[Primary Immunodeficiency: Primary Antibody Disorders in Respiratory Medicine]. / Primäre Immundefekte: Antikörpermangelerkrankungen in der Pneumologie.

Clinical manifestations of primary immunodeficiency are heterogeneous, and early diagnosis is challenging. Leading symptoms are recurrent upper and lower respiratory tract infections. Response to antibiotic therapy is often reduced. Beside infectious complications autoimmunity, autoinflammation and malignant diseases occur frequently. About 50 % of all PID patients are diagnosed after childhood, and the main group are patients with primary antibody deficiencies. Treatment of choice is the immunoglobulin substitution and the prophylactic or therapeutic use of antibiotics. In patients presenting with immunodysregulation, immunosuppression is additionally indicated. Especially due to recurrent lower airway infection and/or interstitial lung diseases PID patients have a decreased live expectancy. Hence, both early diagnosis and sufficient therapy are mandatory.

[Response of dermatomyositis with lung involvement to Janus kinase inhibitor treatment]. / Ansprechen einer Dermatomyositis mit Lungenbeteiligung auf eine Januskinase-Inhibitor-Therapie.

We report on a 32-year-old male patient presenting with anti-MDA-5 and anti-Ro52 antibody positive hypomyopathic dermatomyositis (CADM) with clinically leading interstitial pulmonary involvement. Under several immunosuppressive treatment regimens including high-dose steroids, cyclophosphamide, rituximab, immunoglobulins, plasmapheresis, ciclosporin and mycophenolate mofetil, pulmonary involvement was refractory to progressive. Based on the detection of a clear-cut interferon signature by flow cytometric determination of SIGLEC-1 as an interferon-dependent marker, treatment with the Janus kinase inhibitor tofacitinib was initiated. This resulted in a response to treatment with a significant increase in physical performance, an ameliorated skin condition and computed tomographic (CT) morphologically improved interstitial lung disease with overall good tolerability.

Influence of venous stasis on survival of epigastric flaps in rats.

Venous congestion results in tissue damage and remains the most common reason for failure of transfer of microvascular free flaps if it is not recognised early. The purpose of this study was to measure the critical duration of venous congestion and the resultant survival of flaps according to the duration of venous stasis. A standard epigastric flap was raised and repositioned in 35 rats, seven of which acted as controls. The superficial inferior epigastric vein was fully occluded for four, five, six, or seven hours in the rest (n=7 each group). Subsequently, the rats were monitored for one week, and the resultant necrotic areas were photographed. After five, six, and seven hours of venous stasis, the incidence and area of necrosis were significantly increased (p=0.04 in each) above that of the control. The degree of necrosis after seven hours of venous stasis was significantly greater than that after four or five hours (p=0.01 and 0.02, respectively). The duration of venous congestion is therefore a potential risk for the survival of free flaps, as it results in operative complications and may jeopardise the whole procedure. After a critical period of venous stasis we reach a point of no return, and any attempt to salvage the compromised flap will be in vain. Based on these results, we think that monitoring by an experienced surgeon at intervals of no longer than three hours is essential for the successful salvage of venous congestion in microvascular free flaps.

Rhesus CE expression on patient red blood cells is an independent prognostic factor for adenocarcinoma of the lung.

OBJECTIVES: The influence of blood group antigens on cancerogenesis is shown for distinct tumor types, yet the impact of Rhesus blood group antigens in lung cancer is not clarified. MATERIALS AND METHODS: To investigate the impact of Rhesus blood groups a non-small cell lung cancer (NSCLC) collective (n = 1047) was analyzed retrospectively. Using a second cohort of n = 340 primarily operated stage I-III NSCLC patients, we evaluated immunohistochemistry of CD47-antibody stained tissue samples in correlation to histopathologic subtype and Rhesus blood group. RESULTS AND CONCLUSION: In 516 of 1047 patients blood group data were available. Seven different RhCE phenotypes were grouped as "··ee," "ccE·," and "C·E·." Adenocarcinoma patients with Rh "··ee" revealed improved overall survival (29 (21.2-36.8) m; HR 1.00 [index]) compared with Rh "ccE·" (19 (1.9-36.1) m; HR 1.76 [1.15-2.70]) and Rh "C·E·" (10 (7.4-12.6) m; HR 2.65 [1.70-4.12]) univariately (P < .001) and multivariately (P < .001). Rh "··ee" showed reduced incidence of CNS-metastasis (P = .014) and metastasis count (P = .032) in stage IV adenocarcinoma. Immunohistochemistry associated CD47-positivity with adenocarcinomas (n = 340, P = .048). In n = 51 cases blood group data were available. The prognostic effect of Rh "··ee" compared with Rh "ccE·" and Rh "C·E·" was stated (P = .001), foremost in CD47-positive adenocarcinomas (Rh "··ee" vs. Rh "ccE·" and Rh "C·E·," P = .008). Inversely Rh "ccE·" or Rh "C·E·" was found beneficial in CD47-negative non-adenocarcinomas (P = .046). Phenotypic RhCE expression may be an independent prognostic factor for overall survival in adeno-NSCLC. We hypothesize an erythrocytic-immunologic interaction with tumor tissue, possibly altered by RhCE and CD47, resulting in a metastatic prone condition.

An atlas of bloodstream-accessible bone marrow proteins for site-directed therapy of acute myeloid leukemia.

