A Real-World Assessment of Stage I Lung Cancer Through Electronic Nose Technology.

INTRODUCTION: Electronic nose (E-nose) technology has reported excellent sensitivity and specificity in the setting of lung cancer screening. However, the performance of E-nose specifically for early-stage tumors remains unclear. Therefore, the aim of our study was to assess the diagnostic performance of E-nose technology in clinical stage I lung cancer. METHODS: This phase IIc trial (NCT04734145) included patients diagnosed with a single greater than or equal to 50% solid stage I nodule. Exhalates were prospectively collected from January 2020 to August 2023. Blinded bioengineers analyzed the exhalates, using E-nose technology to determine the probability of malignancy. Patients were stratified into three risk groups (low-risk, [<0.2]; moderate-risk, [≥0.2-0.7]; high-risk, [≥0.7]). The primary outcome was the diagnostic performance of E-nose versus histopathology (accuracy and F1 score). The secondary outcome was the clinical performance of the E-nose versus clinicoradiological prediction models. RESULTS: Based on the predefined cutoff (<0.20), E-nose agreed with histopathologic results in 86% of cases, achieving an F1 score of 92.5%, based on 86 true positives, two false negatives, and 12 false positives (n = 100). E-nose would refer fewer patients with malignant nodules to observation (low-risk: 2 versus 9 and 11, respectively; p = 0.028 and p = 0.011) than would the Swensen and Brock models and more patients with malignant nodules to treatment without biopsy (high-risk: 27 versus 19 and 6, respectively; p = 0.057 and p < 0.001). CONCLUSIONS: In the setting of clinical stage I lung cancer, E-nose agrees well with histopathology. Accordingly, E-nose technology can be used in addition to imaging or as part of a "multiomics" platform.

Does a brief surgeon training in negotiation theory principles decrease rates of contralateral prophylactic mastectomy?

PURPOSE: Despite the lack of any oncologic benefit, contralateral prophylactic mastectomy (CPM) use among women with unilateral breast cancer is increasing. This patient-driven trend is influenced by fear of recurrence and desire for peace of mind. Traditional educational strategies have been ineffective in reducing CPM rates. Here we employ training in negotiation theory strategies for counseling and determine the effect on CPM rates. METHODS: In consecutive patients with unilateral breast cancer treated with mastectomy from 05/2017 to 12/2019, we examined CPM rates before and after a brief surgeon training in negotiation skills. This comprised a systematic framework for patient counseling utilizing early setting of the default option, leveraging social proof, and framing. RESULTS: Among 2144 patients, 925 (43%) were treated pre-training and 744 (35%) post-training. Those treated in the 6-month transition period were excluded (n = 475, 22%). Median patient age was 50 years; most patients had T1-T2 (72%), N0 (73%), and estrogen receptor-positive (80%) tumors of ductal histology (72%). The CPM rate was 47% pre-training versus 48% post-training, with an adjusted difference of -3.7% (95% CI -9.4 to 2.1, p = 0.2). In a standardized self-assessment survey, all 15 surgeons reported a high baseline use of negotiation skills and no significant change in conversational difficulty with the structured approach. CONCLUSION: Brief surgeon training did not affect self-reported use of negotiation skills or reduce CPM rates. The choice of CPM is a highly individual decision influenced by patient values and decision styles. Further research to identify effective strategies to minimize surgical overtreatment with CPM is needed.

Insights and perspectives on the enigmatic alary muscles of arthropods.

Three types of muscles, cardiac, smooth and skeletal muscles are classically distinguished in eubilaterian animals. The skeletal, striated muscles are innervated multinucleated syncytia, which, together with bones and tendons, carry out voluntary and reflex body movements. Alary muscles (AMs) are another type of striated syncytial muscles, which connect the exoskeleton to the heart in adult arthropods and were proposed to control hemolymph flux. Developmental studies in Drosophila showed that larval AMs are specified in embryos under control of conserved myogenic transcription factors and interact with excretory, respiratory and hematopoietic tissues in addition to the heart. They also revealed the existence of thoracic AMs (TARMs) connecting to specific gut regions. Their asymmetric attachment sites, deformation properties in crawling larvae and ablation-induced phenotypes, suggest that AMs and TARMs could play both architectural and signalling functions. During metamorphosis, and heart remodelling, some AMs trans-differentiate into another type of muscles. Remaining critical questions include the enigmatic modes and roles of AM innervation, mechanical properties of AMs and TARMS and their evolutionary origin. The purpose of this review is to consolidate facts and hypotheses surrounding AMs/TARMs and underscore the need for further detailed investigation into these atypical muscles.

