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Non-small cell lung cancer is often diagnosed at advanced stages, and many patients are still treated with classical chemotherapy. The unselective nature of chemotherapy often results in severe myelosuppression. Previous studies showed that protein-coding mutations could not fully explain the predisposition to myelosuppression. Here, we investigate the possible role of enhancer mutations in myelosuppression susceptibility. We produced transcriptome and promoter-interaction maps (using HiCap) of three blood stem-like cell lines treated with carboplatin or gemcitabine. Taking advantage of publicly available enhancer datasets, we validated HiCap results in silico and in living cells using epigenetic CRISPR technology. We also developed a network approach for interactome analysis and detection of differentially interacting genes. Differential interaction analysis provided additional information on relevant genes and pathways for myelosuppression compared with differential gene expression analysis at the bulk level. Moreover, we showed that enhancers of differentially interacting genes are highly enriched for variants associated with differing levels of myelosuppression. Altogether, our work represents a prominent example of integrative transcriptome and gene regulatory datasets analysis for the functional annotation of noncoding mutations., (© 2024 Zhigulev et al.)

Introduction: Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease affecting mainly young women., Background: The respiratory manifestations are characterized by a progressive cystic destruction of the lung parenchyma. Extrapulmonary involvement includes benign renal tumours called angiomyolipomas and abdominal lymphatic masses called lymphangioleiomyomas. At the pathological level, the cellular proliferation found in LAM is in part due to the presence of mutations in the tumour suppressor genes TSC1 and TSC2 (Tuberous Sclerosis Complex). These mutations lead to the activation of the mTOR pathway, which is currently the main therapeutic target. mTOR inhibitors such as sirolimus or everolimus have shown a beneficial effect on the decline in pulmonary function and a reduction of angiomyolipoma size, but are necessary in only some patients., Perspectives: LAM cells have migratory properties mediated by the formation of new lymphatic vessels. They are also able to secrete metalloproteases, which enhance their invasiveness. Moreover, the expression of estrogen and progesterone receptors by LAM cells suggests a possible role for sex hormones in the pathogenesis of the disease., Conclusion: A better understanding of mTOR-independent mechanisms would allow the development of novel therapeutic approaches., (Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Pulmonary Mucosa-Associated Lymphoid Tissue (MALT)-type lymphoma is the most frequent primary pulmonary lymphoma. We report the case of a patient who presented a pulmonary MALT-type lymphoma treated with chloraminophen, with a recurrence 5 years later characterized with pulmonary lesions associated with a gastric location. This observation underlines some anatomical and clinical aspects of pulmonary MALT-type lymphoma, and leads to discuss the evolution of its physiopathological and therapeutic concepts. In particular, the contributions of positron emission tomography and molecular biology allow the analysis of possible multifocal affections of this disease., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Introduction: Pulmonary metastases from meningioma are rare and present with specific clinical and radiological features. The diagnostic and therapeutic management of metastatic meningioma illustrate the concept of orphan thoracic oncology., Case Report: We report the case of a 58-year-old male, former smoker, with a previous history of atypical meningioma and resected lung adenocarcinoma. During oncologic surveillance, a computed-tomography scan disclosed multiple well-defined homogeneous nodules in the right lung. These nodules were hypermetabolic at positron-emission tomography with fluorodesoxyglucose. Pathological examination of metastasectomy specimens revealed metastatic malignant meningioma., Conclusions: Pulmonary metastases may occur in malignant meningioma. Twenty-one cases have been reported over the past 20 years. As for all rare tumours, multidisciplinary consensus is mandatory, in the absence of evidence-based recommendations based on prospective trials or observational studies., (Copyright © 2010 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Unlabelled: A 71 year-old man with primary Sjögren's syndrome developed pulmonary opacities within two years of the diagnosis. Videothoracoscopic lung biopsy demonstrated high grade, B-cell, CD20+, large-cell lymphoma, associated with Epstein-Barr virus (RNA EBERs of the virus were expressed by the lymphoma cells). The condition initially improved with rituximab-CHOP treatment, but recurrence of the lymphoma was fatal., Conclusion: High-grade B-cell lymphoma associated with EBV can occur in Sjögren's syndrome in the absence of long-term immunosuppressive therapy., (Copyright 2010 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: We report the case of a patient with an isolated pulmonary mucosa associated lymphoid tissue (MALT) lymphoma that revealed an acquired immune deficiency syndrome (AIDS)., Case Report: A 30 year old man from Central Africa was admitted to hospital with cough, dyspnoea and general weakness. A diagnosis of HIV infection was made promptly. The thoracic CT scan revealed diffuse bilateral ground glass opacities as well as consolidation of the right upper lobe. After a non-diagnostic endoscopy the diagnosis of a low grade B cell MALT lymphoma (CD20+) was made by lung biopsy and confirmed by the presence of the t(11;18) translocation. No extrathoracic lymphoma was found. Treatment with rituximab and triple anti-retroviral therapy led to a rapid and complete remission that was maintained for 3 years after the diagnosis., Conclusion: Pulmonary MALT lymphoma may reveal AIDS. A combination of rituximab and anti-retroviral therapy led to complete remission in this patient.

