Magnitude of benefit of adjuvant chemotherapy for non-small cell lung cancer: meta-analysis of randomized clinical trials

Several randomized trials investigating the benefit of adjuvant chemotherapy after surgery in non-small cell lung cancer (NSCLC) have provided conflicting results. With over 7000 patients included, we analyzed results of 13 reports over the past 10 years in which patients received either platinum-containing chemotherapy or not. The major endpoint was to assess the magnitude of the benefit of adjuvant chemotherapy in terms of the absolute benefit. All phase III randomized trials and meta-analyses published as peer-reviewed papers or as abstracts from 1994 to 2007 were eligible. A literature-based meta-analysis was performed; event-based overall- and disease-free survival (OS/DFS) and Relative Risks (RRs) with 95% confidence intervals (CIs) were derived. Magnitudes of benefit were evaluated with: absolute benefit and the number of patients treated for one patient to benefit. Seven sub-populations were examined. Combined effect estimation was computed with fixed- and random-effect models; a heterogeneity test was also applied. Twelve trials plus an individual patient meta-analysis (7334 patients) were gathered; the trials were designed to determine if cisplatin- or carboplatin-based chemotherapy improves survival over surgery. When data were pooled and plotted, significant differences in favor of chemotherapy were seen in OS in all seven sub-population, with a relative benefit of 7-12% and an absolute benefit ranging from 2.5% to 4.1%. A more significant trend for chemotherapy was found in DFS. No significant heterogeneity was observed for all outcomes and sub-populations. The absolute benefit of adjuvant chemotherapy remains essentially the same regardless of how data are screened. While significant differences are clearly found in this analysis, the small magnitude of benefit seen with this large population, especially when considering the number of patients needed for one to benefit, raises important issues when weighing risks and benefits of treatment for individual patients.     

Acupuncture for Symptom Management in Cancer Care: an Update

In a previous systematic review of the worldwide literature of randomized controlled trials (RCTs) involving needle insertion into acupuncture points for symptom management in cancer patients, we identified only one high-quality RCT that was deemed to have a low risk of bias. Medline, Embase, CINAHL, Cochrane (all databases), Scopus, and PubMed were searched from inception through December 2011 with no language limits applied. A total of 41 RCTs met all inclusion criteria and were rated. In the current review, we examined 18 trials published since our last report. The purpose of this update was to emphasize important recent findings and discuss how concerns such as blinding, separating non-specific placebo effects from specific needling effects, determining biologic mechanisms and dosing parameters, evaluating determinants of response such as expectation, controlling for sources of bias, and the lack of standardization in treatment and study methods may affect the interpretation of study results.     

The non-Hodgkin''s lymphomas: Pathology, staging, treatment

The non-Hodgkin's lymphomas include a broad range of neoplasms derived from the T cells and B cells and their precursors in the lymphoid system. Although they are not among the most common cancers, the lymphomas have engendered a great deal of interest among researchers because of their interesting biology and responsiveness to therapy. The non-Hodgkin's lymphomas include at least ten major subtypes of diseases with different morphologic characteristics and clinical behavior. Based upon survival characteristics, it is convenient to divide the lymphomas into three broad categories, low grade, intermediate grade, and high grade. The low grade lymphomas usually arise in middle age or older individuals (median age, 55 years). They are derived from B cells and often have a folicular architectural pattern. They usually present with advanced stages of disease, often by virtue of bone marrow involvement. Nevertheless, patients are usually asymptomatic and may even have spontaneous regressions of disease. These lymphomas are responsive to a broad range of therapies including irradiation, single agent or multiagent chemotherapy, or combined modality therapy. They also are affected by treatment with biologicals such as alpha interferon and monoclonal antibodies. Unfortunately, response to any of these therapies is often transient and relapse is common. The intermediate grade lymphomas include the common large cell lymphomas (follicular or diffuse) and diffuse mixed cell lymphoma. These lymphomas, together with the high grade immunoblastic lymphoma, are often grouped together for the development of management strategies. These lymphomas may be derived from B cells or T cells. They occur over a broader age range than the low grade lymphomas and they are much more aggressive in their natural behavior. Effective treatment programs have been developed for both limited and advanced clinical stages of disease. In limited disease, moderately intensive chemotherapy is often combined with involved field irradiation. In advanced stage disease, more aggressive combination chemotherapy programs are usually employed. From 40% to 80% of patients may be cured with these approaches, depending upon the initial extent of disease. Two types of high grade lymphoma-lymphoblastic and small noncleaved cell are particularly aggressive in their behavior. Lymphoblastic lymphoma is a T cell lymphoma that often arises in adolescent males and presents with a large mediastinal mass, marrow, and CNS involvement. It closely resembles acute lymphoblastic leukemia (ALL) and similarly intensive chemotherapy programs as are utilized in ALL may be successful in its management. Small noncleaved cell lymphoma is a B cell lymphoma that commonly presents with bulky disease, often involving intra-abdorninal sites such as the mesentery and gastrointestinal tract. This lymphoma has a short cell cycle time and rapid tumor doubling time and prompt initiation of treatment is indicated, in view of the poor prognosis for patients who present with either of these high grade lymphomas in the presence of adverse prognostic factors such as an elevated lactic dehydrogenase (LDH) or bone marrow involvement, investigational programs such as intensive systemic therapy combined with whole body irradiation, and bone marrow transplantation are being explored.     

