p63 expression in assessment of bronchioloalveolar proliferations of the lung.

Discrimination of well-differentiated pulmonary adenocarcinoma from reactive bronchioloalveolar epithelium can be difficult on routine histology, especially with small biopsies. Ancillary studies to help in this distinction are desirable. p63, a p53-homologous nuclear protein, is a marker of reserve cells of the bronchus and terminal lobular unit. In this study, 33 cases of adenocarcinoma (20 open lung and 13 transbronchial/percutaneous biopsies) and 43 cases of benign lungs with fibrosis and metaplasia (22 open lung and 21 transbronchial/percutaneous biopsies) were studied for nuclear p63 expression by immunohistochemistry (Dako, Carpinteria, CA, USA). Five additional cases each of atypical adenomatous hyperplasia and adenosquamous carcinoma and three cases of squamous carcinoma (all open lung biopsies) were also stained. The diagnostic categories of benign lung conditions were usual interstitial pneumonia, parenchymal scar, cryptogenic organizing pneumonia and diffuse alveolar damage. In neoplastic cases, p63 positivity was calculated as percentage of all tumor cells examined. In areas of normal lung, p63 decorated the reserve cells of large and small airways and occasional cells of the distal lobular unit. In fibrotic reactive processes, an interrupted but distinct pattern of nuclear staining was present in all cases, with staining of basal cells of the airways as well as bronchiolar- and squamous-metaplastic epithelium (43/43, 100%). p63 immunoreactivity was less uniform in areas of acute lung injury within these cases. One adenocarcinoma and two cases of atypical adenomatous hyperplasia showed strong immunoreactivity (>80%), while three adenocarcinomas highlighted only rare tumor nuclei (<5% of tumor cells). Morphologic areas where p63 immunostaining was not helpful included the junction of normal lung and lepidic growth of adenocarcinoma, and retrograde spread of adenocarcinoma into small airways. Our results highlight the differential expression of p63 across various bronchioloalveolar lesions. Moreover, p63 may be helpful in distinguishing reactive from neoplastic glandular proliferations in the lung.     

Diminution in Kerosene-Mediated Induction of Drug Metabolizing Enzymes by Asbestos in Rat Lungs

Abstract: In order to determine the pulmonary toxicity of kerosene and its ignition product (soot) in asbestos exposed subjects, the activities of phase I and phase II drug metabolizing enzymes in rat lungs after single intratracheal coexposure to Indian chrysotile asbestos and kerosene or its soot and Indian chrysotile were assayed. Exposure to kerosene or its soot resulted in a significant increase in the level of microsomal cytochrome P-450 and the activity of P-450 dependent monooxygenase, benzo(a)pyrene hydroxylase, as well as in the activities of microsomal epoxide hydrase and cytosolic glutathione-S-transferase (GST). However, in chrysotile exposed animals a reverse pattern in these parameters was recorded. The co-exposure to chrysotile and kerosene or chrysotile and soot led to a significant depletion in cytochrome P-450 level and a decrease in the activities of benzo(a)pyrene hydroxylase, epoxide hydrase and GST when compared to kerosene and soot controls, respectively. These results suggest that asbestos by altering the pulmonary drug metabolizing enzyme system may increase the toxic potential of kerosene and its ignition product in the respiratory system.     

The physiological regulation of toll-like receptor expression and function in humans

Eleven mammalian toll-like receptors (TLRs 1–11) have been identified to date and are known to play a crucial role in the regulation of immune responses; however, the factors that regulate TLR expression and function in vivo are poorly understood. Therefore, in the present study, we investigated the physiological regulation of TLR expression and function in humans. To examine the influence of diurnal rhythmicity on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers ( n = 8) at time points coinciding with the peak and nadir in the endogenous circulating cortisol concentration. While no diurnal rhythmicity in the expression of TLRs 1, 2, 4 or 9 was observed, the upregulation of costimulatory (CD80 and CD86) and antigen-presenting (MHC class II) molecules on CD14⁺ monocytes following activation with specific TLR ligands was greater ( P < 0.05) in samples obtained in the evening compared with the morning. To examine the influence of physical stress on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers ( n = 11) at rest and following 1.5 h of strenuous exercise in the heat (34°C). Strenuous exercise resulted in a decrease ( P < 0.005) in the expression of TLRs 1, 2 and 4 on CD14⁺ monocytes. Furthermore, the upregulation of CD80, CD86, MHC class II and interleukin-6 by CD14⁺ monocytes following activation with specific TLR ligands was decreased ( P < 0.05) in samples obtained following exercise compared with at rest. These results demonstrate that TLR function is subject to modulation under physiological conditions in vivo and provide evidence for the role of immunomodulatory hormones in the regulation of TLR function.     

