An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis.

Myeloid cells are known to suppress antitumour immunity1. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab2-5 given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site.

Modulation of chemoimmunotherapy efficacy in non-small cell lung cancer by sex and histology: a real-world, patient-level analysis.

BACKGROUND: It has been postulated that patient's sex impacts response to immunotherapy. Sex modulation of immunotherapy benefit, however, has not yet been explored using patient-level data, where potential confounders, as well as histologic type, can be accounted for. Here we investigated the association between sex and chemoimmunotherapy efficacy for non-small cell lung cancer (NSCLC) using a large, nation-wide dataset. PATIENTS & METHODS: Stage IV NSCLC patients diagnosed in 2015 were identified in the National Cancer Database (NCDB). Patients were treated with either chemoimmunotherapy or chemotherapy alone. The efficacy of the addition of immunotherapy treatment by sex was investigated using both an adjusted Cox proportional hazards model and propensity-score matching, in both the overall cohort and stratified by histological subtype. RESULTS: 2064 (16%) patients received chemoimmunotherapy and10,733 (84%) received chemotherapy alone. Adjusted survival analysis in the overall cohort showed that both males (hazards ratio (HR)adj: 0.80, 95% CI: 0.74-0.87) and females (HRadj: 0.83, 95% CI: 0.76-0.90) had better OS when treated with chemoimmunotherapy than chemotherapy alone, with no statistically significant interaction between sex and receipt of immunotherapy (p = 0.63). Propensity matching confirmed these results. However, for those with squamous cell histology, male patients derived more benefit from chemoimmunotherapy treatment than females (HRadj: 0.73, 95% CI: 0.58-0.91 vs HRadj: 1.03, 95% CI: 0.76-1.38; p for interaction = 0.07). CONCLUSION: Male patients with squamous cell carcinoma may derive more benefit from chemoimmunotherapy treatment. Histology likely plays an important role in how sex modulates immunotherapy efficacy.

Treatment patterns and overall survival among patients with unresectable, stage III non-small-cell lung cancer.

Aim: To analyze treatment patterns and overall survival (OS) across time (2009-2014) among patients with unresected, stage III non-small-cell lung cancer (NSCLC). Patients & methods: Stage III NSCLC patients aged ≥65 years who initiated therapy were identified using SEER-Medicare data. Results: Among 4564 patients, 84% received chemotherapy (with or without radiotherapy), and 59% received chemoradiotherapy (CRT). Carboplatin + paclitaxel was the most frequent regimen. Median (interquartile range) OS among chemotherapy patients was 13.2 (6.0-28.9) months, and 14.8 (6.7-33.4) months among CRT patients. Among CRT patients, there was no difference in OS across years of CRT initiation. Conclusion: OS remained static across 2009-2014, indicating stagnancy in clinical outcomes for stage III NSCLC patients and a need for more effective therapeutic options.

The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome.

Solid tumors, beyond mere accumulation of cancer cells, form a complex ecosystem consisting of normal epithelial cells, fibroblasts, blood and lymphatic vessels, structural components, and infiltrating hematopoietic cells including myeloid and lymphoid elements that impact tumor growth, tumor spreading, and clinical outcome. The composition of the immune microenvironment is diverse, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, or macrophages. The immune contexture describes the density, location, and organization of these immune cells within solid tumors. In lung cancer, which is the deadliest type of cancer, and particularly in non-small cell lung cancer, its most prevalent form, reports have described some of the interactions between the tumor and the host. These data, in addition to articles on various types of tumors, provide a greater understanding of the tumor-host microenvironment interaction and stimulate the development of prognostic and predictive biomarkers, the identification of novel target antigens for therapeutic intervention, and the implementation of tools for long-term management of patients with cancer.

Dyadic psychosocial intervention for advanced lung cancer patients and their family caregivers: results of a randomized pilot trial.