Local Recurrence is Frequent After Heroic Mastectomy for Classically Inoperable Breast Cancers.

BACKGROUND: Despite advances in neoadjuvant systemic therapy (NST), some patients with aggressive T4 breast cancers do not respond. The efficacy of 'heroic' mastectomy in maintaining local control is unclear. METHODS: In consecutive patients with primary or recurrent T4 cancers with < 50% shrinkage on NST who underwent mastectomy from 2007 to 2017, clinicopathologic characteristics and locoregional recurrence (LRR) were examined. RESULTS: Among 104 patients, 59 (57%) had primary T4M0, 12 (12%) had locally recurrent T4M0, and 33 (32%) had T4M1 disease. Median age was 58.5 years and the majority had high-grade (74%) ductal cancers (85%); 45 (44%) were estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-), 26 (25%) were HER2 positive (HER2+), and 31 (30%) were triple negative (TN). Postoperative complications developed in 41 (39%) patients. At a median follow-up of 37 months, 42 (40%) patients developed LRR. TN (hazard ratio [HR] 7.5) and HER2+ (HR 2.67) subtypes, lymphovascular invasion (LVI; HR 3.80), and positive margins (HR 4.09) were predictive of LRR. The 3-year LRR rate was highest and overall survival (OS) was lowest among patients with TN cancers, at 66% (95% confidence interval [CI] 48-83%) and 30% (95% CI 14-47%), respectively. CONCLUSIONS: After heroic mastectomy, postoperative complications were frequent and LRR occurred in 40% of patients despite a median OS of 3.8 years. Among TN patients, the 3-year LRR rate of 66% and 3-year OS of 30% suggest limited surgery benefit. Careful patient selection is prudent when considering heroic mastectomy.

A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti-PD-1 Agent Pembrolizumab.

Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.3M to 60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T cells were detected in peripheral blood for >100 days in 39% of patients. Following our demonstration that PD-1 blockade enhances CAR T-cell function in mice, 18 patients with MPM also received pembrolizumab safely. Among those patients, median overall survival from CAR T-cell infusion was 23.9 months (1-year overall survival, 83%). Stable disease was sustained for ≥6 months in 8 patients; 2 exhibited complete metabolic response on PET scan. Combination immunotherapy with CAR T cells and PD-1 blockade agents should be further evaluated in patients with solid tumors. SIGNIFICANCE: Regional delivery of mesothelin-targeted CAR T-cell therapy followed by pembrolizumab administration is feasible, safe, and demonstrates evidence of antitumor efficacy in patients with malignant pleural diseases. Our data support the investigation of combination immunotherapy with CAR T cells and PD-1 blockade agents in solid tumors.See related commentary by Aldea et al., p. 2674.This article is highlighted in the In This Issue feature, p. 2659.

Adoption of SSO-ASTRO Margin Guidelines for Ductal Carcinoma in Situ: What Is the Impact on Use of Additional Surgery?

BACKGROUND: Historically, more than one-third of patients with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS) underwent additional surgery. The SSO-ASTRO guidelines advise 2 mm margins for patients with DCIS having BCS and whole-breast radiation (WBRT). Here we examine guideline impact on additional surgery and factors associated with re-excision. PATIENTS AND METHODS: Patients treated with BCS for pure DCIS from August 2015 to January 2018 were identified. Guidelines were adopted on September 1, 2016, and all patients had separately submitted cavity-shave margins. Clinicopathologic characteristics, margin status, and rates of additional surgery were examined. RESULTS: Among 650 patients with DCIS who attempted BCS, 50 (8%) converted to mastectomy. Of 600 who had BCS as final surgery, 336 (56%) received WBRT and comprised our study group. One hundred twenty-eight (38%) were treated pre-guideline and 208 (62%) were treated post-guideline. Characteristics and margin status were similar between groups. The re-excision rate was 38% pre-guideline adoption and 29% post-guideline adoption (p = 0.09), with 91% having only one re-excision. Re-excision for ≥ 2 mm margins was uncommon (6% pre-guideline vs. 5% post-guideline). On multivariate analysis, younger age (OR 0.97, 95% CI 0.94-0.99, p = 0.02) and larger DCIS size (OR 1.43, 95% CI 1.2-1.8, p < 0.001) were predictive of re-excision; guideline era was not. Younger age (OR 0.93, 95% CI 0.9-0.97, p < 0.001) and larger size (OR 1.64, 95% CI 1.3-2.1, p < 0.001) were predictive of conversion to mastectomy, but residual tumor burden was low. CONCLUSIONS: The SSO-ASTRO guidelines did not significantly change re-excision rates for DCIS in our practice, likely since re-excision for margins ≥ 2 mm was uncommon even prior to guideline adoption, dissimilar to historically observed variations in surgeon practices. Younger age and larger DCIS size were associated with additional surgery.