Metastases are an uncommon cause of tumor in the sellar region. We report two cases of small cell lung cancer presenting with visual loss and hypopituitarism resulting from metastasis to the pituitary area.

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disorder of unknown cause characterized by peribronchial, perivascular, and perilymphatic proliferation of abnormal smooth muscle cells leading to cystic lesions. The hypothesis of hormonal dependence and the effectiveness of hormonal therapy have not yet been demonstrated conclusively, and the prevalence of extrathoracic manifestations and the survival of patients with LAM are somewhat contradictory. A multicentric retrospective study was conducted in an attempt to describe better the initial features, the diagnostic procedures, the associated lesions, and, above all, the management and course of LAM in a large homogeneous series of 69 stringently selected patients, with a majority of cases diagnosed since 1990. The aim of the study, based on a review of the literature, also was to provide a comprehensive view of this uncommon disease. The clinical features were in keeping with previous studies, but we found that exertional dyspnea and pneumothorax were the most common features, and chylous involvement was less frequent. LAM was diagnosed after menopause in about 10% of cases. The onset of LAM occurred during pregnancy in 20% of cases, and a clear exacerbation of LAM was observed in 14% of cases during pregnancy. Pulmonary LAM was diagnosed on lung histopathology in 83% of cases, but renal angiomyolipoma, observed in 32% of our patients, may be a useful diagnostic criterion when associated with typical multiple cysts on chest CT scan or with chylous effusion. Chest CT scan was more informative than chest X-ray (normal in 9% of cases), and may be indicated in spontaneous pneumothorax or renal angiomyolipoma in women of childbearing age. About 40% of the patients had a normal initial spirometry, while an obstructive ventilatory defect (44%), a restrictive ventilatory defect (23%), was observed in other patients. Initial diffusing capacity for carbon monoxide was frequently decreased (82%). Hormonal therapy was administered in 57 patients, but a clear > or = 15% improvement of FEV1 was observed in only 4 evaluable patients, treated with tamoxifen and progestogens (n = 2), progestogen (n = 1), and oophorectomy (n = 1). Probably 1 of the most urgent needs for clinical research in LAM is to test the currently available hormonal treatments in the context of international multicenter prospective controlled studies. Pleurodesis was performed in 40 patients. Lung transplantation was performed in 13 patients, 7.8 +/- 5.2 years after onset of LAM, in whom the mean FEV1 was 0.57 +/- 0.15 L. After a follow-up of 2.3 +/- 2.2 years, 9 patients were alive. Mean follow-up from onset of disease to either death or closing date was 8.2 +/- 6.3 years. Overall survival was better than usually reported in LAM, and Kaplan-Meier plot showed survival probabilities of 91% after 5 years, 79% after 10 years, and 71% after 15 years of disease duration.