BACKGROUND: Advanced lung cancer (LC) patients and their families have reported low self-efficacy for self-care/caregiving and high rates of distress, yet few programs exist to address their supportive care needs during treatment. This pilot study examined the feasibility, acceptability, and preliminary efficacy of a 6-session, telephone-based dyadic psychosocial intervention that was developed for advanced LC patients and their caregivers. The program was grounded in self-determination theory (SDT), which emphasizes the importance of competence (self-efficacy), autonomy (sense of choice/volition), and relatedness (sense of belonging/connection) for psychological functioning. The primary outcomes were patient and caregiver psychological functioning (depression/anxiety) and caregiver burden. The secondary outcomes were the SDT constructs of competence, autonomy, and relatedness. METHODS: Thirty-nine advanced LC patients who were within 1 month of treatment initiation (baseline) and their caregivers (51% spouses/partners) completed surveys and were randomized to the intervention or usual medical care. Eight weeks after baseline, they completed follow-up surveys. RESULTS: Solid recruitment (60%) and low attrition rates demonstrated feasibility. Strong program evaluations (mean, 8.6/10) and homework completion rates (88%) supported acceptability. Participants receiving the intervention evidenced significant improvements (P < .0001) in depression, anxiety, and caregiver burden in comparison with usual medical care. Large effect sizes (d ≥ 1.2) favoring the intervention were also found for patient and caregiver competence and relatedness and for caregiver autonomous motivation for providing care. CONCLUSION: These findings support intervention feasibility, acceptability, and preliminary efficacy. By empowering families with the skills to coordinate care and meet the challenges of LC together, this intervention holds great promise for improving palliative/supportive care services in cancer.

Novel 3-hydroxypropyl-bonded phase by direct hydrosilylation of allyl alcohol on amorphous hydride silica.

A novel 3-hydroxypropyl (propanol)-bonded silica phase has been prepared by hydrosilylation of allyl alcohol on a hydride silica intermediate, in the presence of platinum (0)-divinyltetramethyldisiloxane (Karstedt's catalyst). The regio-selectivity of this synthetic approach had been correctly predicted by previous reports involving octakis(dimethylsiloxy)octasilsesquioxane (Q8 M8 (H) ) and hydrogen silsesquioxane (T8 H8 ), as molecular analogs of hydride amorphous silica. Thus, C-silylation predominated (∼94%) over O-silylation, and high surface coverages of propanol groups (5 ± 1 µmol/m(2) ) were typically obtained in this work. The propanol-bonded phase was characterized by spectroscopic (infrared (IR) and solid-state NMR on silica microparticles), contact angle (on fused-silica wafers) and CE (on fused-silica tubes) techniques. CE studies of the migration behavior of pyridine, caffeine, Tris(2,2'-bipyridine)Ru(II) chloride and lysozyme on propanol-modified capillaries were carried out. The adsorption properties of these select silanol-sensitive solutes were compared to those on the unmodified and hydride-modified tubes. It was found that hydrolysis of the SiH species underlying the immobilized propanol moieties leads mainly to strong ion-exchange-based interactions with the basic solutes at pH 4, particularly with lysozyme. Interestingly, and in agreement with water contact angle and electroosmotic mobility figures, the silanol-probe interactions on the buffer-exposed (hydrolyzed) hydride surface are quite different from those of the original unmodified tube.

Closer look at the operating definition of protein recovery in CE.

Analyte recovery is an important figure to assess protein adsorption on fused-silica capillaries. In 1991, Regnier et al. estimated recovery by assuming the loss of analyte from adsorption and thus the decrease in peak area measured by two detectors to be proportional to the length of the capillary section between them. In this report, we closely examine this concept and its adaptation to commercial CE instruments to determine protein recovery. We hypothesize that, once a steady-state migration is reached, protein adsorption is a first-order process with respect to protein concentration and surface density of adsorbing sites. This hypothesis is shown to be valid over a reasonably wide range of capillary effective length and, as a result, protein recovery decreases exponentially with the migrated distance. However, unlike the traditional recovery figure obtained through a conventional spike process, protein recovery measured by this approach does not have the same merit since it is strongly dependent from capillary dimensions and applied electric field. Nevertheless, protein recovery and the slope of the logarithmic protein peak area versus length plot are useful figures to compare protein adsorption on different capillary surfaces. Several literature reports dealing with the application of Regnier concept to calculate protein recovery are discussed.