Extranodal Tumor Deposits in the Axillary Fat Indicate the Need for Axillary Dissection Among T1-T2cN0 Patients with Positive Sentinel Nodes.

BACKGROUND: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated the safety of omitting axillary lymph node dissection (ALND) in T1-T2cN0 patients with fewer than three positive sentinel nodes (SLNs) undergoing breast-conservation therapy. While microscopic extracapsular extension (mECE) > 2 mm is associated with increased nodal burden, the significance of extranodal tumor deposits (ETDs) in the axillary fat is uncertain. METHODS: Consecutive patients with T1-T2cN0 breast cancer undergoing sentinel node biopsy and ALND for SLN metastases from January 2010 to December 2018 were identified. ETDs were defined as intravascular tumor emboli or metastatic deposits in the axillary fat. Clinicopathologic characteristics and nodal burden were compared by ETD status. RESULTS: Among 1114 patients, 113 (10%) had ETDs: 81 (72%) were intravascular tumor emboli and 32 (28%) were soft tissue deposits. Patients with ETDs had larger tumors (median 2.2 vs. 2.1 cm; p = 0.033) and more often had mECE (83% vs. 44%; p < 0.001). On univariable analysis, presence of ETDs (odds ratio [OR] 9.66, 95% confidence interval [CI] 6.36-14.68), larger tumors (OR 1.47, 95% CI 1.25-1.72), and mECE (OR 10.73, 95% CI 6.86-16.78) were associated with four or more additional positive non-SLNs (NSLNs; all p < 0.001). On multivariable analysis, ETDs remained associated with four or more positive NSLNs (OR 5.67, 95% CI 3.53-9.08; p < 0.001). ETDs were strongly associated with four or more positive NSLNs (OR 7.15, 95% CI 4.04-12.67) among patients with one to two positive SLNs (n = 925). CONCLUSIONS: Among T1-T2cN0 patients with SLN metastases, ETDs are strongly associated with four or more positive NSLNs at ALND. Even among those who may otherwise meet the criteria for omission of ALND, the presence of ETDs in axillary fat warrants consideration of ALND.

Reactive oxygen species-dependent Toll/NF-κB activation in the Drosophila hematopoietic niche confers resistance to wasp parasitism.

Hematopoietic stem/progenitor cells in the adult mammalian bone marrow ensure blood cell renewal. Their cellular microenvironment, called 'niche', regulates hematopoiesis both under homeostatic and immune stress conditions. In the Drosophila hematopoietic organ, the lymph gland, the posterior signaling center (PSC) acts as a niche to regulate the hematopoietic response to immune stress such as wasp parasitism. This response relies on the differentiation of lamellocytes, a cryptic cell type, dedicated to pathogen encapsulation and killing. Here, we establish that Toll/NF-κB pathway activation in the PSC in response to wasp parasitism non-cell autonomously induces the lymph gland immune response. Our data further establish a regulatory network where co-activation of Toll/NF-κB and EGFR signaling by ROS levels in the PSC/niche controls lymph gland hematopoiesis under parasitism. Whether a similar regulatory network operates in mammals to control emergency hematopoiesis is an open question.

Two Independent Functions of Collier/Early B Cell Factor in the Control of Drosophila Blood Cell Homeostasis.

Blood cell production in the Drosophila hematopoietic organ, the lymph gland, is controlled by intrinsic factors and extrinsic signals. Initial analysis of Collier/Early B Cell Factor function in the lymph gland revealed the role of the Posterior Signaling Center (PSC) in mounting a dedicated cellular immune response to wasp parasitism. Further, premature blood cell differentiation when PSC specification or signaling was impaired, led to assigning the PSC a role equivalent to the vertebrate hematopoietic niche. We report here that Collier is expressed in a core population of lymph gland progenitors and cell autonomously maintains this population. The PSC contributes to lymph gland homeostasis by regulating blood cell differentiation, rather than by maintaining core progenitors. In addition to PSC signaling, switching off Collier expression in progenitors is required for efficient immune response to parasitism. Our data show that two independent sites of Collier/Early B Cell Factor expression, hematopoietic progenitors and the PSC, achieve control of hematopoiesis.