Purpose: To determine the clinical characteristics of the subpopulation of patients not included in clinical trials, their outcome, and the reasons for their ineligibility and non-participation., Patients and Methods: We studied 57 patients (out of 178 consecutive patients with SCLC), who were not included in any of the three successive clinical trials completed at our center during the study period. We also compared 37 patients excluded from the largest clinical trial to their 73 included counterparts., Results: Reasons for ineligibility (n = 53) included low Karnofsky index (n = 17), advanced age (n = 12), non-feasible long-term follow-up (n = 12), previous history of cancer (n = 8), contraindication for anthracyclines (n = 5), and other medical reasons (n = 11). Only four eligible patients were not included in the trials. As compared to patients included in the studies, non-included patients had a significantly lower Karnofsky index, were older, presented more frequently with metastatic disease, and had a lower response rate to treatment and a shorter survival. However, exclusion from the trial was not an independent prognostic factor by multivariate analysis., Conclusions: Selection biases were unlikely in the three trials, based on the high ratio of included/eligible patients. However, the subgroup of patients included in the trials was not representative of the patient population as a whole because of restrictive eligibility criteria. Results from published clinical trials to the overall population should be extrapolated only with caution. We suggest that the proportion and major characteristics of ineligible and non-participating patients be mentioned in any publication of a clinical trial.

Four cases of lymphomatoid granulomatosis are reported, three of them involving the lung. Histological features included a true angiocentric and angiodestructive polymorphic cellular proliferation. This included histiocytes, plasma cells, many reactive T-cells and rare large, atypical cells which were of the B phenotype. Epstein-Barr virus was detected in the atypical cells by in situ hybridization in three cases, with expression of both latent membrane proteins (LMP)-1 and Epstein-Barr nuclear antigen-2 in two cases and expression of only LMP-1 in the third case. Expression of both of these proteins suggests a defect in the T-cell-mediated immunity and that Epstein-Barr virus is not only a silent passenger but may also be involved in the pathogenesis of the disease. This could have implications for therapy.

Human Recombinant Granulocyte Colony Stimulating Factor (G-CSF) allows rapid neutrophil recovery after chemotherapy-induced leukopenia. In a prospective series of 54 patients with extensive small cell lung cancer, we evaluated the feasibility and efficacy of accelerated delivery of the AVI chemotherapy regimen. Treatment consisted of Doxorubicin 50 mg/m2 day 1, Etoposide 120 mg/m2 day 1-3 and Ifosfamide 2 g/m2 (+ Mesna 4 g) day 1 and 2 given every 2 weeks and followed by G-CSF (Neupogen, Amgen Roche 5 micrograms/kg/day s.c. day 4-14). Twenty-seven (50%) patients could not receive the total of six courses, seven because of severe septic complication, 10 because of Grade 4 thrombopenia, seven because of non-response and three because of patient refusal. Chemotherapy had to be delayed in 58 out of the 244 administered courses and this was due to thrombopenia in 48% of cases. The probability of optimal dose-on-time administration was 64% at three courses. The mean actually received dose intensity was 93% at six courses (27 patients treated). It was increased by 76% compared to our previously published conventional 3-week interval chemotherapy. The median neutrophil nadirs were stable during the successive treatment courses while haemoglobin and platelet values significantly worsened from cycle 1 to cycle 6. The overall response rate after three courses was 77% in the 48 evaluable patients. The median survival is 8 months overall and 5 months disease free. The actuarial survival is 22% at 2 years. We conclude that substantial dose intensification with accelerated chemotherapy and G-CSF support is feasible. However, the rate of severe infectious episodes is too high and thrombopenia is the main limiting factor. Either growth factors active on the megacaryocytic lineage or haematological rescue with peripheral blood stem cells might be useful in this setting.

