A proliferative to invasive switch is mediated by srGAP1 downregulation through the activation of TGF-ß2 signaling.

Many breast cancer (BC) patients suffer from complications of metastatic disease. To form metastases, cancer cells must become migratory and coordinate both invasive and proliferative programs at distant organs. Here, we identify srGAP1 as a regulator of a proliferative-to-invasive switch in BC cells. High-resolution light-sheet microscopy demonstrates that BC cells can form actin-rich protrusions during extravasation. srGAP1low cells display a motile and invasive phenotype that facilitates their extravasation from blood vessels, as shown in zebrafish and mouse models, while attenuating tumor growth. Interestingly, a population of srGAP1low cells remain as solitary disseminated tumor cells in the lungs of mice bearing BC tumors. Overall, srGAP1low cells have increased Smad2 activation and TGF-ß2 secretion, resulting in increased invasion and p27 levels to sustain quiescence. These findings identify srGAP1 as a mediator of a proliferative to invasive phenotypic switch in BC cells in vivo through a TGF-ß2-mediated signaling axis.

Long-Term Stability of the Electronic Sensor Component of a Digital Pill System in Real-World Storage Settings.

Background: Digital pill systems comprise an ingestible sensor integrated into a gelatin capsule that overencapsulates medication allowing real-time measures of medication ingestion. These systems may improve the manner in which medication adherence can be assessed and supported. Objective: In this investigation, we tested the durability of the ingestible sensor as part of a clinical trial to measure the feasibility and acceptability of the system to measure adherence to once daily tenofovir disoproxil fumarate/emtricitabine (NCT03842436). Methods: Digital pills not dispensed during the study were stored in a pharmacy. Seventeen sensors were selected from digital pills stored for at least 12 months and activated in a simulated gastric environment. A radiofrequency spectrum analyzer and the reader device used in the clinical trial to capture ingestion events were used to measure activation of emitters. A passing evaluation was defined as an energized emitter within 30 minutes of immersion, ability to broadcast a signal for 10 minutes, and successful acquisition by the reader. Results: All ingestible sensors passed the stability test. Mean activation time in simulated gastric fluid was 3.33 minutes (SD = 1.47); emitters remained active for a mean of 47.72 minutes (SD = 1.78). These parameters matched guidelines defined in the ID-Cap system requirements for use in patients. Conclusions: Ingestible sensor components of the ID-Cap system were therefore stable after long-term storage.

Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall.

BACKGROUND: To explore correlation between the quality of surgery and outcome in high-risk soft tissue sarcoma (STS) patients treated within a phase III randomized trial. PATIENTS AND METHODS: In the trial, all patients received three cycles of preoperative chemotherapy (CT) with epirubicin 120 mg/m(2) and ifosfamide 9 g/m(2) and were randomly assigned to receive two further postoperative cycles. Radiotherapy (RT) could be delivered in the preoperative or postoperative setting. The association between surgical margins and overall survival (OS) was studied in a univariate and multivariate fashion. RESULTS: Two hundred and fifty-two patients completed the whole treatment and were operated conservatively. At a median follow-up of 60 months (IQR, 45-74 months), the 5-year OS was 0.73, even in patients with positive and negative margins. The 5-year cumulative incidence (CI) of local recurrence (LR) in patients with positive and negative microscopic margins was 0.17 (standard error, SE, 0.08) and 0.03 (SE, 0.01), respectively. In the subgroup of patients receiving combined preoperative CT-RT and with positive surgical margins, the CI of LR was 0. CONCLUSIONS: In this setting of high-risk STS treated by preoperative CT or CT-RT, the negative impact of positive margins on the outcome was limited. When close margins can be anticipated preoperative CT-RT may be a reasonable option to maximize the chance of cure.

Neuroendocrine cell hyperplasia as an unusual form of interstitial lung disease.