The Drosophila JAK-STAT pathway in blood cell formation and immunity.

Genetic alterations affecting the JAK-STAT signaling pathway are linked to several malignancies and hematological disorders in humans. Despite being one of the most extensively studied pathways, there remain many gaps to fill. JAK-STAT components are widely conserved during evolution. Here, we review the known roles of the JAK-STAT pathway in Drosophila immunity: controlling the different steps of hematopoiesis, both under physiological conditions and in response to immune challenge, and contributing to antiviral responses. We then summarize what is currently known about JAK-STAT signaling in renewal of the adult intestine, under physiological conditions or in response to ingestion of pathogenic bacteria.

Patterns of symptoms following surgery for esophageal cancer.

PURPOSE/OBJECTIVE: To explore patterns of symptoms before and after surgery for cancer of the esophagus. DESIGN: Longitudinal, descriptive study. SETTING: An urban comprehensive cancer center in the northeastern United States. SAMPLE: 218 patients with cancer of the esophagus undergoing esophagectomy. METHODS: Symptoms were assessed by self-report before surgery, at the first postoperative visit, and at 6 and 12 months postsurgery. MAIN RESEARCH VARIABLES: Symptoms and demographic and clinical variables, including stage, treatment, gender, and comorbidities. FINDINGS: Patients with esophageal cancer reported numerous symptoms before and after esophagectomy. Several patterns of symptoms were identified. General cancer symptoms (e.g., pain, cough, shortness of breath, weight loss) were reported as worse after surgery but recovered to baseline by one year. A second pattern of esophageal-specific symptoms (feeling full too quickly, feeling bloated, nausea, and diarrhea) worsened after surgery and did not recover to baseline by one year. Reflux was the only symptom that did not worsen after surgery but did worsen significantly during the first year of recovery. CONCLUSIONS: Patients with esophageal cancer experienced multiple prolonged symptoms following surgical treatment for their disease. General cancer symptoms resolved by one year post-treatment, whereas esophageal-specific symptoms worsened after surgery and did not recover to baseline. IMPLICATIONS FOR NURSING: Identification of symptom patterns preoperatively and during recovery can assist nurses in developing intervention protocols to minimize long-term complications for patients with esophageal cancer. KNOWLEDGE TRANSLATION: Patients with esophageal cancer are at risk for multiple prolonged symptoms following surgery. Symptom assessment should occur often after surgery and include a broad range of symptoms.

Size control of the Drosophila hematopoietic niche by bone morphogenetic protein signaling reveals parallels with mammals.

The Drosophila melanogaster larval hematopoietic organ, the lymph gland, is a model to study in vivo the function of the hematopoietic niche. A small cluster of cells in the lymph gland, the posterior signaling center (PSC), maintains the balance between hematopoietic progenitors (prohemocytes) and their differentiation into specialized blood cells (hemocytes). Here, we show that Decapentaplegic/bone morphogenetic protein (Dpp/BMP) signaling activity in PSC cells controls niche size. In the absence of BMP signaling, the number of PSC cells increases. Correlatively, no hemocytes differentiate. Controlling PSC size is, thus, essential for normal blood cell homeostasis. Activation of BMP signaling in the PSC requires expression of the Dally-like heparan-sulfate proteoglycan, under the control of the Collier/early B-cell factor (EBF) transcription factor. A Dpp > dpp autoregulatory loop maintains BMP signaling, which limits PSC cell proliferation by repressing the protooncogene dmyc. Dpp antagonizes activity of wingless (Wg)/Wnt signaling, which positively regulates the number of PSC cells via the control of Dmyc expression. Together, our data show that Collier controls hemocyte homeostasis via coordinate regulation of PSC cell number and PSC signaling to prohemocytes. In mouse, EBF2, BMP, and Wnt signaling in osteoblasts is required for the proper number of niche and hematopoietic stem cells. Our findings bring insights to niche size control and draw parallels between Drosophila and mammalian hematopoiesis.

Drosophila: a model for studying genetic and molecular aspects of haematopoiesis and associated leukaemias.

