Histopathological findings in cutaneous small-vessel vasculitis associated with solid-organ malignancy.

BACKGROUND: Histopathological findings in biopsy specimens from patients with cutaneous small-vessel vasculitis (CSVV) secondary to solid-organ malignancy have not been previously reported. OBJECTIVES: We aimed to understand better the differences in histopathological findings between biopsy specimens from patients with CSVV associated with solid-organ malignancies and patients with CSVV secondary to other causes. METHODS: From a previously published group of patients with CSVV and solid-organ malignancy, we identified patients with available histopathology slides of biopsy specimens. We compared histopathological findings from these patients with those from 68 previously published patients with Henoch-Schönlein purpura not associated with solid-organ malignancy (60% male). RESULTS: We identified 15 patients (eight male, 53%) with available slides from biopsy specimens. The mean age of these patients with solid-organ malignancy-associated CSVV was 66·6 years, compared with 45·8 years in the Henoch-Schönlein purpura cases not associated with solid-organ malignancy (P < 0·001). Solid-organ malignancy-associated CSVV was less likely to demonstrate papillary dermal oedema (P = 0·04), papillary dermal inflammation (P < 0·001) and lymphocytes (P < 0·001), and more likely to have plasma cells (P = 0·02). Additionally, we detected nonsignificant differences in the presence of histiocytes (P = 0·05), intravascular thrombosis (P = 0·052) and microabscess formation (P = 0·06). CONCLUSIONS: CSVV associated with solid-organ malignancies tended to have deeper dermal involvement and a different cellular milieu from cases not associated with solid-organ malignancies. In addition, the patients with CSVV with solid-organ malignancies were significantly older than those without. Prospective studies with age-matched controls are needed to determine the clinical significance of the histopathological differences in solid-organ malignancy-associated CSVV.

Myeloid marker S100A8/A9 and lymphocyte marker, soluble interleukin 2 receptor: biomarkers of hidradenitis suppurativa disease activity?

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory and debilitating disease of the skin. No biomarkers for this disease exist. OBJECTIVES: We set out to test whether angiotensin-converting enzyme (ACE), lysozyme, soluble interleukin 2 receptor (sIL-2R) and S100A8/A9 (calprotectin) are elevated in patients with HS. METHODS: Serum was collected from 29 patients with HS at different stages of the disease, and from 51 controls. ACE, lysozyme, sIL-2R and S100A8/A9 levels were measured. Clinical observation of disease activity was scored according to the Hurley grading system and by a physician global score (PGS) of disease severity. RESULTS: Serum levels of lysozyme and ACE were not increased above the normal reference values in controls or patients with HS. Levels of sIL-2R and S100A8/A9 were significantly higher in patients with HS than in controls (P<0·001 for both sIL-2R and S100A8/A9). Based on the receiver operating characteristic curves, the optimum sIL-2R and S100A8/A9 cut-off values were 375 U mL(-1) and 680 ng mL(-1), respectively, with a sensitivity of 0·79 and specificity of 0·78 for sIL-2R, and 0·86 and 0·88, respectively, for S100A8/A9. No correlations with Hurley classification scores were found. However, when using PGS of disease activity to categorize patients, levels of S100A8/A9, but not sIL-2R, tended to be higher in patients with more active disease. CONCLUSIONS: Levels of S100A8/A9 and sIL-2R, but not ACE or lysozyme, are elevated in the serum of patients with HS. However, there is no correlation between S100A8/A9 or sIL-2R levels and disease stage according to the Hurley classification system. Further research is needed to study the potential of S100A8/A9 to score disease activity in larger cohorts of patients and to predict disease flares.

Host defence during Klebsiella pneumonia relies on haematopoietic-expressed Toll-like receptors 4 and 2.

In this study, the relative roles of Toll-like receptor (TLR)2 and TLR4 were investigated independently and together. Moreover, we studied the role of haematopoietic compartment in anti-Klebsiella host defence. We infected TLR2 and TLR4 single-, and TLR2×4 double knockout (KO) animals with different doses of Klebsiella pneumoniae. In addition, bone marrow chimeric mice were created and infected. TLR4 played a more prominent role in antibacterial defence than TLR2, considering that only TLR4 KO mice demonstrated enhanced bacterial growth in lungs and spleen 24 h after infection with 3×10³ colony-forming units of Klebsiella compared with wild-type (WT) mice. In late-stage infection or after exposure to a higher infectious dose, bacterial counts in lungs of TLR2 KO animals were elevated compared with WT mice and TLR2×4 KO animals were more susceptible to infection than TLR4 KO mice. TLR signalling in cells of haematopoietic origin is of primary importance in host defence against K. pneumoniae. These data suggest that: 1) TLR4 drives the antibacterial host response after induction of pneumonia with relatively low Klebsiella doses; 2) TLR2 becomes involved at a later phase of the infection and/or upon exposure to higher bacterial burdens; and 3) haematopoietic TLR2 and TLR4 are important for an adequate host response during Klebsiella pneumonia.