STUDY OBJECTIVES: Two patients diagnosed with interstitial lung disease (ILD) secondary to pulmonary neuroendocrine cell (PNEC) hyperplasia are presented. BACKGROUND: Pulmonary neuroendocrine cell hyperplasia (PNECH) is a rare entity worldwide and few cases presenting as ILD have been reported. Following the consensus criteria established by the American Thoracic Society (ATS) and the European Respiratory Society (ERS), three patients from among 500 ILD patients over the last 10 years in our institution were diagnosed with PNECH. The diagnosis was established by open lung biopsy using specific stains to demonstrate neuroendocrine cells in lung tissue. METHODS: Patients were questioned on their medical and pathological history, occupational or environmental exposure to toxic substances and any relationship with smoking. In addition, were recorded symptoms at presentation, physical signs, analytic and respiratory function results, chest X-ray and CT scan features, bronchoscopy findings including bronchoalveolar lavage and transbronchial biopsy, and open lung biopsy findings. RESULTS: In these two patients, PNECH was the only cause of their diffuse lung disease. Clinical signs and symptoms (cough, expectoration and progressive dyspnea) were similar to other idiopathic interstitial pneumonias and radiologic features (ground-glass infiltrates in mosaic pattern) were consistent with those of non-specific interstitial pneumonia or the onset of hypersensitivity pneumonitis. Functional respiratory alterations were consistent with restrictive pattern. Transbronchial and open biopsy findings are described, as well as the treatment and course of the disease. The two patients had a favorable outcome. CONCLUSIONS: Two cases of ILD secondary to PNEC hyperplasia are presented, with clinical and radiological findings that might be mistaken for other types of idiopathic interstitial pneumonias. The disease course is described and the possible etiopathogenic role that PNECs might play in the development of lung fibrosis is discussed.

The anatomy and vascularity of the lunate: considerations applied to Kienböck's disease.

PURPOSE: The purpose of this study was to assess the anatomy and vascularity of the lunate. The genesis of lunatomalacia requires some combination of vascular risk and mechanical predisposition. The findings will be correlated with the major existing theories of the cause of Kienböck's disease. METHODS: We studied 27 cadaver upper limbs using latex injection and the Spalteholz technique. We investigated the blood supply to the lunate. In 24 wrists we evaluated the incidence and distribution of anatomic features, arthrosis, and soft tissue lesions. We correlated the lunate morphology and ligaments disruptions with the arthritic changes. RESULTS: The lunate morphology results as classified by Antuña-Zapico were five type I (20.8%), 18 type II (75%) and one type III (4.2%). The lunate was found to have a separate facet for the hamate in 11 cases (45.8%). The most common size of the facet was found to be 3 mm (range, 3-6 mm). Arthrosis was identified with most frequency in the radius (88.2%) and lunate (94.1%). The triangular fibrocartilage complex was found torn in 58.3%, the lunotriquetral interosseous ligament was torn in 20.8% and the scapholunate interosseous ligament (SLIL) was torn in 54.2% of the wrists. There was a correlation between the presence of arthrosis at the hamate and the presence of a lunate facet (P=0.027) and a correlation between the presence of a tear in the SLIL and arthrosis in the scaphoid (P=0.002). The nutrient vessels entered the lunate through the dorsal and volar poles in all the specimens. The dorsal intercarpal and radiocarpal arches supply blood to the lunate from a plexus of vessels located directly over the lunate's dorsal pole. Vessels entered the dorsal aspect of the lunate through one to three foramina. One to five nutrient vessels were observed entering the volar pole through various ligament insertions, including the ligament of Testut-Kuentz (radio-scapho-lunate (RSL) ligament) and the radiolunate triquetrum ligament (or dorsoradial carpal ligament) and ulnar lunate triquetral ligament. CONCLUSIONS: The lunate had consistent dorsal and palmar arteries entering the bone in all the specimens. The blood supply and foramina number is greater in the volar pole of the lunate than the dorsal pole. The lunate blood supply comes from different ligaments. In the etiopathogeny of Kienböck's disease it is possible that an acute or chronic, traumatic or non-traumatic injury of the vessel bearing ligaments, particularly because of their structure and the location of the RSL ligament, may have an important role in the appearance of lunate necrosis.

Management of metallic mercury injection in the hand.

This case report discusses a patient who injected 20 mL of metallic mercury subcutaneously in his left hand during an attempted suicide. The blood mercury level was 118 microg/L and the urinary mercury level was 43 microg/L, which confirmed the diagnosis of metallic mercury poisoning. A good result was obtained in this patient and the local and systemic toxicity and its management are discussed. A chelation therapy with dimercaprol and early surgical excision of injected material are recommended because this treatment effectively lowers mercury blood levels and controls the local inflammatory reaction. Intraoperative fluoroscopy is useful to confirm the extent of removal.

[Nonspecific interstitial pneumonia: epidemiologic and clinical characteristics]. / Neumonía intersticial no específica: Características clínicas y epidemiológicas.

