[Acquired alpha-thalassemia in an 86-year-old patient with myelodysplastic syndrome]. / Une alpha thalassémie acquise chez un patient de 86 ans avec un syndrome myélodysplasique.

BACKGROUND: Alpha thalassemia-myelodysplastic syndrome (ATMDS) is one of the possible complications related to the genetic instability typical of clonal hemopoietic disorders such as myelodysplastic syndromes (MDS). Hemoglobin H acquisition, which is hemoglobin without alpha chains and with 4 beta chains is the hallmark of this disease. OBSERVATION: An 86-year-old male with chronic, microcytic anemia was referred due to a fall in his hemoglobin level. The blood smear was remarkable for intense anisocytoses and poikilocytosis. Bone marrow analysis was followed by a diagnosis of MDS with a good prognostic score. Peripheral blood coloration with brilliant cresyl blue showed "golf ball-like" erythrocytes. Hemoglobin electrophoresis is notable for the presence of H hemoglobin. The new generation sequencing confirmed the diagnosis of ATMDS showing a non-sense mutation in the gene ATRX. CONCLUSION: The diagnosis of ATMDS should be considered in the presence of the association of MDS, microcytic anemia and marked blood smear abnormalities such as anisocytosis and poikilocytosis. A little less than 10% of all MDS are complicated by ATMDS.

Thermal considerations in murine tumor killing using hematoporphyrin derivative phototherapy.

Tumor cell killing utilizing hematoporphyrin derivative (HPD) phototherapy was studied in a murine tumor model to assess the relative importance of intratumor temperature in causing the tumoricidal effect. Temperature measurements and tumor killing without HPD strongly suggest that HPD phototherapy as reported previously by other workers has at least partially a hyperthermic effect. Also, it is shown that, in this tumor model, tissue light attenuation restricts the radius of action of the light-HPD interaction to approximately 4 mm.

Photodynamic effect of hematoporphyrin derivative as a function of optical spectrum and incident energy density.

Tumor cell killing effect of hematoporphyrin derivative (HPD) and light was studied in culture to determine the dependence of this effect on treatment variables. Particular attention has been given to the spectral characteristics of the light and the absorption properties of hematoporphyrin. A human tumor cell line was treated using HPD and three broad bands of light ranging from the short- to the long-wavelength end of the visible spectrum. Cell killing was assessed by trypan blue exclusion. A transformed mouse embryo cell line was treated in a similar manner, and its reproductive efficiency was determined following treatment. Results of both studies are consistent with the hypothesis that the photocytotoxic action of HPD plus light is directly proportional to the number of light quanta absorbed by the HPD in each cell. For thin layers of cells, such as in situ carcinoma, it appears that short-wavelength radiation falling in the porphyrin Soret band around 400 nm may have from 12 to 30 times the killing power as does red light.

Recurrent mutations refine prognosis in chronic lymphocytic leukemia.

Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

Management of malignant airway obstruction: clinical and dosimetric considerations using an iridium-192 afterloading technique in conjunction with the neodymium-YAG laser.

Fourteen patients with malignant airway obstruction have had 21 placements of a flexible nylon catheter for afterloading Iridium-192 using the flexible fiberoptic bronchoscope. Prescribed therapy was completed in 13 patients (18 courses). All patients had prior full-dose external irradiation, and no effective surgical or chemotherapeutic options remained. While many have had a trial of neodymium-YAG (yttrium-aluminum-garnet) laser therapy alone, eight patients received laser treatment one to three weeks prior to planned brachytherapy to provide immediate relief of symptoms and/or facilitate access and safe catheter placement. Most patients (64%) had recurrent squamous cell lung cancer. A dose of 3000 cGy is currently specified to 5 mm and 10 mm in the bronchus and trachea, respectively. Nine of the 13 treated patients have had follow-up bronchoscopy at approximately three months post-treatment with improvement documented in seven and progression in two patients. One patient was clinically improved without follow-up bronchoscopy, and three patients have had insufficient follow-up. A single patient treated with laser and 6000 rad at 5 mm developed a bronchoesophageal fistula. No other complication has been observed. The technique is simple and safe with the use of laser therapy when needed and appears to offer effective palliation in most patients even when standard therapy is exhausted.