Exploring stakeholders perspectives on TB contact investigation in Cali, Colombia: a qualitative study.

Introduction: Contact investigation is a proven intervention for tuberculosis (TB) case finding and prevention. Although widely endorsed by national public health authorities and the World Health Organization, many countries struggle to implement it effectively. The objective of the study is to describe and characterize the barriers and facilitators of TB contact investigation in Cali, Colombia from the perspective and experience of the key stakeholders involved. Methods: We collected data from group discussions during two workshop sessions with clinic and public health staff involved in TB contact investigation (June 2019 and March 2020 respectively) and semi-structured interviews with TB cases and their household contacts (July 2019 to April 2020). We undertook an inductive thematic analysis with the RADaR technique to characterize the barriers and facilitators of the TB contact investigation process. Results: The two workshops included 21 clinics and 12 public health staff. We also conducted 26 semi-structured interviews with TB cases and their household contacts. Using thematic analysis, we identified four common themes: Healthcare Operations, Essential Knowledge, Time Limitations and Competing Responsibilities, and Interpersonal Interactions. The main barriers to conducting household visits were low data quality, stigma and mistrust, safety concerns for health workers, and limited resources. The main barriers to TB uptake by contacts were competing responsibilities, low TB risk perceptions among contacts, and difficulty accessing diagnostic tests for contacts. In contrast, good communication and social skills among health workers and accurate TB knowledge facilitated successful household visits and TB test uptake, according to key stakeholders. Conclusion: This study provides a deeper understanding of TB contact investigation barriers and facilitators in a high-prevalence urban setting in a middle-income country from the perspective and experience of key stakeholders. The study shed light on the barriers that hinder household contacts engagement and TB test uptake such as issues of systemic capacity and TB knowledge. Also, highlighted facilitators such as the importance of interpersonal communication skills among health workers in the public and private sector. The insights from this study can serve as a valuable resource for public health organizations seeking to enhance their contact investigation efforts and improve TB control in similar settings.

Longitudinal nucleocapsid antibody testing reveals undocumented SARS-CoV-2 infections in patients with lung cancer.

Patients diagnosed with lung cancer (LC) exhibit increased susceptibility to SARS-CoV-2 infection. Rodilla et al. monitor the levels of plasma anti-nucleocapsid antibodies within a cohort of fully vaccinated LC patients and reveal that the actual infection rate is nearly twice the documented rate, indicating a significant prevalence of unreported cases.

Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial.

Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often develop resistance to current standard third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments are approved in the osimertinib-relapsed setting. In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR-mutant NSCLC whose disease progressed on third-generation TKI monotherapy but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase, the recommended phase 2 combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate, and key secondary endpoints included progression-free survival and overall survival. The safety profile of amivantamab and lazertinib was generally consistent with previous experience of each agent alone, with 4% experiencing grade ≥3 events; no new safety signals were identified. In an exploratory cohort of 45 patients who were enrolled without biomarker selection, the primary endpoint of investigator-assessed overall response rate was 36% (95% confidence interval, 22-51). The median duration of response was 9.6 months, and the median progression-free survival was 4.9 months. Next-generation sequencing and immunohistochemistry analyses identified high EGFR and/or MET expression as potential predictive biomarkers of response, which will need to be validated with prospective assessment. ClinicalTrials.gov identifier: NCT02609776 .

Targeting angiogenesis from multiple pathways simultaneously: BIBF 1120, an investigational novel triple angiokinase inhibitor.

Angiogenesis is considered one of the major components of tumor progression and metastasis. Interfering with the formation and stabilization of tumor blood vessels could increase tumor response rates and may translate into improved clinical outcomes in cancer patients. The clinical efficacy demonstrated in phase III trials with bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor ligand, suggests that targeting angiogenesis is a rational approach to cancer management. Agents that target additional proangiogenic intracellular signaling pathways also have the potential to contribute to our anticancer armamentarium. Novel targeted agents that have antiangiogenic properties have been developed in recent years such as sorafenib, sunitinib, vandetanib, and others. Many of them inhibit additional pathways beyond vascular endothelial growth factor signaling. One of these investigational targeted agents is a triple angiokinase inhibitor known as BIBF 1120. This compound targets not only vascular endothelial growth factor receptors, but also fibroblast growth factor receptors, and platelet-derived growth factor receptors. The preliminary clinical efficacy of BIBF 1120 is discussed in the context of the most relevant clinical data in several malignancies including non-small cell lung cancer.

