Omission of excisional therapy is associated with an increased risk of invasive cervical cancer after cervical intraepithelial neoplasia III.

BACKGROUND: Using data from the population-based Geneva Cancer Registry we evaluated the risk of invasive cervical cancer following carcinoma in situ (CIS) or cervical intraepithelial neoplasia (CIN) III according to type of treatment. METHODS: Included in the study were all women diagnosed with CIS/CIN III in Geneva (Switzerland) between 1970 to 2002 (n=2658) and followed for invasive cervical cancer occurrence until 31st December 2008. We calculated age and period standardised incidence ratios (SIR) and multiadjusted hazard ratios (HR) of invasive cervical cancer by treatment groups. RESULTS: During follow-up, 17 women developed invasive cervical cancer, conferring a SIR of 5.1 (95% confidence intervals [CI] 3.0-8.1). The risk of cervical cancer was significantly increased until 10 years after diagnosis. The risk was highest for women ≥ 50 years (SIR=7.3, 95% CI: 2.7-15.8) and for women who did not undergo excisional treatment (SIR=25, 95% CI: 12.0-46.0). The multiadjusted HR of invasive cervical cancer for women who did not undergo surgical excisional treatment was 9.4 (95% CI: 2.8-32.2) compared with women who did. CONCLUSION: Women diagnosed with CIS/CIN III are at increased risk of developing invasive cervical cancer. This risk is particularly high for women who did not have excision of cervical lesions.

[Targeted therapy in lung cancer: molecular testing using cytological specimens]. / Thérapies ciblées du cancer pulmonaire: tests moléculaires à partir d'échantillons cytologiques.

Important advances in lung cancer treatment have been made over the last decade. Several drugs designed to target molecular pathways involved in cancer-cell growth and survival have been shown to be effective in a selected fraction (<20%) of non-small cell lung cancer patients. Somatic mutations in several genes (i.e.: EGFR and KRAS) can predict patient's response to targeted therapies. Those mutations are commonly detected on histopathological samples (core-needle biopsy/ surgical resection). However, when tissue biopsies are not available, molecular testing has to be performed on cytological specimens. Issues raised by molecular testing on cytological specimen are discussed in this article.

[Fine needle aspiration of the thyroid: the value of on-site evaluation]. / Ponction à l'aiguille fine de la thyroïde: intérêts de l'évaluation cytologique immediate.

Thyroid nodules are very common in the general population and most of them are benign. Fine needle aspiration (FNA) of the thyroid is routinely used because it is a rapid, simple, accurate and cost-effective technique which allows the adequate selection of patients who should be managed surgically. However, the diagnostic yield of FNA is variable and depends of multiple factors including the one who performs FNA, the aspiration and cytological slide preparation techniques, and cytopathologist's experience. On-site evaluation of thyroid FNA material and close clinico-pathological collaboration offer many advantages and optimizes the yield of FNA.

Late adult onset of Langerhans cell histiocytosis mimicking glioblastoma multiforme.

Langerhans cell histiocytosis (LCH) with multiple organ involvement is a rare disorder in adults. Extrapituitary involvement of the central nervous system (CNS) is uncommon. We report the unusual case of a 55-year-old woman presenting with a left-sided hemiataxia-hemiparesis, left hemisensory loss and short-lasting episodes of an alien left hand due to lesions of the internal capsule and the right thalamus, extending into the mesencephalon associated with extensive surrounding edema, without pituitary involvement. The neuroradiological image suggested glioblastoma multiforme. Brain biopsy revealed inflammatory tissue and "pseudotumoral" multiple sclerosis was suspected. Biopsy of concomitant lung and bone lesions disclosed Langerhans cell histiocytosis. The treatment with pulsed steroids in association with mycophenolate mofetil led to a sustained, clinical neurological remission.

Diverse glandular pathologies coexist with high-grade squamous intraepithelial lesion in cyto-histological review of atypical glandular cells on ThinPrep specimens.