We report a retrospective study of the pathological features in 69 primary pulmonary non-Hodgkin's lymphomas which have previously been clinically reviewed. The tumours consisted of 61 (88%) low-grade and eight (12%) high-grade malignant lymphomas. Fifty-four of the low-grade malignant lymphomas were MALT lymphomas. Lymphoepithelial lesions were observed in bronchial, bronchiolar and alveolar lining. All tumours were composed of nodules, forming a lymphangitic pattern at the periphery and a confluent central mass. Invasion of pleura and vessels was often seen but this without any consequence on survival. Granulomas were found in 20% of cases. Six of the eight high-grade tumours were centroblastic and another two were B-cell lymphomas of undetermined type. In four cases, associated areas of low-grade malignant lymphoma with lympho-epithelial lesions indicated a preexisting MALT lymphoma. Clinical data suggest that limited surgery or non-aggressive chemotherapy can provide long-term survival in patients with such slowly developing neoplasms. However, non-invasive diagnostic methods need to be developed.

A prospective analysis of serum levels of C-reactive protein (CRP) has been conducted on a series of 39 small cell lung cancer (SCLC) patients during the first course of chemotherapy in order to evaluate the predictive value of this marker on tumoral extension at diagnosis and response to therapy. Serum levels of CRP were measured before chemotherapy (day 0) and during the first two days of treatment (day 1, day 2). Twenty-three of 32 evaluable patients (71%) had extensive disease. The mean pre-treatment CRP level was significantly higher in this group than in the group of patients with limited disease (52.3 mg/l vs 15.8 mg/l, P = 0.02). Twenty-three patients responded to treatment and nine did not. The evolution of serum CRP levels in both groups was compared between day 0 and day 2. A more than two-fold increase of initial CRP levels showed a 100% predictive value for response. On the other hand, a decrease by more than 50% of initial serum levels was associated with a negative predictive value of 75% for response. We conclude that the follow-up of CRP levels during initial chemotherapy of SCLC might be useful in the initial evaluation of tumoral extension and in the early prediction of response to therapy.

Undifferentiated small cell lung cancer differs from the other types of primary lung cancer in its neuroendocrine origin, its important potential for metastatic dissemination and its sensitivity to antimitotic drugs. These specific features condition the originality of its clinical presentation which frequently includes paraneoplastic endocrine syndromes. The frequent metastases are responsible for its poor prognosis and raise difficult methodological problems since the detection of metastatic sites depends on the sensitivity and specificity of the tests used to identify these sites. Chemotherapy, which is very active against this type of tumour, forms the basis of the conventional treatment where 2 sets of drug combinations are administered: either anthracycline + epidophyllotoxin + alkylating agent, or platinum salt + epidophyllotoxin. Owing to haematopoietic myeloid growth factors, dosage intensification, in the hope of overcoming the chemoresistance mechanisms responsible for the usually very temporary response, opens new and promising research lines.

We studied 70 patients with biopsy-proven pulmonary non-Hodgkin's lymphomas without extrathoracic involvement or mediastinal adenopathy to determine the clinical, imaging, and endoscopic features of this condition in a homogeneous series. In low-grade (LG) lymphomas, symptoms were cough, dyspnea, chest pain, hemoptysis. Imaging features consisted of localized alveolar opacities, infiltrative diffuse opacities, atelectasis, and pleural effusions. Inflammatory changes of the mucosa were present in some patients, leading to bronchial stenosis in 7; biopsies showed lymphomatous infiltration in 12. Prognosis of LG lymphomas was excellent, with 93.6 percent survival at five years. High-grade lymphomas differed from LG lymphomas principally by a more aggressive course and a worse survival. Inflammatory changes occurred in seven of nine cases leading to stenosis in two, and biopsies showed lymphomatous involvement in five. The profile of primary pulmonary lymphomas in this study could help clinicians consider this condition and prompt them to evaluate new diagnostic tools.