Lung Cancer and Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Identifying Important Knowledge Gaps for Investigation.

Patients with lung cancer are especially vulnerable to coronavirus disease 2019 (COVID-19) with a greater than sevenfold higher rate of becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19, a greater than threefold higher hospitalization rate with high complication rates, and an estimated case fatality rate of more than 30%. The reasons for the increased vulnerability are not known. In addition, beyond the direct impact of the pandemic on morbidity and mortality among patients with lung cancer, COVID-19, with its disruption of patient care, has also resulted in substantial impact on lung cancer screening and treatment/management.COVID-19 vaccines are safe and effective in people with lung cancer. On the basis of the available data, patients with lung cancer should continue their course of cancer treatment and get vaccinated against the SARS-CoV-2 virus. For unknown reasons, some patients with lung cancer mount poor antibody responses to vaccination. Thus, boosting vaccination seems urgently indicated in this subgroup of vulnerable patients with lung cancer. Nevertheless, many unanswered questions regarding vaccination in this population remain, including the magnitude, quality, and duration of antibody response and the role of innate and acquired cellular immunities for clinical protection. Additional important knowledge gaps also remain, including the following: how can we best protect patients with lung cancer from developing COVID-19, including managing care in patient with lung cancer and the home environment of patients with lung cancer; are there clinical/treatment demographics and tumor molecular demographics that affect severity of COVID-19 disease in patients with lung cancer; does anticancer treatment affect antibody production and protection; does SARS-CoV-2 infection affect the development/progression of lung cancer; and are special measures and vaccine strategies needed for patients with lung cancer as viral variants of concern emerge.

New approaches to prepare hydride silica.

Two synthetic schemes to produce a hydride-modified support that serves as an intermediate for the preparation of bonded phases for liquid chromatography (LC) and capillary electrophoresis (CE) are investigated. The strategies differ in the silane reagent utilized (trichlorosilane (TCS) or triethoxysilane (TES)) and the manner water is incorporated into the reaction. In the first approach, TCS in toluene reacts with a previously humidified silica substrate so that the reaction is confined to the silica surface. In the second approach, TES and a small amount of aqueous HCl are dissolved in THF, and this hydrolysate is diluted by a great factor in cyclohexane, prior to reaction with the silica substrate. Atomic force microscopy (AFM) images of the hydride film on wafers revealed that, unlike the traditional approach that produced a patchy coating, both new methods provided a homogeneous layer on the substrate's surface. IR and NMR spectra from porous silica particles clearly confirmed a successful surface modification. AFM and water contact angles (WCA) were used to examine the effect of dilution of the TES hydrolysate in cyclohexane on the trend of the film to polymerize on wafers and found that a dilution factor of at least 100 is required to attain a molecularly thin hydride layer. WCA and CE also revealed a strong susceptibility of the hydride silica intermediate to hydrolyze, even at low pH. Compared to TCS, the lower reactivity and volatility of TES resulted in a much more desirable experimental approach.

Predictors of chemoradiotherapy versus single modality therapy and overall survival among patients with unresectable, stage III non-small cell lung cancer.