OBJECTIVE: To identify in cytology, high-grade squamous intraepithelial lesions with endocervical glandular extension in cases previously diagnosed as atypical glandular cells (AGC), analyse possible reasons for the diagnostic pitfall and document the frequency of glandular pathology coexisting with high-grade cervical intraepithelial lesion in histology. METHODS: Thirty-nine ThinPrep cervical smear (Pap) tests reported as AGC of undetermined significance and showing high-grade lesions on histology [cervical intraepithelial neoplasia (CIN) 2 or 3, endometrial or extrauterine adenocarcinoma] were reviewed retrospectively to identify the cases of high-grade squamous intraepithelial lesion with endocervical glandular extension, using the Bethesda 2001 system. Cyto-histological correlation was performed. RESULTS: A high frequency of diverse glandular pathologies coexisted with high-grade cervical intraepithelial lesions on histology. This included endocervical glandular extension in 63%, benign glandular pathology in 33% and pre-neoplastic or malignant glandular pathology (endocervical glandular dysplasia, adenocarcinoma in situ and metastatic breast carcinoma) in 17% cases. On cytology, the sensitivity was 40%, specificity was 80% and positive predictive value was 86% for endocervical gland extension in high-grade squamous intraepithelial lesions. CONCLUSIONS: Special efforts to recognize endocervical glandular extension in high-grade squamous intraepithelial lesions and glandular neoplasia coexisting with squamous intraepithelial lesions from the heterogeneous category of AGC can contribute to increasing the diagnostic accuracy. The identification of endocervical glandular extension on cervical cytology would alert the gynaecologist to perform a thorough assessment of the endocervix during colposcopy. This could also help to decide on the need to perform deeper conization rather than loop electrosurgical excision procedure to ensure negative margins when colposcopic biopsy shows CIN 2 or 3.

Cytology of benign multicystic peritoneal mesothelioma in peritoneal washings.

OBJECTIVE: To describe the cytological aspect of peritoneal washings in benign multicystic peritoneal mesothelioma (BMPM). METHODS: Three peritoneal washing specimens stained by standard cytological and histological procedures and analysed by light microscopy. RESULTS: The specimens showed an abundance of monomorphous mesothelial cells devoid of atypia or mitoses. The mesothelial cells were calretinin positive. They also showed numerous squamous metaplastic cells arranged in flat sheets or isolated cells. The background contained some inflammatory cells. CONCLUSION: The combination of cytology of the peritoneal washing, histology (cell block and surgical specimen) and clinical history allow differentiation of BMPM from other cystic lesions (cystic lymphangioma and malignant mesothelioma).

Bronchoalveolar cytology for diagnosing pulmonary GVHD after bone marrow transplant in children.

BACKGROUND: Cytological composition of bronchoalveolar lavage (BAL) fluid in pediatric bone marrow transplant (BMT) recipients with pulmonary complications has not been comprehensively described and BAL specific markers of pulmonary GVHD are lacking. The aim of this retrospective study was to assess the role of BAL in the diagnosis of pulmonary GVHD by comparing BAL cytological findings between pediatric allogenic BMT patients with pulmonary complications and oncology children receiving chemotherapy alone. METHODS: Retrospective analysis of BAL specimens for cytology, total and differential cell counts and presence of infections. RESULTS: Seventeen BMT and 13 chemotherapy BAL were analyzed. BAL total cell count was increased but similar between groups (96.9 x 10(4) vs. 98.2 x 10(4), P = NS). BAL cellular composition differed considerably between groups with a significantly higher number of lymphocytes (18% vs. 6.25%, P = 0.03) and a significantly lower number of neutrophils (25.9% vs. 58%, P = 0.02) in BMT BAL specimens. Atypical epithelial cells were significantly more frequent (75% vs. 30.8%, P = 0.027), and significantly more severe (P = 0.01) in BMT patients. The presence and severity of atypia was not associated with infection or pneumotoxic drug exposure (P = NS). CONCLUSION: BAL cytology differs significantly between BMT and chemotherapy patients. The presence BAL lymphocytosis and severe epithelial cell atypia concomitantly to respiratory symptoms and GVHD in other organs may suggest the diagnosis of pulmonary GHVD. Prospective studies assessing the reliability of this finding combined with markers such as epithelial cell apoptosis and increased cytokines are needed.

Primary intrapulmonary thymoma: a systematic review.