Lymphangiomyomatosis (LAM) consists of smooth muscle (SM) cell proliferation of unknown origin involving the lymph nodes and the lung interstitium. From morphological studies showing both SM differentiation of the proliferating cells and lymphatic hyperplasia, hypotheses were suggested concerning the origin of the proliferation. Two cases of LAM were investigated by electron microscopy and immunohistochemistry; tissues were obtained by lymph node and open lung biopsies. Cytoplasmic and matrix protein markers were used in order to clarify the pattern of differentiation of the proliferating cells and to characterize their connective tissue environment. The proliferating cells present ultrastructural characteristics of SM cells; they contain vimentin, desmin, and alpha-SM actin and are devoid of Factor VIII, favouring a parieto-arterial origin. The connective tissue matrix inside the infiltrate is composed of interstitial collagens and basement membrane components. At the late stage of the disease, remodelling of the interstitial matrix accompanies the infiltrate and remains perilesional.

The real need for extensive staging at the time of diagnosis is discussed in regard to small cell lung carcinoma. We performed a decisional retrospective analysis on a series of 182 patients, based on three staging steps: the first step included physical examination and routine biologic tests. The second step consisted of liver ultrasonography and needle aspiration of any clinically detectable tumor mass, and the third step included bone marrow examination, radionuclide bone scan, thoracic, abdominal, and brain CT scan. A stepwise multivariate logistic regression performed on 11 variables considered in the first step shows that a four-parameter model can predict the spread of the disease (limited or extensive): weight loss, performance status, and elevated LDH or alkaline phosphatase levels. Limited disease can be predicted in two ways: (1) elevated LDH with normal alkaline phosphatases, no weight loss, and good performance status, or (2) normal LDH and alkaline phosphatases. In this series, 28 percent of patients can be predicted as having extensive disease and can be treated with chemotherapy alone without chest irradiation. After the second step, the probability of disease being extensive is only 25 percent, and only 84 (46.15 percent) patients would need to undergo the third step of staging procedures (brain CT scan, bone marrow aspiration and biopsy, radionuclide bone scan) with this method. We conclude that a multistep approach represents a simple staging method and offers the advantage of harmlessness and lower costs for patients not to be evaluated in prospective clinical trials.

Chest radiographs, thin-section computed tomographic (CT) scans, and results of pulmonary function tests in nine women with pulmonary lymphangiomyomatosis and two women with pulmonary tuberous sclerosis were retrospectively evaluated. In all patients, CT demonstrated thin-walled cysts less than 20 mm in diameter scattered at random in all parts of the lungs. In eight patients, cysts larger than 20 mm in diameter were also present. Lung tissue between cysts appeared normal in all 11 patients, except one with septal lines and dependent alveolar areas of attenuation. CT showed cysts in three patients whose radiographs were normal, and it demonstrated that many lesions that appeared reticular on plain radiographs were actually cysts. CT findings correlated better with the diffusion capacity of the lungs for carbon monoxide than did the plain radiographic findings. CT was more sensitive and more precise than radiography at showing the presence and morphology of lung abnormalities.

Small-cell lung carcinoma can be distinguished from other histological types of lung cancer because of its high metastatic potential. Initial staging procedures divide the patients into two main prognostic groups: the so-called "limited" (to the thorax) and the extensive disease patients. Based on the results of a prospective pilot study involving 182 patients and on a review of the literature, the authors discuss the usefulness of initial staging in increasing the number of detectable metastases, assessing tumour burden, evaluating treatment results and identifying prognostic factors. Complete tumour staging at the time of diagnosis appears to be very helpful for a better knowledge of the disease and better therapeutic decisions.

We report four cases of primary pulmonary pseudolymphoma and lymphoma with the usual features of these disorders: lack of symptoms, radiological opacities sometimes multiple with soft wooly contours and air bronchograms, and slowly evolving pattern. The distinction between pseudolymphoma and lymphoma, prior to histological diagnosis is currently controversial. Immunological studies aim at defining whether the lymphoid proliferation is polyclonal or monoclonal (the benign process being considered polyclonal and the malign monoclonal). This distinction works in some cases, as in one of our cases of lymphoplasmacytic lymphoma with a monoclonal IgM gammopathy, a predominance of cells containing IgM on immunofluorescence, and an illness evolving over 9 years. Other cases raise discussion points such as one of our patients with classical histological characteristics of pseudolymphoma, an absence of monoclonal markers on immunofluorescence, but having a monoclonal gammopathy in the serum. This example raises the question as to the possible coexistence of, or a switch over from, a polyclonal to a monoclonal process. In this way the primary pulmonary lymphoproliferative process ought to be considered as one element in a large spectrum ranging from benign to malign disorders and not as distinct illnesses with definitive patterns.