Vertebrate haematopoietic stem cells (HSCs) give rise to a hierarchically organised set of progenitors for erythroid, myeloid, lymphoid and megakaryocyte lineages, and are responsible for lifelong maintenance of the blood system. Dysregulation of the haematopoietic differentiation programme is at the origin of numerous pathologies, including leukaemias. With the discoveries that many transcriptional regulators and signalling pathways controlling blood cell development are conserved between humans and Drosophila melanogaster, the fruit fly has become a good model for investigating the mechanisms underlying the generation of blood cell lineages and blood cell homeostasis. In this review article, we discuss how genetic and molecular studies of Drosophila haematopoiesis can contribute to our understanding of the haematopoietic niche, as well as of the origin and/or progression of haematopoietic malignancies in humans.

Hematopoietic progenitors and hemocyte lineages in the Drosophila lymph gland.

The Drosophila lymph gland (LG) is a model system for studying hematopoiesis and blood cell homeostasis. Here, we investigated the patterns of division and differentiation of pro-hemocytes in normal developmental conditions and response to wasp parasitism, by combining lineage analyses and molecular markers for each of the three hemocyte types. Our results show that the embryonic LG contains primordial hematopoietic cells which actively divide to give rise to a pool of pro-hemocytes. We found no evidence for the existence of bona fide stem cells and rather suggest that Drosophila pro-hemocytes are regulated as a group of cells, rather than individual stem cells. The fate-restriction of plasmatocyte and crystal cell progenitors occurs between the end of embryogenesis and the end of the first larval instar, while Notch activity is required for the differentiation of crystal cells in third instar larvae only. Upon parasitism, lamellocyte differentiation prevents crystal cell differentiation and lowers plasmatocyte production. We also found that a new population of intermediate progenitors appears at the onset of hemocyte differentiation and accounts for the increasing number of differentiated hemocytes in the third larval instar. These findings provide a new framework to identify parameters of developmental plasticity of the Drosophila lymph gland and hemocyte homeostasis in physiological conditions and in response to immunological cues.

Ontogeny of the Drosophila larval hematopoietic organ, hemocyte homeostasis and the dedicated cellular immune response to parasitism.

Over the years, the fruit fly Drosophila melanogaster has become a major invertebrate model to study developmental and evolutionary aspects of both humoral and cellular aspects of innate immunity. Drosophila hematopoiesis which supplies three types of circulating hemocytes, occurs in two spatially and temporally distinct phases during development. The first embryonic phase is described in detail in accompanying reviews in this Int. J. Dev. Biol. Special Issue. The second phase takes place at the end of larval development in a specialised hematopoietic organ, termed the lymph gland. We review here recent studies on the ontogeny of the lymph gland, focusing on the formation and role of the Posterior Signalling Center which acts as a niche for hematopoietic progenitors. We then report recent progress in understanding the dedicated cellular immune response of Drosophila larvae against parasitization by Hymenopterae, a common threat for many Dipterae. This response involves the differentiation of lamellocytes, a cryptic cell fate, revealing the high degree of plasticity of Drosophila hematopoiesis. We end up by integrating studies in Drosophila within a more general picture of insect hematopoiesis and hemocyte homeostasis.

A short receptor downregulates JAK/STAT signalling to control the Drosophila cellular immune response.

The posterior signalling centre (PSC), a small group of specialised cells, controls hemocyte (blood cell) homeostasis in the Drosophila larval hematopoietic organ, the lymph gland. This role of the PSC is very reminiscent of the "niche," the micro-environment of hematopoietic stem cells in vertebrates. We have recently shown that the PSC acts in a non-cell-autonomous manner to maintain janus tyrosine kinase/signal transducers and activators of transcription (JAK/STAT) signalling in hematopoietic progenitors (prohemocytes), thereby preserving the multipotent character necessary for their differentiation into lamellocytes, a cryptic and dedicated immune cell type required to fight specific immune threats such as wasp parasitism. In this report, on the basis of a knock out generated by homologous recombination, we show that a short type I cytokine-related receptor CG14225/Latran is required for switching off JAK/STAT signalling in prohemocytes. This is a prerequisite to massive differentiation of lamellocytes upon wasp parasitisation. In vivo and cell culture assays indicate that Latran forms heteromers with Domeless, the Drosophila type I cytokine signalling receptor related to mammalian GP130, and antagonises Domeless activity in a dose-dependent manner. Our analysis further shows that a primary immune response to wasp parasitism is a strong decrease in cytokine mRNA levels in the lymph gland, followed by an increase in the latran/domeless ratio. We propose that this sequence of events culminates in the complete inhibition of residual JAK/STAT signalling by Latran. JAK/STAT activity has been associated with several human diseases including leukaemia while knock-out studies in mice point to a central role of this pathway in hematopoiesis and regulation of immune functions. The specific function of Drosophila Latran is, to our knowledge, the first in vivo example of a role for a nonsignalling receptor in controlling a dedicated immune response, and thus raises the question of whether short, nonsignalling receptors also control specific aspects of vertebrate cellular immunity.

