. Neuroendocrine tumors (NETs) are slow‐growing and often asymptomatic and the optimal upfront management approach is controversial. Despite the lack of evidence‐based data, the watch‐and‐wait strategy is still included in clinical guidelines. The present article reports the results of a meta‐analysis of phase III clinical trials that have compared active treatment to placebo in patients with metastatic NETs. [ABSTRACT FROM AUTHOR]
LUNG cancer treatment, TREATMENT effectiveness, PROGRESSION-free survival, CELL-mediated cytotoxicity, QUALITY of life, RANDOMIZED controlled trials
Abstract
Recently, targeted agents were reported to improve overall survival, progression‐free survival (PFS), response rate, and quality of life compared with cytotoxic chemotherapies, which provides hope for the treatment of non‐small‐cell lung cancer (NSCLC). The network meta‐analysis is applied to compare the efficacies and adverse events of five targeted agents (erlotinib, gefitinib, vandetanib, dacomitinib, and icotinib) for advanced or metastatic NSCLC. Nine eligible randomized controlled trials from PubMed and Cochrane Library database were included. Weighted mean difference, odds ratio, and surface under the cumulative ranking curve (SUCRA) values were evaluated for the efficacy and adverse events of the five targeted agents in the treatment of NSCLC. With regard to efficacy, the overall response rate (ORR) of advanced or metastatic NSCLC patients treated with gefitinib was relatively higher than those treated with placebo. Compared with patients treated with placebo, the disease control rate (DCR) of patients treated with erlotinib and with gefitinib was relatively higher. Furthermore, in terms of PFS and DCR, the SUCRA value of icotinib was the highest among the five targeted drugs. With regard to ORR, the SUCRA value of gefitinib was the highest among the five targeted drugs. In terms of fatigue, rash, and cough, erlotinib had the lowest SUCRA value, whereas vandetanib exhibited the lowest SUCRA value in terms of diarrhea. Our study suggests that the efficacies of gefitinib and icotinib for advanced or metastatic NSCLC were comparatively better, whereas the toxicities of erlotinib and vandetanib were relatively greater. The efficacies of gefitinib and icotinib for advanced or metastatic NSCLC were comparatively better, whereas the toxicities of erlotinib and vandetanib were relatively greater. [ABSTRACT FROM AUTHOR]
Cloyd, Jordan M., Konda, Bhavana, Shah, Manisha H., and Pawlik, Timothy M.
Subjects
NEUROENDOCRINE tumors, SOMATOSTATIN, RADIOTHERAPY, CANCER treatment, CLINICAL trials
Abstract
Introduction: Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are unique and complex neoplasms, exhibiting a wide spectrum of diverse clinical behaviors. The contemporary management of well-differentiated GEP-NETs is marked by the availability of a wide range of targeted therapies. Areas Covered: For patients with localized or oligometastatic disease, surgical resection remains the preferred approach and is associated with excellent long-term outcomes. For patients with unresectable but isolated liver metastases, multiple liver-directed therapies, including hepatic arterial based therapies and ablative techniques, exist. For patients with metastatic and progressive disease, a number of systemic therapies exist: molecular targeted agents, peptide receptor radionuclide therapy (PRRT), and systemic chemotherapy. Furthermore, somatostatin analogs (SSA) are an important component of therapy, both effectively controlling symptoms of hormonal overproduction and contributing to slowing tumor progression. Expert Opinion: In the near future, advances in our understanding of tumor biology, genetics, immunology, nanotechnology, and radiation pharmacology should only continue to expand the availability of targeted therapies, improving the outcomes of patients with GEP-NETs. We herein review the management of advanced well-differentiated GEP-NETS with a particular emphasis on the role of targeted therapies. [ABSTRACT FROM AUTHOR]
PROTEIN-tyrosine kinase inhibitors, SORAFENIB, CELL proliferation, CANCER chemotherapy, CANCER relapse, DRUG toxicity, HEMATOPOIETIC stem cells, GENETIC mutation, SURVIVAL, TUMOR classification, DRUG approval, DISEASE remission, ACUTE myeloid leukemia, GENETICS, PROGNOSIS, THERAPEUTICS
Abstract
FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is responsible for the proliferation and survival of hematopoietic stem cells in acute myeloid leukemia. Although patients with FLT3 mutations have similar rates of remission following induction chemotherapy, relapse rates are significantly higher and patients with FLT3 mutations have significantly worse outcomes for overall survival and disease-free survival. Early FLT3 inhibitors, such as sorafenib, were non-selective and inhibited several tyrosine kinase receptors resulting in significant toxicity. The treatment of FLT3-positive acute myeloid leukemia has advanced recently with the development of a several FLT3-targeting agents that are either approved or in development. Midostaurin represents the first FDA-approved treatment targeted against FLT3, and there are several promising agents currently undergoing clinical trials. Although certain mutations confer resistance to earlier generation FLT3-targeted tyrosine kinase inhibitors, newer agents show activity in the presence of these mutations. [ABSTRACT FROM AUTHOR]
Gómez-España, M. A., Gallego, J., González-Flores, E., Maurel, J., Páez, D., Sastre, J., Aparicio, J., Benavides, M., Feliu, J., and Vera, R.