AIM: This article reviews the literature on the clinical features, diagnosis and management of primary intrapulmonary thymoma. METHODS: Medline, Embase and Cochrane Library searches were performed on all relevant Anglo-Saxon language articles. The search words included "primary pulmonary thymoma" and "intrapulmonary thymoma". Secondary references were obtained from key articles. Prognostic and treatment strategies were analyzed by the Kaplan-Meier method, comparisons between curves were made using log rank test. RESULTS: The searches yielded 25 cases of primary intrapulmonary thymoma. Median follow-up was 9 months (1 day to 13 years). At follow-up, 14 patients were tumor free, one patient had a local recurrence 8 years after radiotherapy, one patient responded favorably to radiotherapy, six patients died and three patients were lost to follow-up. The presence of a paraneoplastic syndrome decreased survival (P=0.02), however, histological subgroup (P=0.216), clinical stage (P=0.63) and tumor size (P=0.288) did not affect survival. Survival in surgically managed patients was significantly better than in conservatively managed patients (P=0.039). Adjuvant radiotherapy did not provide any benefit (P=0.4). CONCLUSION: Complete resection of primary intrapulmonary thymomas appears sufficient in non-malignant tumors. Because of the risk of late local recurrence, long-term regular clinical follow-up is warranted.

Development of a quantitative TaqMan RT-PCR for respiratory syncytial virus.

Respiratory syncytial virus (RSV) is a ubiquitous RNA virus of the family Paramyxoviridae that may interfere with graft tolerance and with other interstitial lung diseases. The low viral titre observed in the immunodeficient transplanted patients requires a highly sensitive detection method. Although different tests already exist for the detection of RSV, reverse transcription-polymerase chain reaction (RT-PCR) has been shown to have the best sensitivity. In this study, a SYBR Green assay was established for the detection of RSV A and RSV B in a common screening test, and two quantitative TaqMan RT-PCRs were developed to quantify both RSV subgroups separately. Standard dilutions obtained from RSV cell infections were included in each test, and the assay was normalised using a housekeeping gene. RSV was found in 16% of the transplanted patients tested. The quantitative TaqMan assay is fast, reproducible, specific and very sensitive, and could facilitate considerably the detection of RSV virus. This would in-turn facilitate studies on the role of RSV in graft rejection.

Carcinoma arising in congenital lung cysts.

We report on a patient presenting with a bronchioloalveolar carcinoma fortuitously detected in the wall of a bronchogenic cyst. Evidence suggests that unstable epithelial cells contained within the cyst wall may lead to premalignant proliferation and neoplasia. In the current case, we demonstrated an increased proliferative activity in some areas of the cyst consistent with atypical adenomatous hyperplasia. Hence, we stress the importance of close follow-up of all suspected congenital lung cysts because of their potential malignant degeneration.

Fungal infections in transplant recipients.

Fungi are ubiquitous and the respiratory tract is exposed to aerosolized spores of both fungi that are "pathogenic" even in the normal host, such as Cryptococus neoformans, and those that are "opportunistic", such as Candida and Aspergillus species, among others. Although these latter species may occasionally form fungal balls or induce allergic phenomena in the normal host, they produce more invasive diseases in immunosuppressed patients. Among these diseases, pseudomembranous aspergillosis has recently been described. The diagnostic approach to these entities, and, in particular, the thin dividing line between colonization and infection are addressed, along with the diagnostic value of the various procedures. New prophylactic regimens are reviewed such as the possibility of using amphotericin aerosols in combination with systemic azole administration. The authors would emphasize the importance of restoring lung defences by not only decreasing immunosuppressive regimens but also considering the use of newly available recombinant cytokines such as growth factors, to reduce neutropenia, for instance, in addition to antifungal drugs when infection is diagnosed. However, immunomodulation procedures are far from being well established.

Short- and long-term results of total vs subtotal thyroidectomies in the surgical treatment of Graves' disease.

OBJECTIVE: Approximately one out of five patients with Graves' disease (GD) undergoes a thyroidectomy after a mean period of 18 months of medical treatment. This retrospective and non-randomized study from a teaching hospital compares short- and long-term results of total (TT) and subtotal thyroidectomies (ST) for this disease. METHODS: From 1987 to 1997, 94 patients were operated for GD. Thirty-three patients underwent a TT (mostly since 1993) and 61 a ST (keeping 4 to 8 grams of thyroid tissue--mean 6 g). All patients had received propylthiouracil and/or neo-mercazole and were in a euthyroid state at the time of surgery; they also took potassium iodide (lugol) for ten days before surgery. RESULTS: There were no deaths. Transient hypocalcemia (< 3 months) occurred in 32 patients (15 TT and 17 ST) and persistent hypocalcemia in 8 having had TT. Two patients developed transient recurrent laryngeal nerve palsy after ST (< 3 months). After a median follow-up period of seven years (1-15) with five patients lost to follow-up, 41 patients having had a ST are in a hypothyroid state (73%), thirteen are euthyroid (23%), and two suffered recurrent hyperthyroidism, requiring completion of thyroidectomy. All 33 patients having had TT--with follow-ups averaging two years (0.5-8)--are receiving thyroxin substitution. CONCLUSIONS: There were no instances of persistent recurrent laryngeal nerve palsy in either group, but persistent hypoparathyroidism occurred more frequently after TT. Long after ST, hypothyroidism developed in nearly three of four cases, whereas euthyroidy was maintained in only one-fourth; recurrent hyperthyroidy was rare.