Neither too much nor too little: reactive oxygen species levels regulate Drosophila hematopoiesis.

Owing to their fast diffusion, reactive oxygen species (ROS) are important tissue signalling components. High levels of ROS are generally considered as deleterious to cells. In vivo experiments in the Drosophila hematopoietic organ now challenge this view by showing that high ROS levels are intrinsically required to prime myeloid-like progenitors to differentiate.

The hematopoietic niche: a Drosophila model, at last.

The niche provides a specialised microenvironment necessary for maintenance of stem cells in a non differentiated state. While the hematopoietic stem cell (HSC) niche in vertebrates was the first to be recognized, Drosophila niches supporting germline stem cells were characterised first. Recent evidence for the existence of a niche maintaining hematopoietic precursors in Drosophila opens the way to study in vivo the niche/hematopoietic precursors interactions. The availability of a large collection of cell markers, mutants and sophisticated genetic tools makes Drosophila an attractive model for investigating the cellular and molecular mechanisms that are involved in these interactions.

Control of blood cell homeostasis in Drosophila larvae by the posterior signalling centre.

Drosophila haemocytes (blood cells) originate from a specialized haematopoietic organ-the lymph gland. Larval haematopoietic progenitors (prohaemocytes) give rise to three types of circulating haemocytes: plasmatocytes, crystal cells and lamellocytes. Lamellocytes, which are devoted to encapsulation of large foreign bodies, only differentiate in response to specific immune threats, such as parasitization by wasps. Here we show that a small cluster of signalling cells, termed the PSC (posterior signalling centre), controls the balance between multipotent prohaemocytes and differentiating haemocytes, and is necessary for the massive differentiation of lamellocytes that follows parasitization. Communication between the PSC and haematopoietic progenitors strictly depends on the PSC-restricted expression of Collier, the Drosophila orthologue of mammalian early B-cell factor. PSC cells act, in a non-cell-autonomous manner, to maintain JAK/STAT signalling activity in prohaemocytes, preventing their premature differentiation. Serrate-mediated Notch signalling from the PSC is required to maintain normal levels of col transcription. The key role of the PSC in controlling blood cell homeostasis is reminiscent of interactions between haematopoietic progenitors and their micro-environment in vertebrates, thus further highlighting the interest of Drosophila as a model system for studying the evolution of haematopoiesis and cellular innate immunity.

Induction chemotherapy, extrapleural pneumonectomy, and postoperative high-dose radiotherapy for locally advanced malignant pleural mesothelioma: a phase II trial.

INTRODUCTION: Extrapleural pneumonectomy (EPP) and adjuvant high-dose radiation therapy (RT) are associated with a median survival of 3 years in early-stage malignant pleural mesothelioma (MPM) but of less than 1 year in locally advanced disease. Although local control after EPP and RT is excellent, most patients die of distant metastases. We designed this clinical trial to test the feasibility of induction chemotherapy followed by EPP and RT in locally advanced MPM with the ultimate aim of improving survival. METHODS: Patients with MPM and stage III or IV disease were eligible. Induction therapy was four cycles of gemcitabine and cisplatin. Patients without disease progression by computed tomography underwent EPP followed by adjuvant hemithoracic RT (54 cGy). RESULTS: From January 2002 to January 2004, 21 patients (17 men, four women; median age 60 years) were entered into the study. Histology was epithelioid in 14 patients and mixed or sarcomatoid five patients. Pretreatment disease stage was III in 13 patients and IV in six patients. Nineteen patients received induction chemotherapy. Response to induction therapy was complete in zero patients, partial in five patients, stable disease in six patients, and progression of disease in eight patients. Eight of nine patients undergoing surgical exploration had EPP. The median survival of all patients was 19 months. Patients who had an EPP had a median survival of 33.5 months. Patients with unresectable tumors had a median survival of 9 months (p = 0.01). CONCLUSION: Induction chemotherapy with gemcitabine and cisplatin followed by EPP and adjuvant RT for locally advanced MPM is feasible and leads to a better median overall survival than that previously reported with EPP and RT alone.