Abstract
Colorectal cancer (CRC) is the second cause of cancer death in Spain, the objective of this guide published by the Spanish Society of Medical Oncology is to develop a consensus for the diagnosis and management of metastatic disease. The optimal treatment strategy for patients with metastatic CRC should be discussed in a multidisciplinary expert team to select the most appropriate treatment, and integrate systemic treatment and other options such as surgery and ablative techniques depending on the characteristics of the tumour, the patient and the location of the disease and metastases. [ABSTRACT FROM AUTHOR]
Sosa Iglesias, Venus, Theys, Jan, Groot, Arjan J., Barbeau, Lydie M. O., Lemmens, Alyssa, Yaromina, Ala, Losen, Mario, Houben, Ruud, Dubois, Ludwig, and Vooijs, Marc
Abstract
Background: Lung cancer is the leading cause of cancer death worldwide. More effective treatments are needed to increase durable responses and prolong patient survival. Standard of care treatment for patients with non-operable stage III-IV NSCLC is concurrent chemotherapy and radiation. An activated NOTCH signaling pathway is associated with poor outcome and treatment resistance in non-small cell lung cancer (NSCLC). NOTCH/γ-secretase inhibitors have been effective in controlling tumor growth in preclinical models but the therapeutic benefit of these inhibitors as monotherapy in patients has been limited so far. Because NOTCH signaling has been implicated in treatment resistance, we hypothesized that by combining NOTCH inhibitors with chemotherapy and radiotherapy this could result in an increased therapeutic effect. A direct comparison of the effects of NOTCH inhibition when combined with current treatment combinations for NSCLC is lacking. Methods: Using monolayer growth assays, we screened 101 FDA-approved drugs from the Cancer Therapy Evaluation Program alone, or combined with radiation, in the H1299 and H460 NSCLC cell lines to identify potent treatment interactions. Subsequently, using multicellular three-dimensional tumor spheroid assays, we tested a selection of drugs used in clinical practice for NSCLC patients, and combined these with a small molecule inhibitor, currently being tested in clinical trials, of the NOTCH pathway (BMS-906024) alone, or in combination with radiation, and measured specific spheroid growth delay (SSGD). Statistical significance was determined by one-way ANOVA with post-hoc Bonferroni correction, and synergism was assessed using two-way ANOVA. Results: Monolayer assays in H1299 and H460 suggest that 21 vs. 5% were synergistic, and 17 vs. 11% were additive chemoradiation interactions, respectively. In H1299 tumor spheroids, significant SSGD was obtained for cisplatin, etoposide, and crizotinib, which increased significantly after the addition of the NOTCH inhibitor BMS-906024 (but not for paclitaxel and pemetrexed), and especially in triple combination with radiation. Synergistic interactions were observed when BMS-906024 was combined with chemoradiation (cisplatin, paclitaxel, docetaxel, and crizotinib). Similar results were observed for H460 spheroids using paclitaxel or crizotinib in dual combination treatment with NOTCH inhibition and triple with radiation. Conclusions: Our findings point to novel synergistic combinations of NOTCH inhibition and chemoradiation that should be tested in NSCLC in vivo models for their ability to achieve an improved therapeutic ratio. [ABSTRACT FROM AUTHOR]
Gordon, Max J., Churnetski, Michael, Alqahtani, Hamood, Rivera, Xavier, Kittai, Adam, Amrock, Stephen M., James, Spencer, Hoff, Sheila, Manda, Sudhir, Spurgeon, Stephen E., Choi, Michael, Cohen, Jonathon B., Persky, Daniel, and Danilov, Alexey V.