BACKGROUND AND OBJECTIVES: Patients diagnosed with non-specific interstitial pneumonia (NSIP) in 2 hospitals in Barcelona, Spain, were studied to investigate the factors that could contribute to the etiology of disease. PATIENTS AND METHOD: The consensus diagnostic criteria established by the American Thoracic Society/European Respiratory Society were followed. The study included 16 patients, 10 men (65%) and 6 women (35%), all diagnosed with NSIP by open lung biopsy. Patients were questioned on pathological history, occupational or environmental exposure, medicinal drug use, contact with birds, and relationship with smoking. In addition, were recorded symptoms and physical signs, laboratory and respiratory function results, chest X-ray and computerized tomography scan features, fiberbronchoscopy findings and open lung biopsy findings. RESULTS: Eleven patients (69%) -10 men (100%) and one woman (12%) -were smokers: 4 were active and 7 former smokers; 8 (80%) patients had fibrotic NSIP and three (50%) had cellular NSIP. Nine (56%) patients had a medication history, and 5 received chronic non-steroideal anti-inflammatory drug treatment. Occupational exposure to bleach, detergents, and ammonia or chloride products was documented in 6 cases. Three patients had contact with manufactured plastic products and isocyanate inhalation. CONCLUSIONS: Smoking and medication use were prevalent in NSIP patients. Ibuprofen and celecoxib clearly provoked symptoms in one NSIP patient. Further studies are required to clarify the role of detergents, isocyanates and other occupation-related substances as triggering factors.

Septal thickening: HRCT findings and differential diagnosis.

Thickening of the interlobular septa is a common and easily recognized high-resolution computed tomography feature of many diffuse lung diseases. In some cases, it is the predominant radiological finding. This article reviews the spectrum of entities that commonly present with thickening of the interlobular septa as the main radiological feature and establishes a practical approach for the differential diagnosis.

Rupture of all the flexor tendons in the hand due to malunion of a distal radius fracture.

We report the case of a patient in whom the flexor digitorum superficialis and flexor digitorum profundus tendons to the index, middle, ring and little fingers ruptured 6 years following malunion of a distal radius fracture. There was no history of rheumatoid disease. The distal ulna was displaced volarly and perforated the volar wrist capsule. There was a cumulative biological effect from chronic synovitis and mechanical compression due to the ulnar head impinging upon the normal anatomic course of the flexor tendons to the ring and little fingers. We discuss the physiopathology of this rare lesion and postulate that flexor tendon rupture to the index and middle fingers will occur on the volar surface of the radius when there is a malunion with dorsal tilt.

[Massive hemorrhage due to nodular hyperplasia of Brunner's glands in antiphospholipid syndrome]. / Hemorragia masiva por hiperplasia nodular de glándulas de Brunner en el síndrome antifosfolipídico.

Gastrointestinal hemorrhage is an exceptional complication of antiphospholipid syndrome and most reported cases are secondary to ischemic lesions. Brunner's gland hyperplasia is an infrequent and usually asymptomatic condition that has been associated with chronic renal failure. We report a patient with primary antiphospholipid syndrome who, after mechanic heart valve replacement and while in a state of drug-induced anticoagulation, experienced a life-threatening upper gastrointestinal hemorrhage due to nodular hyperplasia of Brunner's glands. This entity may be considered in the differential diagnosis of upper gastrointestinal bleeding in patients with antiphospholipid syndrome, most of whom are treated with oral anticoagulatory drugs, and particularly in patients with chronic renal failure.

Lung transplantation in young infants with interstitial pneumonia.

OBJECTIVES: We describe our experience with infants suffering from interstitial pneumonia referred for lung transplantation. METHODS: From April 1998 to December 2000, three infants were admitted to our lung transplantation program: a 9-month-old girl (patient 1) suffering from surfactant protein C deficiency who had high oxygen requirements (fraction of inspired oxygen: 70% to 90%), and two boys, ages 2 (patient 2) and 9 months (patient 3), who were ventilator-dependent due to chronic pneumonitis of infancy. RESULTS: Patients were transplanted at the age of 5 months (patient 2) and 13 months (patients 1 and 3) at 87 to 105 days after being accepted for lung transplantation. All cases underwent a sequential double lung transplant on cardiopulmonary bypass. The immunosuppressive regime included tacrolimus, prednisone, and azathioprine. Patients 2 and 3 also received basiliximab. Two cases suffered a mild rejection episode that responded to high-dose steroids. Patient 2 was ventilator-dependent for 8 months after transplant, owing to severe bronchomalacia and left main bronchus stenosis. Bronchial stenosis resolved after pneumatic dilatation and endobronchial stenting. This patient also presented with a pulmonary artery anastomosis stricture that required percutaneous balloon dilatation. All three patients are at home, carrying out normal activities for their age, with no respiratory symptoms after a period of 8 to 29 months of follow-up. CONCLUSIONS: Interstitial pneumonia of infancy is a rare disease with a bad prognosis and no specific treatment; therefore, lung transplantation represents a good therapeutic option for these infants.