Role of the distal balloon protection technique in the prevention of cerebral embolic events during carotid stent placement.

BACKGROUND AND PURPOSE: We sought to quantitatively and qualitatively evaluate the release of atheromatous plaque debris induced by carotid stenting procedures. METHODS: Eight patients with severe carotid atheromatous stenoses were treated by stent implantation under distal balloon protection. Blood samplings were obtained after stent deployment in the blood pooled below the inflated protection balloon. The samples were centrifuged and evaluated for plaque debris with the use of light microscopy. The debris release was quantitatively estimated by dividing the total volume of debris obtained by the mean debris size. Five patients without endovascular procedure were used as a control group. RESULTS: The 2 main debris types found were nonrefringent cholesterol crystals (4 to 389 microm; 115 to 8697 in number) and lipoid masses (7 to 600 microm; 341 to 34 000 in number). There was a statistically significant difference compared with the samples obtained in the control group (P:=0.017). CONCLUSIONS: Blood samples collected during stent implantation procedures contain a large quantity of atheromatous plaque debris. This emphasizes the role of distal protection techniques in avoiding migration of this plaque material into the cerebral circulation.

Matrix metalloproteinases correlate with alveolar-capillary permeability alteration in lung ischemia-reperfusion injury.

BACKGROUND: Matrix metalloproteinases (MMPs) are able to degrade the endothelial basal lamina and increase vascular permeability. METHODS: In a porcine model of isolated-reperfused lung, we studied the alveolar-capillary permeability and the zymographic expression of MMP-9 and MMP-2 in the bronchoalveolar lavage fluid of lungs submitted ex vivo to ischemia in three preservation solutions [modified Euro-Collins (EC), low-potassium-dextran, modified-blood]. Twenty-two pigs were randomly divided into three groups according to the preservation solution used. One lung of each pig was rapidly reperfused and analyzed (control lung) although the other lung was reperfused and analyzed after 8 hr of ischemia (ischemic lung). RESULTS: Alveolar-capillary permeability, evaluated by the transferrin leak index, was increased after 8 hr of ischemia compared with controls in the three groups, but was significantly higher in the modified EC group. In the EC group, after 8 hr of ischemia, both proMMP-9 and MMP-9 increased significantly (8.8- and 22-fold, respectively) compared with controls and this increase correlated with the transferrin leak index. Neither proMMP-9 nor MMP-9 increased with the other two preservation solutions. The MMP-2 increase after ischemia was smaller and was also restricted to the EC group. CONCLUSION: MMP expression is enhanced during lung ischemia-reperfusion, especially in the presence of EC and this phenomenon correlates with the alteration of alveolar-capillary permeability.

Lung recruitment and lung volume maintenance: a strategy for improving oxygenation and preventing lung injury during both conventional mechanical ventilation and high-frequency oscillation.

OBJECTIVE: To determine whether using a small tidal volume (5 ml/kg) ventilation following sustained inflation with positive endexpiratory pressure (PEEP) set above the critical closing pressure (CCP) allows oxygenation equally well and induces as little lung damage as high-frequency oscillation following sustained inflation with a continuous distending pressure (CDP) slightly above the CCP of the lung. MATERIAL AND METHODS: Twelve surfactant-depleted adult New Zealand rabbits were ventilated for 4 h after being randomly assigned to one of two groups: group 1, conventional mechanical ventilation, tidal volume 5 ml/kg, sustained inflation followed by PEEP > CCP; group 2, high-frequency oscillation, sustained inflation followed by CDP > CCP. RESULTS: In both groups oxygenation improved substantially after sustained inflation (P < 0.05) and remained stable over 4 h of ventilation without any differences between the groups. Histologically, both groups showed only little airway injury to bronchioles, alveolar ducts, and alveolar airspace, with no difference between the two groups. Myeloperoxidase content in homogenized lung tissue, as a marker of leukocyte infiltration, was equivalent in the two groups. CONCLUSIONS: We conclude that a volume recruitment strategy during small tidal volume ventilation and maintaining lung volumes above lung closing is as protective as that of high-frequency oscillation at similar lung volumes in this model of lung injury

Systemic pulmonary artery shunt using a bovine mesenteric venous graft in newborns.