Pulmonary function in mitral stenosis.

The reported results of pulmonary function testing in patients with mitral stenosis are summarized, including a few studies done after operative correction of the mitral stenosis. The physiologic effects of increased pulmonary water explain most of the reversible abnormalities in pulmonary function. Fixed pathologic changes that occur with longstanding interstitial edema may account for the irreversible nature of other alterations in pulmonary function.

Severe hypoxemia associated with liver disease: Mayo Clinic experience and the experimental use of almitrine bismesylate.

Severe hypoxemia associated with chronic liver disease is an uncommon disorder most likely due to an intrapulmonary vascular abnormality that has characteristics of both ventilation-perfusion mismatching and diffusion limitation. Anatomically, the intrapulmonary vascular abnormalities can occasionally be detected by angiography. Physiologically, the gas exchange abnormalities can be substantiated by contrast-enhanced two-dimensional echocardiography. Although orthodeoxia and platypnea have frequently been found in these patients, echocardiographic data suggest that vascular abnormalities can exist in the absence of orthodeoxia. We describe 11 patients who had severe hypoxemia and chronic liver disease and review their pulmonary angiographic, contrast echocardiographic, and arterial blood gas findings. Among five of these patients who were given almitrine bismesylate, an experimental medication thought to alter ventilation-perfusion relationships in patients with chronic obstructive pulmonary disease, one had improved oxygenation. We recommend that patients with hypoxemia associated with chronic liver disease have detailed studies to rule out reversible forms of hypoxemia and that those with severe hypoxemia undergo testing to determine the existence of intrapulmonary vascular abnormalities, especially if liver transplantation is considered.

Bronchoscopic phototherapy with hematoporphyrin derivative for treatment of localized bronchogenic carcinoma: a 5-year experience.

Between December 1980 and April 1986 at our institution, 38 patients with cancer that involved the tracheobronchial tree (a total of 40 carcinomas) completed at least one course of hematoporphyrin derivative phototherapy. A complete response occurred in 13 patients (with 14 carcinomas). Eleven of these carcinomas did not recur during follow-up periods that ranged from 3 to 53 months. Three carcinomas recurred at 9, 12, and 35 months, respectively. For 26 carcinomas, the response was less than complete, and alternative therapy was necessary. The carcinomas in patients with a complete response were radiographically occult, were less than 3 cm2 in surface area, and appeared superficial at bronchoscopy. Our experience supports the use of hematoporphyrin derivative phototherapy as an alternative to surgical resection in carefully selected patients.

Endoscopic management of lung cancer with hematoporphyrin derivative phototherapy.

This paper demonstrates the potential use of hematoporphyrin derivative in the phototherapy of bronchogenic cancer. We report on 10 patients (a total of 11 carcinomas) with cancer involving the tracheobronchial tree who completed one course of this new treatment administered via the flexible fiberoptic bronchoscope. Four superficial carcinomas showed a complete response; five larger carcinomas showed a partial response, Two patients, each with a large cancer extending beyond the bronchial wall, died within 11 days after treatment.

Neodymium-YAG laser therapy of malignant airway obstruction. A preliminary report.

Neodymium-YAG laser therapy of malignant obstructing airway lesions via a flexible endoscope offers a promising new means of treatment. Twenty-two patients with obstructing airway lesions were treated. Two fatal complications occurred. The patients experienced increased comfort in breathing, increased exercise tolerance, and more effective cough with clearance of secretions. Treatment of larger numbers of patients with careful monitoring of the results should be performed to define further the usefulness, complications, and limitations of this new therapeutic tool.

Pulmonary aspects of chronic liver disease and liver transplantation.

A vast spectrum of pulmonary pathologic conditions occurs in association with chronic liver diseases, and clinically important manifestations, such as arterial hypoxemia, can result. Both pulmonary vascular and parenchymal abnormalities can contribute to the dysfunction, as evidenced by results of pulmonary function tests and gas exchange studies. The clinical implications of identifying such pulmonary problems range from alleviation of symptoms, especially dyspnea, to comprehensive assessment of patients before and after liver transplantation. Physicians should be aware of these potential pulmonary disorders that can complicate liver disease and liver transplantation so that management of affected patients can be improved.