Intravascular ultrasound of the elastic pulmonary arteries: a new approach for the evaluation of primary pulmonary hypertension.

OBJECTIVE: To assess the structural and functional characteristics of pulmonary arteries by intravascular ultrasound (IVUS) in the setting of primary pulmonary hypertension, and to correlate the ultrasound findings with haemodynamic variables and mortality at follow up. DESIGN: Prospective observational study. SETTING: University hospital (tertiary referral centre). PATIENTS: 20 consecutive patients with primary pulmonary hypertension (16 female; mean (SD) age, 39 (14) years). METHODS: Cardiac catheterisation and simultaneous IVUS of pulmonary artery branches at baseline and after infusion of epoprostenol. RESULTS: 33 pulmonary arteries with a mean diameter of 3.91 (0.80) mm were imaged, and wall thickening was observed in all cases, 64% being eccentric. Mean wall thickness was 0.37 (0.13) mm, percentage wall area 31.0 (9.3)%, pulsatility 14.6 (4.8)%, and pulmonary/elastic strain index 449 (174) mm Hg. No correlation was observed between IVUS findings and haemodynamic variables. Epoprostenol infusion increased pulsatility by 53% and decreased the pulmonary/elastic strain index by 41% (p = 0.0001), irrespective of haemodynamic changes. At 18 (12) months follow up, nine patients had died. A reduced pulsatility and an increased pulmonary/elastic strain index were associated with increased mortality at follow up (12.0 (4.4)% v 16.4 (4.4)%, p = 0.03; 369 (67) v 546 (216) mm Hg, p = 0.02). CONCLUSIONS: IVUS demonstrated pulmonary artery wall abnormalities in all patients with primary pulmonary hypertension, mostly eccentric. The severity of the changes did not correlate with haemodynamic variables, and epoprostenol improved pulmonary vessel stiffness. There was an association between impaired pulmonary artery functional state as determined by IVUS and mortality at follow up.

Miliary lung disease revisited.

This article reviews the high-resolution computed tomography imaging features of miliary pattern, a characteristic radiologic manifestation of diffuse micronodular lung disease. The most common entities with this pattern are miliary tuberculosis, pneumoconiosis, sarcoidosis, metastases, and hypersensitivity pneumonia. According to the distribution of the nodules in relation to the secondary lobule, high-resolution computed tomography findings divide miliary patterns into 3 groups: centrilobular, perilymphatic, and random presentation. The radiologic features that help in the differential diagnosis are discussed.

Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema.

Previously, it had been shown that T-lymphocytes are the predominant inflammatory cells found in the alveolar wall of smokers and their numbers correlated with the extent of emphysema. However, the phenotype of these cells was not defined. The aim of this study was to describe the different T-cell phenotypes and investigate the possible presence of apoptosis in the lung parenchyma of smokers. Samples from lungs were obtained at surgery from 15 patients who smoked and six who had never smoked. Samples were frozen and prepared for histological and immunocytochemical examination. Slides were stained for CD3+, CD4+, CD8+, gammadelta T-cells, CD56 natural killers ((NK) cells), and elastase (neutrophils). Anti-CD95 monoclonal antibodies and in situ end-labelling techniques were used to detect Fas expression and apoptosis. Positive staining cells were expressed as cells-mm alveolar wall-, percentage of total cells, and Fas/APO and apoptosis index. Emphysema was identified macroscopically, microscopically and reported as present or absent. All subjects had pulmonary function tests before surgery. Neutrophils were the predominant cell in the lung parenchyma of nonsmokers and smokers without emphysema. In smokers with emphysema, the CD3+ and CD8+ were the predominant cells (p<0.05) in the alveolar wall. gammadelta cells were increased in all smokers and no increased numbers of NK cells was found. The T-cell numbers x mm alveolar wall(-1) showed a bilinear relationship with the amount smoked increasing at an inflection point of 30 packs yr(-1) (R2= 0.345; p < 0.01). Apoptosis in smokers showed a bilinear relationship with the amount smoked increasing sharply in smokers with emphysema (R2=0.3613; p < 0.009). It is concluded that the pathogenesis of emphysema might be mediated by T-lymphocytes, mainly CD8+ cytolytic T-cells, and that apoptosis might be one of the mechanisms of lung destruction leading to the development of emphysema. If this is the case, it could be speculated that T-cell inflammation is a response to antigenic stimuli originating in the lung and induced by cigarette smoking.