Subjects
CHRONIC lymphocytic leukemia, RETROSPECTIVE studies, CANCER prognosis, IMMUNOTHERAPY, PROGRESSION-free survival
Daskalakis, Kosmas, Norlén, Olov, Karakatsanis, Andreas, Hellman, Per, Larsson, Rolf, Nygren, Peter, and Stålberg, Peter
Subjects
SMALL intestine, NEUROENDOCRINE tumors, ANTINEOPLASTIC agents, TARGETED drug delivery, TUMOR markers, TUMORS
Abstract
Small intestinal neuroendocrine tumors (SI-NETs) are generally considered resistant to systemic treatment. To date, predictive markers for drug activity are lacking. Tumor samples from 27 patients with SI-NETs were analyzed ex vivo for sensitivity to a panel of cytotoxic drugs and targeted agents using a short-term total cell kill assay. Samples of renal cancer, colorectal cancer (CRC), ovarian cancer and chronic lymphocytic leukemia (CLL) were included for comparison. For the SI-NET subset, drug sensitivity was analyzed in relation to clinicopathological variables and pre-treatment biomarkers. For cytotoxic drugs, SI-NETs demonstrated similar or higher sensitivity to 5-FU, platinum, gemcitabine and doxorubicin compared with CRC. For several of the targeted kinase inhibitors, SI-NET was among the most sensitive solid tumor types. CLL and ovarian cancer were generally the most sensitive tumor types to both cytotoxic drugs and protein kinase inhibitors. SI-NET was more sensitive to the mTOR inhibitor sirolimus than the other solid tumor types tested. Individual SI-NET samples demonstrated great variability in ex vivo sensitivity for most drugs. Cross-resistance between different drugs also varied considerably, being higher among protein kinase inhibitors. Age, stage, grade, peritoneal carcinomatosis and extra-abdominal metastases as well as serum chromogranin A and urine 5-HIAA concentrations at diagnosis did not correlate to drug sensitivity ex vivo. SI-NETs exhibit intermediate sensitivity ex vivo to cytotoxic and targeted drugs. Clinicopathological factors and currently used biomarkers are not clearly associated to ex vivo sensitivity, challenging these criteria for treatment decisions in SI-NET. The great variability in drug sensitivity calls for individualized selection of therapy. [ABSTRACT FROM AUTHOR]
ADJUVANT treatment of cancer, RECTAL cancer patients, CETUXIMAB, DATABASES, CANCER chemotherapy
Abstract
Abstract: Patients with locally advanced rectal cancer (LARC) are at tremendous risk of metastatic diseases. To improve the prognoses of LARC patients, the efficacy of adding targeted agents to neoadjuvant therapy has been investigated by many researchers but remains controversial. A literature search of relevant databases was conducted through December 2016, 804 studies were identified and 32 investigations were ultimately included. A total of 1196 patients from 31 cohorts of 29 studies were eligible for quantitative synthesis in this single‐arm setting meta‐analysis. As pathologic complete response (pCR) shows promise as a prognosis indicator, we focused on pCR rates to evaluate whether adding targeted agents to neoadjuvant therapies improves the outcome of LARC patients. In our study, we revealed pooled estimates of pCR of 27% (95%CI, 21–34%) and 14% (95%CI, 9–21%) for bevacizumab‐relevant cohorts and cetuximab‐relevant cohorts, respectively. The safety of adding targeted agents to neoadjuvant therapy was also evaluated by pooling the data of Grade 3/4 toxicity. In conclusion, our study revealed that adding bevacizumab to the neoadjuvant therapy regimens provides appreciable pCR for LARC patients. Meanwhile, the efficacy of cetuximab remains inconclusive, RCTs with larger scale and better study design that stress more on mutational status are needed. [ABSTRACT FROM AUTHOR]
Hermine, Olivier, Ramos, Juan Carlos, and Tobinai, Kensei
Abstract
Adult T-cell leukemia-lymphoma (ATL), a rare and aggressive T-cell malignancy caused by human T-cell lymphotropic virus type 1 (HTLV-1), is associated with a poor prognosis. Evidence-based standard treatment options are lacking and outcomes are generally unsatisfactory, particularly for patients with relapsed or refractory disease. Continued research is contributing to changing treatment landscape as a number of existing and investigational agents are evaluated. We describe the epidemiology of HTLV-1 and ATL, discuss the biology behind the disease, review current treatment practices and guidelines, and provide an overview of emerging therapies in ATL, with a focus on those for relapsed or refractory disease. [ABSTRACT FROM AUTHOR]
Merveilleux du Vignaux, Claire, Maury, Jean-Michel, and Girard, Nicolas
Subjects
ANTINEOPLASTIC agents, CELLULAR signal transduction, DRUG design, GENES, IMMUNOTHERAPY, THYMUS tumors, TREATMENT effectiveness
Abstract
Opinion Statement: The management of thymic tumours is a paradigm of multidisciplinary collaboration. Chemotherapy may be administered part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy, or as an exclusive treatment if local treatment is not achievable. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. Given the limited activity of cytotoxic agents in the advanced, refractory setting, novel and innovative agents are needed. The better understanding of thymic carcinogenesis may provide a rationale in this setting.Targeted agents approved for other solid tumors that have shown activity in thymic tumors include mTOR, KIT inhibitors, as well as somatostatin analogues. Anti-angiogenic agent sunitinib may be considered a standard in advanced lines of treatment. Ongoing studies are assessing the opportunity of targeting emerging targets, including PI3K, CDK, and immune checkpoint PD-1/PD-L1. [ABSTRACT FROM AUTHOR]