Ancillary therapies in the management of lung cancer: photodynamic therapy, laser therapy, and endobronchial prosthetic devices.

Endoscopic therapy for cancer that involves the tracheobronchial tree is currently available for two distinct types of lesions: radiographically occult superficial squamous cell carcinoma and advanced malignant tumors that cause severe airway obstruction. Photodynamic therapy, which uses a photosensitizing agent, is effective for managing early superficial squamous cell carcinoma. Neodymium:yttrium-aluminum-garnet laser therapy has been effective in the palliative management of patients with advanced or recurrent malignant obstructive airway lesions, either alone or in combination with intraluminal radiation therapy. Most recently, endobronchial prosthetic devices (stents) have been used in patients with advanced airway obstruction. The use of each of these modalities in the management of lung cancer is reviewed.

Photodynamic therapy for early stage squamous cell carcinoma of the lung.

OBJECTIVE: To study the effectiveness of photodynamic therapy (PDT) as a therapeutic strategy in roentgenographically occult squamous cell carcinoma of the lung. MATERIAL AND METHODS: A carefully selected group of 21 patients (with 23 cancers) who had early stage squamous cell carcinoma of the lung and were eligible for surgical treatment were offered PDT as an alternative to resection. Patients underwent close follow-up with bronchoscopic surveillance and were offered resection if cancer persisted after no more than two sessions of PDT. RESULTS: A complete response was identified in 15 patients (16 cancers) after an initial PDT session. A complete response that lasted longer than 12 months was noted in 11 patients (52%). After PDT, the minimal follow-up period was 24 months. A subsequent primary lung cancer developed in 5 of the 21 patients (24%). Ten patients ultimately had surgical treatment, in 3 (30%) of whom N1 disease was identified at the time of resection. Two patients refused a surgical procedure and received alternative therapy. Therefore, nine patients (43%) were spared an operation (95% confidence interval, 21.8 to 66.6%). The mean duration of follow-up for these nine patients was 68 months (range, 24 to 116). CONCLUSION: On the basis of this investigation, we can conclude with 95% confidence that at least 22% of patients with early stage squamous cell lung cancer who are candidates for PDT can be spared surgical resection.

Pericardial reconstruction of the membranous trachea after resection of adenoid cystic carcinoma (cylindroma).

An intraluminal adenoid cystic carcinoma (cylindroma) in the patient reported herein involved just the membranous portion of the distal region of the trachea and extended caudally to include the carina and the membranous portions of both main-stem bronchi--a total linear involvement of 6 cm. The tumor occluded 90% of the airway in its greatest extension. Conservative resection of this extensive tumor was successfully performed by membranous tracheal reconstruction with a pedicled autogenous pericardial patch graft.

Detection of hematoporphyrin fluorescence during fiberoptic bronchoscopy to localize early bronchogenic carcinoma.

Photoelectric detection of fluorescence from hematoporphyrin-containing "occult" bronchogenic carcinoma is a potentially useful technique for localizing and delineating such cancers. A method is presented which would enable use of a fluorescence-detection system simultaneously with conventional illumination during flexible bronchofiberscopic examination. Preliminary data suggest that quantities of hematoporphyrin as small as 5 picograms can be detected on the surface of tumors by this method.

Transthoracic needle biopsy: accuracy and complications in relation to location and type of lesion.

Transthoracic needle biopsy has become a frequently used method for obtaining tissue for diagnosis of pulmonary lesions. The procedure carries an inherent risk of pneumothorax and hemorrhage, the latter usually manifested by transient hemoptysis. Data on 430 patients who underwent transthoracic needle aspirations from 1968 through 1977 were studied to determine accuracy and complications of this procedure as related to lesion type and location. Malilgnant disease, most often metastatic, was present in all but 10 patients. Also, 86% of patients were more than 50 years of age and most were not candidates for operation. Sufficient tissue for diagnosis was obtained in 82% of cases. The diagnostic yield diminished significantly in central lesions less than 2 cm in size. Pneumothorax and hemoptysis or pulmonary hemorrhage were the most common complications. Biopsy of central lesions, especially those in the mediastinum, were more often associated with pneumothorax, whereas lesions near the hilar region were more susceptible to hemorrhagic complications. Two deaths occurred, both from hemorrhage after biopsy in cavitating lesions with air/fluid levels. The incidence of pneumothorax was also higher in cavitating lesions. Fewer complications occurred with biopsy of lesions along the pleural surface and lesions in the periphery of the lung.