Anti fi larial potential of the fruits and leaves extracts of Pongamia pinnata on cattle filarial parasite Setaria cervi

The effect of aqueous and alcohol extracts of the fruits and leaves of Pongamia pinnata (Linn.) Merr. (Syn. Pongamia glabra Vent, leguminosae) on the spontaneous movements of both the whole worm and the nerve-muscle preparation of Setaria cervi and on the survival of micro fi lariae in vitro was studied. The aqueous and alcohol extracts of fruits and the alcohol extract of leaves caused an inhibition of spontaneous movements of the whole worm and the nerve-muscle preparation of S. cervi. The initial stimulatory effect was not observed with the aqueous extract of fruits on the nerve-muscle preparation. The concentration required to inhibit the movements of the whole worm preparation was 250 micro g/mL for aqueous, 120 micro g/mL for alcohol extract of fruits and 270 microgram/mL for alcohol extracts of the leaves. The concentrations of P. pinnata extracts required to produce an equivalent effect on the nerve-muscle preparation were 25 micro g/mL, 5 micro g/mL and 20 micro g/mL, respectively, suggesting a cuticular permeability barrier.     

Development of Acute Adult T-cell Leukemia Following PD-1 Blockade Therapy for Lung Cancer

Immune checkpoint inhibitors (ICIs) are widely used for the treatment of various cancers. However, paradoxical exacerbation of neoplasms, referred to as “hyperprogressive disease,” has been reported in a proportion of patients treated with anti-programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) blockade. We herein report a case of acute adult T-cell leukemia (ATL) that developed shortly after the administration of nivolumab, a PD-1 inhibitor, to treat non-small-cell lung cancer. There were no signs of ATL before the administration of nivolumab, and seropositivity for human T-cell leukemia virus type-1 (HTLV-1) was confirmed after the development of acute ATL. We speculate that nivolumab likely contributed to the development of acute ATL.     

10-Year Experience with the Modified Pectoralis Major Flap: The Use of the Deltopectoral Flap to Reduce Skin Tension

Purpose: Pectoralis major myocutaneous flap has been the work horse flap for head and neck reconstruction. However, due to the bulky nature of the pedicle it is not uncommon to struggle to achieve tension free closure of the neck skin incision. This case series presents a modified pectoralis major flap technique to overcome the difficulty of tight closure or the need to graft the residual cutaneous defect. Method: This 10-year study includes 73 patients who underwent modified pectoralis major flap reconstruction for complex laryngo-pharyngeal defects following resection of tumours involving larynx, hypopharynx oropharynx and cervical oesophagus. The modified technique involves accommodating a deltopectoral fasciocutaneous flap which rotates over the pedicle to insert into the neck incision providing extra tissue to achieve a tension free closure. Results: 73 patients underwent the procedure, 80% were male. Mean age of patients was 62.8years. Larynx was the most common site and the average size of the tumour was 34.8 mm. 13 patients developed minor complications such as wound dehiscence out of which 10 were managed conservatively, 3 patients required additional reconstructive procedures. 13 patients developed pharyngocutaneous fistula and 6 developed Neopharyngeal stenosis. 51 patients achieved good swallowing and 55 developed intelligible speech following recovery. Conclusion: We recommend the use of this technique as an effective method to achieve tension free neck incision closure and improved cosmetic results especially in centres which do not have free flap facility readily available.     

Associated comorbidities in psoriasis and inflammatory bowel disease

Background The association between psoriasis and inflammatory bowel disease (IBD) has been previously reported although a great deal remains unknown about associated comorbidities. Objectives The aim of this study was to examine comorbidities in individuals diagnosed with both psoriasis and IBD, and to compare those with individuals diagnosed with psoriasis‐only. We also looked at differences within the IBD group by clearly defining that cohort. Methods We included 146 patients diagnosed with both psoriasis and IBD and 146 controls diagnosed of psoriasis‐only without previous records of IBD, matched by gender, ethnicity and age (±5 years). Patients were obtained from the research patient data repository of Brigham and Women’s Hospital (BWH) and Massachusetts General Hospital. Controls were obtained from the psoriatic arthritis and psoriasis follow‐up study (PAFS) at BWH. The comparison between the two groups included socio‐demographics, comorbidities and laboratory inflammation parameters. Results Compared to individuals with psoriasis‐only, patients with both psoriasis and IBD had significantly higher rates of autoimmune thyroiditis (2.1% vs. 6.8%), hepatitis (0.7 vs. 6.2%) and diabetes (11.0% vs. 26.7%). In addition, of the 146 patients with psoriasis and IBD, 60 (41.1%) were diagnosed with seronegative arthritis. The average C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR) of the last visits in our clinics were significantly elevated compared to the individuals with psoriasis‐only (ESR, 33.5 vs. 4.0 mm/h; CRP, 9.1 vs. 2.3 mg/L; both P‐values <0.0001). Conclusions We found that patients with both, psoriasis and IBD have a number of further associated comorbidities, some at significantly higher levels than individuals with psoriasis‐only. Common inflammatory pathways and genetic predispositions for specific patterns in the immune response may play an important role in the evolution of associated conditions.