INTRODUCTION: Concurrent chemoradiotherapy (cCRT) was the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) prior to the PACIFIC trial, however, patients also received single modality therapy. This study identified predictors of therapy and differences in overall survival (OS). METHODS: This retrospective study included stage III NSCLC patients aged ≥65 years, with ≥1 claim for systemic therapy (ST) or radiotherapy (RT) within 90 days of diagnosis, identified in SEER-Medicare data (2009-2014). Patients who had overlapping claims for chemotherapy and RT ≤90 days from start of therapy were classified as having received cCRT. Patients who received sequential CRT or surgical resection of tumor were excluded. Predictors of cCRT were analyzed using logistic regression. OS was compared between therapies using adjusted Cox proportional hazards models. RESULTS: Of 3,799 patients identified, 21.7% received ST; 26.3% received RT; and 52.0% received cCRT. cCRT patients tended to be younger (p <0.001), White (p = 0.002), and have a good predicted performance status (p<0.001). Patients who saw all three specialist types (medical oncologist, radiation oncologist, and surgeon) had increased odds of receiving cCRT (p<0.001). ST and RT patients had higher mortality risk versus cCRT patients (hazard ratio [95% CI]: ST: 1.38 [1.26-1.51]; RT: 1.75 [1.61, 1.91]); p<0.001). CONCLUSIONS: Several factors contributed to treatment selection, including patient age and health status, and whether the patient received multidisciplinary care. Given the survival benefit of receiving cCRT over single-modality therapy, physicians should discuss treatment within a multidisciplinary team, and be encouraged to pursue cCRT for patients with unresectable stage III NSCLC.

Neoadjuvant Tyrosine Kinase Inhibition in Locally-advanced Non-small Cell Lung Cancer: Two Cases and a Brief Literature Review.

BACKGROUND: Despite their remarkable efficacy in metastatic non-small cell lung cancer (NSCLC), EGFR- and ALK-targeted therapies have not been shown to confer any survival benefit in stage III disease, even in subsets of patients with driver mutations. CASE STUDIES: Here, two patients with unresectable stage III NSCLC carrying mutations in the ALK (case 1) and EGFR (case 2) genes are presented. Treatment of the patient carrying an ALK mutation with an ALK inhibitor and the patient carrying an EGFR mutation with an EGFR inhibitor resulted in dramatic and durable responses. CONCLUSION: These cases demonstrated that ALK or EGFR mutation-positive stage III NSCLC patients can be treated with the corresponding inhibitors. They also highlight the urgent need for prospective data to assess their potential efficacy in order to improve patient outcomes.

Bone Bruises in Children and Adolescents Not Associated With Ligament Ruptures [corrected].

Background: Clinical characteristics of uncomplicated bone bruises (ie, not associated with a ligament rupture, meniscal tear, or fracture of the knee) in young athletes have scarcely been reported. Purpose: To identify mechanisms of injury, characterize bone bruise patterns, and identify clinical factors relating to recovery in young patients suffering uncomplicated bone bruises about the knee. Study Design: Case series; Level of evidence, 4. Methods: A review of clinical records and magnetic resonance imaging (MRI) findings of patients seen at a single institution was completed. Results: We identified 62 children and teenagers (mean age, 13.9 years; range, 8-18 years) who had a total of 101 bone bruises on MRI. The injuries occurred during a variety of organized and recreational sporting activities, the most common being football, basketball, and soccer. The majority (61.4%) of bone bruises occurred as a result of noncontact mechanisms. Patients reported a mean pain scale score of 6.3 of 10 (range, 2-10) on presentation. Frequent clinical findings included non-joint-line tenderness (64.5%), limited range of motion (58.1%), joint-line tenderness (54.8%), and positive meniscal signs (50.0%). The majority of bone bruises (61.4%) were located medially, and the most common bone bruise type was subcortical (58.4%), followed by medullary/reticular (35.6%) and articular impaction (5.9%). The only factor related to time to recovery was mechanism of injury; patients reporting a noncontact mechanism required significantly more time to recover than those reporting a contact mechanism (mean, 99.7 ± 74.8 vs 65.7 ± 38.8 days, respectively; F = 3.753, P = .049). Conclusion: In this case series of 62 pediatric patients with non-anterior cruciate ligament (ACL) bone bruises, the majority occurred in the medial compartment, suggesting that these bone bruises result from a mechanism distinct from the pivot-shift mechanism, classically thought to cause ACL injuries.

Complementary therapies and integrative oncology in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition).