A new bovine mesenteric venous graft 3 or 4 mm in diameter was used for performing systemic pulmonary artery shunts in six cyanotic newborns (aged 2 to 30 days) from March 1997 onward. Clinical and echocardiographic studies proved that all shunts were patent and functioning well after an average of 8.8 months despite no postoperative anticoagulation or antiplatelet regimen. Histological examination of two grafts explanted at the time of bidirectional cavopulmonary anastomosis showed no dense fibrotic mural infiltration, calcification, or anastomotic hyperplasia. Bovine mesenteric venous grafts can be used for the construction of systemic pulmonary artery shunts with advantages similar to that of human vein allografts, such as the facility of implantation, good short- and mid-term patency, easy takedown, and avoidance of complications presumably specific to polytetrafluoroethylene.

Keratinocyte growth factor protects alveolar epithelium and endothelium from oxygen-induced injury in mice.

Keratinocyte growth factor (KGF) has been used successfully to prevent alveolar damage induced by oxygen exposure in rodents. However, this treatment was used intratracheally and before oxygen exposure, which limited its clinical application. In the present study, mice were treated with the recombinant human KGF intravenously before (days -2 and -1) or during (days 0 and +1) oxygen exposure. In both cases, lung damage was attenuated. KGF increased the number of cells incorporating bromodeoxyuridine (BrdU) in the septa and in bronchial epithelium of air-breathing mice but not of oxygen-exposed mice, indicating that the protective effect of KGF is not necessarily associated with proliferation. Oxygen-induced damage of alveolar epithelium and, unexpectedly, of endothelium was prevented by KGF treatment as seen by electron microscopy. We investigated the effect of KGF on different mechanisms known to be involved in oxygen toxicity. The induction of p53, Bax, and Bcl-x mRNAs during hyperoxia was to a large extent prevented by KGF. Surfactant proteins A and B mRNAs were not markedly modified by KGF. The anti-fibrinolytic activity observed in the alveoli during hyperoxia was to a large extent prevented by KGF, most probably by suppressing the expression of plasminogen activator inhibitor-1 (PAI-1) mRNA and protein. As PAI-1 -/- mice are more resistant to hyperoxia, KGF might act, at least in part, by decreasing the expression of this protease inhibitor and by restoring the fibrinolytic activity into the lungs.

Physiological changes in respiratory function associated with ageing.

Physiological ageing of the lung is associated with dilatation of alveoli, enlargement of airspaces, decrease in exchange surface area and loss of supporting tissue for peripheral airways ("senile emphysema"), changes resulting in decreased static elastic recoil of the lung and increased residual volume and functional residual capacity. Compliance of the chest wall diminishes, thereby increasing work of breathing when compared with younger subjects. Respiratory muscle strength also decreases with ageing, and is strongly correlated with nutritional status and cardiac index. Expiratory flow rates decrease with a characteristic alteration in the flow-volume curve suggesting small airway disease. The ventilation-perfusion ratio (V'A/Q') heterogeneity increases, with low V'A/Q' zones appearing as a result of premature closing of dependent airways. Carbon monoxide transfer decreases with age, reflecting mainly a loss of surface area. In spite of these changes, the respiratory system remains capable of maintaining adequate gas exchange at rest and during exertion during the entire lifespan, with only a slight decrease in arterial oxygen tension, and no significant change in arterial carbon dioxide tension. Ageing tends to diminish the reserve of the respiratory system in cases of acute disease. Decreased sensitivity of respiratory centres to hypoxia or hypercapnia results in a diminished ventilatory response in cases of heart failure, infection or aggravated airway obstruction. Furthermore, decreased perception bronchoconstriction and diminished physical activity may result in lesser awareness of the disease and delayed diagnosis.