Monitoring and analysis of oxygenation and ventilation during rigid bronchoscopic neodymium-YAG laser resection of airway tumors.

Neodymium-YAG (yttrium-aluminum-garnet) laser resection of obstructing and inoperable tumors of the large airways is used as palliative therapy to improve the quality of survival in patients by alleviating airway obstruction. Rapid changes in oxygenation and ventilation can occur during these procedures. In a study of 14 patients, transcutaneous oxygen (PtcO2) and carbon dioxide (PtcCO2) monitors responded slowly to these changes and frequently provided misleading values. Pulse oximetry (SNO2) accurately reflected arterial oxygen saturation but did not indicate severe desaturation until arterial oxygen tension approached dangerously low values. Thus, we did not find PtcO2 or PtcCO2 monitoring to be clinically useful during neodymium-YAG laser resection of airway tumors through a rigid bronchoscope. SNO2 was clinically useful and accurate; however, a large decrement in oxygenation may occur before changes in oxygen saturation ensue and are detected.

Clinical application of a new endoscopic technique for detection of in situ bronchial carcinoma.

Hematoporphyrin is preferentially concentrated by cancer tissue and therefore is a potentially useful chemical marker. This report demonstrates the effectiveness of a photoelectric hematoporphyrin fluorescence detector used simultaneously with flexible fiberoptic bronchoscopy as a means of detecting and localizing bronchogenic carcinoma. The detector generates an audio signal when fluorescence is within the visual field of the bronchoscope. Of interest is that an audio signal was generated which indicated hematoporphyrin fluorescence in areas where no mucosal abnormality had been seen. These areas proved to be carcinoma in situ.

Detection and localization of In situ carcinoma of the bladder with hematoporphyrin derivative.

The extent and localization of in situ carcinoma of the urinary bladder are frequently difficult to assess. We have studied this problem by employing intravenous hematoporphyrin derivative, an endoscopic detection device, and complete pathologic bladder mapping. These preliminary investigations indicate that hematoporphyrin derivative localizes in dysplastic and neoplastic transitional cell epithelium and that these abnormal areas can be detected during a cytoscopic examination with the use of our detection device.

Frequency and clinical implications of increased pulmonary artery pressures in liver transplant patients.

OBJECTIVE: To characterize the pulmonary hemodynamics and identify predictors of pulmonary hypertension in a group of patients before liver transplantation and to determine whether pulmonary hypertension in these patients is related to survival. MATERIAL AND METHODS: In 362 patients before their first liver transplantation (between 1985 and 1993), the clinical history, laboratory data, and results of pulmonary function tests were recorded. Pulmonary artery (PA) catheterization was performed after induction of anesthesia at the time of transplantation. Monthly follow-up was maintained. RESULTS: A hyperdynamic circulation was often present -- an increased mean cardiac output (7.6 L/min), increased mean PA pressure (20.9 mm Hg), correlation of mean PA pressure with cardiac output (r = 0.25; P<0.001), and decreased mean pulmonary vascular resistance (60 dynes times s/cm5). Mean PA pressures were more than 25 mm Hg in 72 patients (20%). Pulmonary hypertension (defined as mean PA pressure of more than 25 mm Hg and pulmonary vascular resistance in excess of 120 dynes times s/cm5) occurred in 15 patients (4%). Pulmonary function tests revealed obstruction in 7%, restriction in 18%, and low diffusing capacity in 46%. By univariate analysis, lower forced expiratory volume in 1 second, forced vital capacity, and total lung capacity were the only preoperative factors associated with pulmonary hypertension (P<0.05). Survival was significantly lower in patients with acute fulminant hepatitis (P<0.001), the group with the highest mean PA pressure, than in those with other diagnoses. Increased PA pressures or mild to moderate pulmonary hypertension was not found to be associated with a worse survival by univariate or multivariate analysis. CONCLUSION: Increased PA pressure is common in liver transplant patients (20%). "True" pulmonary hypertension occurred in only 4% of our patients and was not associated with an adverse outcome.