A 60-year-old male patient with small carcinoma of the lung was treated with chemotherapy and radiotherapy. The tumour regressed, but two squamous cell carcinomas appeared in the contralateral lung. The first one was discovered after 3 months' treatment and developed slowly; the second one, diagnosed after 9 months' treatment, was rapidly progressive. The patient died 13 months after the beginning of treatment, and only the squamous cell carcinomas could be confirmed on autopsy. Such cases may reflect either selection of tumours that were present from the beginning of treatment, or development of other malignancies, or treatment-induced histological changes in the original tumour.

The diagnosis in the same patient of the two diseases is very often delayed. Generally, tuberculosis is diagnosed first, and then cancer when the radiologic lesions extend despite of antituberculous treatment. In half of our cases, tuberculous lesions could not be individualized from cancer on the chest X-ray films. Antineoplastic chemotherapies may favour the development of tuberculosis, or atypical mycobacteriosis, in cancer patients, and it must be considered as an opportunistic infection in such patients. Clinicians should be aware of the possible coexistence of the two diseases and, in practice, ask for fiberoptic bronchoscopy and sputum cytology in tuberculous patients presenting atypical features, and for sputum examination in cancer patients.

A cyclic and sequential combination of adriamycin, vincristine (or VM 26) and cyclophosphamide was used, with a follow up of 4 to 33 months in 38 patients with a "micro-cellular" carcinoma of the lung. Radiotherapy was used in association in a variable manner. Chemotherapy alone resulted in marked regression of the lesions (regression is greater than 50%) in approximately 65 per cent of cases and a level of complete regression which varied from 31 to 45 per cent according to the degree of diffusion of the lesions at the time of admission. In this study, survival in apparently localised forms was 70 per cent after one year and 55 per cent at eighteen months, whilst it was 34 per cent at one year and nil at eighteen months in patients with evidence of metastatic disease at the time of entry. These encouraging results indicate a hope for improvement, in certain patients reacting favourably to this protocol, in the still grave prognosis of "small cell" carcinoma of the lung.

A series of 49 patients with pulmonary hamartoma subjected to operation is described. 28 patients were male and 21 female, with a mean age of 49.8 years. Most cases were discovered on routine chest films. Six patients had radiologic changes produced by obstruction, while 43 had a rounded peripheral opacity. Fine calcifications were present in four cases. In no case was diagnosis achieved by bronchoscopy, whereas one of the more recent cases was diagnosed by percutaneous fine needle biopsy. Sinner has shown that this last technique can establish diagnosis in most cases. As such tumors are invariably benign and grow slowly, diagnosis by percutaneous biopsy renders operation unnecessary: periodic follow up only is required.

We report a case, cytologically diagnosed, of broncho-alveolar cancer associated with localised interstitial pulmonary fibrosis. This association of fibrosis with bronchiolo-alveolar cancer is classical and a pathogenic affiliation has been deduced by the majority of authors. We review the pathogenesis in relation to recent datas concerning the activation of successive oncogenes: the first stage of carcinogenesis may correspond to the activation of an oncogene coding for a fibroblastic growth factor leading to fibrosis.

We studied the clinical and radiological features of pulmonary metastases present in 4 out of 22 patients with medullary carcinoma of thyroid. Two patients presented with common metastases: macronodules in one, and micronodules in the other one. The other two patients presented initially with reticulonodular perihilar lesions on chest X-ray, leading to the diagnosis of sarcoidosis in both of them. The observation of such pulmonary metastases is original: initially latent, they progress very slowly, and they correspond to a lymphangitic spread of the tumour with amyloid deposition in peribronchovascular structures without alveolar involvement, as shown in one of our cases with pathologic study.