Solitary epidermolytic acanthoma: a clinical and histopathological study.

BACKGROUND: Epidermolytic acanthoma (EA) is an uncommon cutaneous entity that typically presents as a solitary lesion, or, less commonly, as multiple or disseminated discrete lesions. It usually appears at or after middle-age, and has been reported in various locations including the face, trunk, extremities and genitalia. Histopathologically, EA shows epidermolytic hyperkeratosis (EHK) involving either the entire thickness of the epidermis or just the granular and upper spinous layers. OBJECTIVE AND METHODS: To describe the clinical and microscopic features of EA, we retrospectively reviewed all cases diagnosed as EA at the Skin Pathology Laboratory at Boston University between 1999 and 2009. RESULTS: Solitary EA is more common in men (65%) and usually presents as a hyperkeratotic papule on the trunk (45%) or extremities (25%). Histopathologically, all cases of solitary EA showed the classical features of hyperkeratosis, acanthosis and EHK. Three architectural patterns were observed on scanning magnification: papillomatous (55%), cup-shaped (40%) and acanthotic (15%). Additional common features encountered included focal parakeratosis (85%), and a sparse to mild superficial perivascular lymphocytic infiltrate (90%). CONCLUSION: This large case series of solitary EA reviews the clinical features of this entity and describes several new histological variants.

The mannose cap of mycobacterial lipoarabinomannan does not dominate the Mycobacterium-host interaction.

Pathogenic mycobacteria have the ability to persist in phagocytic cells and to suppress the immune system. The glycolipid lipoarabinomannan (LAM), in particular its mannose cap, has been shown to inhibit phagolysosome fusion and to induce immunosuppressive IL-10 production via interaction with the mannose receptor or DC-SIGN. Hence, the current paradigm is that the mannose cap of LAM is a crucial factor in mycobacterial virulence. However, the above studies were performed with purified LAM, never with live bacteria. Here we evaluate the biological properties of capless mutants of Mycobacterium marinum and M. bovis BCG, made by inactivating homologues of Rv1635c. We show that its gene product is an undecaprenyl phosphomannose-dependent mannosyltransferase. Compared with parent strain, capless M. marinum induced slightly less uptake by and slightly more phagolysosome fusion in infected macrophages but this did not lead to decreased survival of the bacteria in vitro, nor in vivo in zebra fish. Loss of caps in M. bovis BCG resulted in a sometimes decreased binding to human dendritic cells or DC-SIGN-transfected Raji cells, but no differences in IL-10 induction were observed. In mice, capless M. bovis BCG did not survive less well in lung, spleen or liver and induced a similar cytokine profile. Our data contradict the current paradigm and demonstrate that mannose-capped LAM does not dominate the Mycobacterium-host interaction.

Comparison of PulsioFlex® uncalibrated pulse contour method and a modified Fick principle with transpulmonary thermodilution measurements in critically ill patients.

Monitoring of cardiac index (CI) by uncalibrated pulse contour (PC) methods has been shown to be inaccurate in critically ill patients. We tested accuracy and trending of a new pulse contour method and a modified Fick method using central venous oxygen saturation. We studied 21 critically ill and mechanically ventilated patients (age 20-86 years) monitored by PC (PulsioFlex®) and transpulmonary thermodilution (TPTD, PiCCO2®) as reference. At baseline, reference and PC-derived CI (CIPC) were recorded and CI obtained by Fick's method (FM, CIFICK). After four hours, measurements were performed analogously for trending analysis. CI are given in l/min/m2 as mean±standard deviation. At baseline CITPTD was 3.7±0.7, CIPC 3.8±0.7 and CIFICK 5.2±1.8. After 4 hours, CITPTD was 3.5±0.6, CIPC 3.8±1.2 and CIFICK 4.8±1.7. Mean bias for PC at baseline was -0.1 (limits of agreement [LOA] -1.4 to 1.2) and -0.4 (LOA -2.6 to 1.9) after four hours. Percentage errors (PE) were 34% and 60% respectively. FM revealed a bias of -1.5 (LOA -4.8 to 1.8, PE 74%) at baseline and -1.5 (LOA -4.5 to 1.4, PE 68%) at four hours. With an exclusion window of 10% of mean cardiac index, trending analysis by polar plots showed an angular bias of 5° (radial LOA±57°) for PC and 16° (radial LOA±51°) for FM. Although PC values at baseline were marginally acceptable, both methods fail to yield clinically acceptable absolute values. Likewise, trending ability is not adequate for both methods to be used in critically ill patients.