Elastofibroma dorsi as a cause of shoulder pain or snapping scapula.

Elastofibroma dorsi is a benign soft tissue tumor, not well-known because of its low incidence, located in the chest wall in the subscapular area. In 10 patients with elastofibroma dorsi, the clinical symptoms were snapping scapula or shoulder pain. In three of the patients, the previous diagnosis was shoulder impingement, and the patients were treated without success. The clinical diagnosis was confirmed by magnetic resonance imaging. Surgical treatment resolved the symptoms in all patients. This tumor should be considered in the differential diagnosis of snapping scapula or shoulder impingement.

Osteoid osteoma of the coracoid process.

Osteoid osteoma is a small, benign, and painful tumor most commonly affecting the extra-articular portions of the long bones, especially the femur or tibia. Osteoid osteoma of the coracoid process is so rare that we have found only three previously reported cases in the international literature. We describe our experience in managing a case of osteoid osteoma in this unusual location.

[Lymphangioleiomyomatosis: study of 15 patients]. / Linfangioleiomiomatosis: estudio de 15 pacientes.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is an uncommon disease of not well-known evolution. We describe the clinical features and follow-up of a group of patients diagnosed of LAM in a hospital pulmonary transplantation programme. PATIENTS AND METHODS: 15 women (mean age: 43, range: 36-52) diagnosed of LAM, 9 at the Hospital Vall d'Hebron and 6 referred from other hospitals, for preoperative evolution of lung transplantation, were retrospectively studied. RESULTS: Dyspnea appeared in all cases and it was the main symptom. Pleural problems in the early evolution of the disease were also very frequent (12 out of 15 patients). For this reason, pleurodesis was performed in 7 patients and pleurectomy in 2 (one of them bilateral). Thoracic CT scan showed very characteristic cystic images and abdominal CT proved the presence of extrathoracic associated angiomyolipomas in one case. In two patients, LAM was diagnosed after studying the explanted lung. These two patients had been previously misdiagnosed of emphysema and pulmonary haemosiderosis. Survival since the beginning of symptoms was 82 and 49%, 5 and 10 years later, respectively. Six out of eight patients who underwent lung transplantation had a long postoperative survival. CONCLUSIONS: LAM seems to be as infrequent in Catalunya as in other countries, even if some cases could be misdiagnosed. Lung transplantation is useful in the advanced stages of the disease and, in our experience, it has improved respiratory insufficiency in half of the patients.

[Langerhans cell histiocytosis. Clinical longitudinal study of 21 patients]. / Histiocitosis de células de Langerhans. Estudio clínico y evolución a largo plazo de 21 pacientes.

BACKGROUND: Clinical data of patients with Langerhans cell histiocytosis are well established, although new diagnostic methods and specially long term evolution of the disease with lung involvement are not well-known. METHODS: In all cases, patients were diagnosed by means of pathologic study of the lung samples, either by transbronchial biopsy in 7 patients, or by surgical lung biopsy in 8 patients. Six patients were diagnosed by bone biopsy. Other patients were diagnosed by bronchoalveolar lavage (BAL). In 4 patients, who underwent BAL, the study of antibodies CD1 (CD1a) was positive (> 5%). Lymphocytopenia was detected in 28% of patients, whereas no decrease in delayed cutaneous hypersensitivity tests was detected in any of them. After a follow-up study of 12.8 years (range: 4-22 years), 7 patients had dead, 6 patients showed severe lung involvement and other 5 patients did not have lung affection. CONCLUSIONS: The diagnosis of Langerhans cell histiocytosis has improved by detection of immunologic and histochemical markers recently introduced. The study of the delayed cutaneous hypersensitivity tests did not show anergy or hipoergy. Long term evolution of patients with lung involvement is poor.

[Granulocytic sarcoma: unusual form of presentation for acute nonlymphoblastic leukemia]. / Sarcoma granulocítico: Forma infrecuente de presentación de la leucemia aguda no linfoblástica.

A case of acute non-lymphoblastic leukaemia is reported which appeared as granulocytic sarcoma (GS) with no leukaemic expression in peripheral blood. Aside of the patient's advanced age, the rarity of this entity at the onset of ANLL and the location of the tumour, on the back of the patient's left upper thigh are outstanding features. The difficult diagnosis of such non-leukaemic cases is also stressed here, with regard to the differential diagnosis with non-Hodgkin's lymphoma (NHL). It is concluded that the incidence of GS as a tumour of soft tissues in the extremities is more common in patients over 75 years of age, its frequency being 17-fold that of NHL for the same age and location.