BACKGROUND: This chapter aims to differentiate between "alternative" therapies, often promoted falsely as viable options to mainstream lung cancer treatment, and complementary therapies, adjunctive, effective techniques that treat symptoms associated with cancer and its mainstream treatment, and to describe the evidence base for use of complementary therapies. METHODS AND DESIGN: A multidisciplinary panel of experts in oncology and integrative medicine evaluated the evidence for complementary (not alternative) therapies in the care of patients with lung cancer. Because few complementary modalities are geared to patients with only a single cancer diagnosis, symptom-control research conducted with other groups of patients with cancer was also included. Data on complementary therapies such as acupuncture, massage therapy, mind-body therapies, herbs and other botanicals, and exercise were evaluated. Recommendations were based on the strength of evidence and the risk-to-benefit ratio. RESULTS: Patients with lung and other poor-outlook cancers are particularly vulnerable to heavily promoted claims for unproved or disproved "alternatives." Inquiring about patients' use of these therapies should be routine because these practices may be harmful and can delay or impair treatment. Mind-body modalities and massage therapy can reduce anxiety, mood disturbance, and chronic pain. Acupuncture assists the control of pain and other side effects and helps reduce levels of pain medication required. Trials of acupuncture for chemotherapy-induced neuropathy and postthoracotomy pain show promising results. Herbal products and other dietary supplements should be evaluated for side effects and potential interactions with chemotherapy and other medications. CONCLUSIONS: Complementary therapies have an increasingly important role in the control of symptoms associated with cancer and cancer treatment.

A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors.

PURPOSE: Based on our mouse xenograft model demonstrating that intermittent high-dose gefitinib sensitizes tumors to subsequent treatment with taxanes, we initiated this phase I trial to explore docetaxel in combination with escalating doses of intermittent gefitinib (Iressa) given prior to docetaxel. METHODS: This was a phase I study where patients with advanced cancer were treated with escalating doses of gefitinib (1,000, 1,500, 2,250, 3,000 mg) on days 1 and 2 followed by docetaxel (75 mg/m2) on day 3 of a 21 day cycle. Gefitinib pharmacokinetic data were obtained on days 1, 2, and 3 of cycles 1 and 2 at each dose level. RESULTS: 18 patients were enrolled in this study with the most frequent tumor types being non-small cell lung cancer and head and neck squamous cell cancer. The dose-limiting toxicity was neutropenia (n=1 at dose level 2, n=2 at dose level 4). Rash, diarrhea, and fatigue were the most common grade 1-2 toxicities. Pharmacokinetic data indicated no accumulation of gefitinib between cycles 1 and 2 and no clear correlation between gefitinib plasma levels and toxicity. Partial responses were observed in one patient with head and neck squamous cell carcinoma and one patient with anaplastic thyroid cancer. CONCLUSION: The recommended dose for phase II studies is gefitinib 2,250 mg on days 1 and 2, followed by docetaxel 75 mg/m2 on day 3.

Concurrent Chemotherapy and Radiation Therapy for Inoperable Locally Advanced Non-Small-Cell Lung Cancer.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 72-year-old man with a 40-pack-year tobacco history developed a cough and decreased exercise tolerance. A chest x-ray demonstrated a right-upper-lobe opacity. Chest computed tomography (CT) scan revealed a 2.5-cm mass in the right upper lobe with multiple mediastinal lymph node disease ( Fig 1 ). A positron emission tomography (PET) scan confirmed the lung lesion and the mediastinal lymphadenopathy without distant metastases. Brain magnetic resonance imaging results were negative. The biopsy specimen revealed adenocarcinoma with no actionable mutations present. Cervical mediastinoscopy was positive for carcinoma in level 2, 3, 4R, and 7 lymph nodes; level 4L was negative. The patient's stage was T1bN2M0, stage IIIA. His medical history was significant for hyperlipidemia and hypothyroidism. He had smoked one pack a day for 40 years and had quit 15 years earlier. Physical examination was unrevealing, and the patient had an Eastern Cooperative Oncology Group performance status of 0. Because of the extent of lung cancer in the mediastinum, the patient's cancer was deemed inoperable, and he was referred for consideration of concurrent chemotherapy and radiation.