Altered guanine nucleoside triphosphate binding to transducin by cholera toxin-catalysed ADP-ribosylation.

The influence of cholera toxin (CTX)-catalysed ADP-ribosylation on binding of guanine nucleoside triphosphates to transducin was studied by measuring the binding of the GTP analogue, guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S]), to illuminated bovine rod outer segment (ROS) membranes treated with or without CTX. Besides the well-documented inhibition of the transducin GTPase activity, CTX treatment inhibited binding of GTP[gamma S] to illuminated ROS membranes. This inhibition was due to an approximately two-fold lower apparent affinity for the nucleotide, while the density of binding sites was not altered. CTX decreased the association rate of GTP[gamma S] by a factor of about two. Competition experiments with GTP, guanosine 5'-[beta, gamma]iminotriphosphate or GDP showed that the apparent affinities for both guanine nucleoside triphosphates, but not for GDP, were lowered by about two-fold upon CTX treatment. In contrast to CTX, pertussis toxin treatment of ROS membranes reduced the density of binding sites available to GTP[gamma S], while the apparent affinity of the remaining sites was unchanged. It is concluded that ADP-ribosylation of transducin by CTX not only inhibits its GTPase activity but also decreases the affinity for guanine nucleoside triphosphates, data which suggest that the arginine moiety modified by CTX is involved in both binding and hydrolysis of GTP.

Mechanical ventilation and the titer of antibodies as risk factors for the development of transfusion-related lung injury.

Purpose. Onset of transfusion-related acute lung injury (TRALI) is suggested to be a threshold-event. Data is lacking on the relation between titer of antibodies infused and onset of TRALI. We determined whether onset of TRALI is dependent on the titer of MHC-I antibodies infused in a combined model of ventilator-induced lung injury and antibody-induced TRALl. Methods. BALB/c mice were ventilated for five hours with low (7.5 ml/kg) or high (15 ml/kg) tidal volume. After three hours of MV, TRALI was induced by infusion of 0.5 mg/kg, 2.0 mg/kg or 4.5 mg/kg MHC-I antibodies. Control animals received vehicle. After five hours of MV, animals were sacrificed. Results. MV with high tidal volumes resulted in increased levels of all markers of lung injury compared to animals ventilated with low tidal MV. In ventilator-induced lung injury, infusion of 4.5 mg/kg of antibodies further increased pulmonary wet-to-dry ratio, pulmonary neutrophil influx and pulmonary KC levels, whereas infusion of lower dose of antibodies did not augment lung injury. In contrast, mice ventilated with low tidal volumes did not develop lung injury, irrespective of the dose of antibody used. Conclusions. In the presence of injurious MV, onset of TRALI depends on the titer of antibodies infused.

[Radiotherapy in adenoid cystic carcinoma]. / Die Strahlentherapie beim adenoidzystischen Karzinom.

Between 1962 and 1982, 45 patients with adenoid cystic carcinomas (ACC) of various localizations received a radiotherapy-treatment. Most of the cases had advanced tumors or recurrences. 41 patients underwent radiotherapy either alone or following an operation, in 35 cases with curative intention. 6 patients had already distant metastases at the beginning of treatment. In 4 cases only a palliative treatment of metastases of the skeleton and the lung was performed. Median two- and five-year survival of 35 patients with localized tumors was 83% and 45%, respectively (29/35 two-years and 14/31 five years). Best results were obtained by operation and postoperative radiotherapy (10/18 = 55.5% five year-survival). Radiotherapy alone resulted in a five-year survival of only 37.5% (3/8). Advanced ACC or postoperative recurrences should be treated by surgery as radically as possible, followed by a radiotherapy with generously sized portals and doses between 60 to 65 Gy. Radiotherapy alone leads to comparatively poor results. Large and inoperable tumors may well be treated by a combination of hyperthermia and radiotherapy.