ATM mutations in patients with hereditary pancreatic cancer

Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition. SIGNIFICANCE: The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes.     

Variable Genomic Landscapes of Advanced Melanomas with Heavy Pigmentation

BackgroundIn the current study, we examined the real-world prevalence of highly pigmented advanced melanomas (HPMel) and the clinicopathologic, genomic, and ICPI biomarker signatures of this class of tumors.Materials and MethodsOur case archive of clinical melanoma samples for which the ordering physician requested testing for both PD-L1 immunohistochemistry (IHC) and comprehensive genomic profiling (CGP) was screened for HPMel cases, as well as for non-pigmented or lightly pigmented advanced melanoma cases (LPMel).ResultsOf the 1268 consecutive melanoma biopsies in our archive that had been submitted for PD-L1 IHC, 13.0% (165/1268) were HPMel and 87.0% (1103/1268) were LPMel. In the HPMel cohort, we saw a significantly lower tumor mutational burden (TMB, median 8.8 mutations/Mb) than in the LPMel group (11.4 mut/Mb), although there was substantial overlap. In examining characteristic secondary genomic alterations (GA), we found that the frequencies of GA in TERTp, CDKN2A, TP53, and PTEN were significantly lower in the HPMel cases than in LPMel. A higher rate of GA in CTNNB1, APC, PRKAR1A, and KIT was identified in the HPMel cohort compared with LPMel.ConclusionsIn this study, we quantified the failure rates of melanoma samples for PD-L1 testing due to high melanin pigmentation and showed that CGP can be used in these patients to identify biomarkers that can guide treatment decisions for HPMel patients. Using this practical clinical definition for tumor pigmentation, our results indicate that HPMel are frequent at 13% of melanoma samples, and in general appear molecularly less developed, with a lower TMB and less frequent secondary GA of melanoma progression.     

Live‐attenuated influenza vaccine effectiveness against hospitalization in children aged 2–6 years,the first three seasons of the childhood influenza vaccination program in England, 2013/14–2015/16

IntroductionIn 2013, the United Kingdom began to roll‐out a universal annual influenza vaccination program for children. An important component of any new vaccination program is measuring its effectiveness. Live‐attenuated influenza vaccines (LAIVs) have since shown mixed results with vaccine effectiveness (VE) varying across seasons and countries elsewhere. This study aims to assess the effectiveness of influenza vaccination in children against severe disease during the first three seasons of the LAIV program in England.MethodsUsing the screening method, LAIV vaccination coverage in children hospitalized with laboratory‐confirmed influenza infection was compared with vaccination coverage in 2–6‐year‐olds in the general population to estimate VE in 2013/14–2015/16.ResultsThe overall LAIV VE, adjusted for age group, week/month and geographical area, for all influenza types pooled over the three influenza seasons was 50.1% (95% confidence interval [CI] 31.2, 63.8). By age, there was evidence of protection against hospitalization from influenza vaccination in both the pre‐school (2–4‐year‐olds) (48.1%, 95% CI 27.2, 63.1) and school‐aged children (5–6‐year‐olds) (62.6%, 95% CI 2.6, 85.6) over the three seasons.ConclusionLAIV vaccination in children provided moderate annual protection against laboratory‐confirmed influenza‐related hospitalization in England over the three influenza seasons. This study contributes further to the limited literature to date on influenza VE against severe disease in children.     

A nucleic acid amplification test‐based strategy does not help inform return to work for healthcare workers with COVID‐19

ObjectiveThe objective of this study is to assess the utility of a nucleic acid amplification test‐based approach to shorten isolation of healthcare workers (HCWs) with COVID‐19 in the setting of the highly transmissible omicron variant.MethodsBetween December 24, 2021, and January 5, 2022, HCWs who tested positive for SARS‐CoV‐2 were retested with PCR at least 5 days since onset of symptoms.ResultsForty‐six sequential fully COVID‐19 vaccinated HCWs who had tested positive for SARS‐CoV‐2 underwent follow‐up testing. All the samples were confirmed as omicron variants and only four (8.7%) were negative in the follow‐up test performed at a median of 6 (range 5–12) since onset of symptoms.ConclusionsImplementation of a test‐based strategy is logistically challenging, increases costs, and did not lead to shorter isolation in our institution.