[Combination treatment in radiotherapy]. / Kombinationsbehandlung in der Radiotherapie.

Treatment results after radiotherapy in combination with surgery, hyperthermia and cytotoxic drugs are reported from literature. Own results are presented. Sequential radiochemotherapy does not improve 5-year-survival. Synchronous administration of radiotherapy and chemotherapy is recommended for randomized studies. Drugs that are more effective but less toxic would be desirable.

[Treatment results of radiotherapy of T1-4N0M0 laryngeal cancer from 1963 to 1982]. / Behandlungsergebnisse der Strahlentherapie von Larynxkarzinomen der Stadien T1-4N0M0 aus den Jahren 1963 bis 1982.

Report on 323 patients with squamous-cell-carcinomas of the larynx stage TIS T1-4N0M0 treated between 1963 and 1982. Treatment results of operation with consecutively applied radiotherapy are compared with those of radiotherapy alone under consideration of the different stages. Five-year-survival of patients with glottic carcinomas in the stages TIS T1a/b was 91% in each treatment group, in stage T2 68 and 59% respectively, in stage T3 68 and 37% respectively. Therefore and because of the better vocal function radiotherapy as single treatment is recommended in the early stages TIS T1-2, whereas in stage T3 the combined treatment should be preferred. A detailed analysis of the treatment results of supra- and infra-glottic carcinomas was not possible because of the low number of patients.

[Results in combined hyperthermia/radiotherapy of adenoid cystic carcinomas compared with conventional treatment]. / Erfahrungen mit der kombinierten Hyperthermie/Strahlentherapie adenoidzystischer Karzinome im Vergleich mit herkömmlicher Behandlung.

158 patients with advanced malignancies of the head and neck area were treated by a combined hyperthermia/radiotherapy since 1972. 16 were adenoid cystic carcinoma (ACC). Their treatment results are compared with 28 ACC after radiotherapy alone. All 16 patients with hyperthermia achieved a complete remission. CR in 28 ACC-patients without hyperthermia was 61%. 113 patients with hyperthermia-treated squamous cell carcinomas had a comparatively low CR-rate of 49%. Five-year-survival on the other hand was 50% for ACC after hyperthermia, 57% after a planned postoperative radiation without hyperthermia and 37.5% after a radiotherapy alone in cases of inoperability. The combination of hyperthermia and radiotherapy is indicated in cases of advanced inoperable ACC and leads to a high percentage of local tumour control.

[Radiation therapy and treatment results in carcinoma of the esophagus (author's transl)]. / Strahlentherapie und Behandlungsergebnisse des Osophaguskarzinoms.

Results from radiotherapeutic treatment of 200 patients with malignant tumors of the esophagus are reported. The principal part is represented by squamous cell carcinomas with 88%, followed by adenocarcinomas with 4.5%, by more or less differentiated solid carcinomas with 4%, and small cell carcinomas with 1.5%. Sarcoma was found in three cases, one of them a myosarcoma, another a reticulosarcoma. An ectopic carcinoma of the gastric glands was present in one case. The staging was performed according to the TNM system. A focal dose of 6000 to 6500 rd within 6 or 8 weeks was tried for, using 60Co-gamma-rays. The one-year and five-year survival rates in stage T2N0M0 amounted to 80% and to 17%; no survival was obtained in stage T3N0M0. Out of the total of stage T2-3N0M0 cases 24% obtained one-year survival, and 2% five-year survival. In stages T3N2-3M0 and T3Nx-3M1 after one year 9% and 7% of the patients were alive. The mean survival time of stage T2N0M0 cases was 30.5 months; of T3N0M0, 7.3 months; of T3N1-3M0, 5.2 months; of T3Nx-3M1, 3.8 months. The one-year and five-year survival rates, being related to the irradiation dose administered, amounted to 28% and to 2% after a minimum dose of 5000 rd to the focus. With less than 5000 rd, none of the patients survived two years. The bad results of treatment demand new therapeutic pathways. Short-term pre-irradiation followed by surgical treatment is discussed as well as a combined radiation therapy with cobalt-60 and neutrons or a combined radio-chemotherapy using cytostatics.