The concept of arming antibodies with bioactive payloads for a site-specific therapy of cancer has gained considerable interest in recent years. However, a successful antibody-based targeting approach critically relies on the availability of a tumor-associated target that is not only preferentially expressed in the tumor tissue but is also easily accessible for antibody therapeutics coming from the bloodstream. Here, we perfused the vasculature of healthy and acute myeloid leukemia (AML)-bearing rats with a reactive ester derivative of biotin and subsequently quantified the biotinylated proteins to identify AML-associated bone marrow (BM) antigens accessible from the bloodstream. In total, >1400 proteins were identified. Overall, 181 proteins were >100-fold overexpressed in AML as compared with normal BM. Eleven of the most differentially expressed proteins were further validated by immunohistochemistry and confocal microscopic analyses, including novel antigens highly expressed in AML cells (for example, adaptor-related protein complex 3 ß2) and in the leukemia-modified extracellular matrix (ECM) (for example, collagen-VI-α-1). The presented atlas of targetable AML-associated BM proteins provides a valuable basis for the development of monoclonal antibodies that could be used as carriers for a site-specific pharmacodelivery of cytotoxic drugs, cytokines or radionuclides to the BM in AML.

IL-17C mediates the recruitment of tumor-associated neutrophils and lung tumor growth.

Chronic obstructive pulmonary disease (COPD) is associated with an increased risk for lung cancer and an aberrant microbiota of the lung. Microbial colonization contributes to chronic neutrophilic inflammation in COPD. Nontypeable Haemophilus influenzae (NTHi) is frequently found in lungs of stable COPD patients and is the major pathogen triggering exacerbations. The epithelial cytokine interleukin-17C (IL-17C) promotes the recruitment of neutrophils into inflamed tissues. The purpose of this study was to investigate the function of IL-17C in the pulmonary tumor microenvironment. We subjected mice deficient for IL-17C (IL-17C-/-) and mice double deficient for Toll-like receptor 2 and 4 (TLR-2/4-/-) to a metastatic lung cancer model. Tumor proliferation and growth as well as the number of tumor-associated neutrophils was significantly decreased in IL-17C-/- and TLR-2/4-/- mice exposed to NTHi. The NTHi-induced pulmonary expression of IL-17C was dependent on TLR-2/4. In vitro, IL-17C increased the NTHi- and tumor necrosis factor-α-induced expression of the neutrophil chemokines keratinocyte-derived chemokine and macrophage inflammatory protein 2 in lung cancer cells but did not affect proliferation. Human lung cancer samples stained positive for IL-17C, and in non-small cell lung cancer patients with lymph node metastasis, IL-17C was identified as a negative prognostic factor. Our data indicate that epithelial IL-17C promotes neutrophilic inflammation in the tumor microenvironment and suggest that IL-17C links a pathologic microbiota, as present in COPD patients, with enhanced tumor growth.

Blood group antigen A type 3 expression is a favorable prognostic factor in advanced NSCLC.

OBJECTIVES: Several blood group-related carbohydrate antigens are prognosis-relevant markers of tumor tissues. A type 3 (repetitive A) is a blood group antigen specific for A1 erythrocytes. Its potential expression in tumor tissues has so far not been examined. MATERIAL AND METHODS: We have evaluated its expression in normal lung and in lung cancer using a novel antibody (A69-A/E8). For comparison an anti-A antibody specific to A types 1 and 2 was used, because its expression on lung cancer tissue has been previously reported to be of prognostic relevance. Resected tissue samples of 398 NSCLC patients were analyzed in immunohistochemistry using tissue microarrays. RESULTS AND CONCLUSIONS: Expression of A type 3 was not observed in non-malignant lung tissues. A type 3 was expressed on tumor cells of around half of NSCLC patients of blood group A1 (p<0.001). Whereas no prognostic effect for A type 1/2 antigen was observed (p=0.562), the expression of A type 3 by tumor cells indicated a highly significant favorable prognosis among advanced NSCLC patients (p=0.011) and in NSCLC patients with lymphatic spread (p=0.014). Univariate prognostic results were confirmed in a Cox proportional hazards model. In this study we present for the first time prognostic data for A type 3 antigen expression in lung cancer patients. Prospective studies should be performed to confirm the prognostic value of A type 3 expression for an improved risk stratification in NSCLC patients.

MN1-Fli1 oncofusion transforms murine hematopoietic progenitor cells into acute megakaryoblastic leukemia cells.

Long-term outcome of acute megakaryoblastic leukemia (AMKL) patients without Down's syndrome remains poor. Founding mutations and chimeric oncogenes characterize various AMKL subtypes. However, for around one third of all cases the underlying mechanisms of AMKL leukemogenesis are still largely unknown. Recently, an in-frame fusion of meningeoma 1-friend leukemia virus integration 1 (MN1-Fli1) gene was detected in a child with AMKL. We intended to investigate the potential role of this oncofusion in leukemogenesis of acute myeloid leukemia. Strikingly, expression of MN1-Fli1 in murine hematopoietic progenitor cells was sufficient to induce leukemic transformation generating immature myeloid cells with cytomorphology and expression of surface markers typical for AMKL. Systematic structure function analyses revealed FLS and 3'ETS domains of Fli1 as decisive domains for the AMKL phenotype. Our data highlight an important role of MN1-Fli1 in AMKL leukemogenesis and provide a basis for research assessing the value of this oncofusion as a future diagnostic marker and/or therapeutic target in AMKL patients.

[Iron resorption and the effects of iron supplementation in blood donors]. / Untersuchungen zur Eisen-Resorption und des Effektes der Eisen-Supplementierung bei Blutspendern.

Topical values for some haematological factors such as Hb and Ery as well as transferrin and ferritin were determined in 7 female blood donors and 8 male blood donors during the years of their work as blood donors. Subsequently, an iron resorption test was carried out which unexpectedly resulted in low rates of resorption ranging from 5.6% in men to 3.7% in women. After supplementing with vitaferro for 3 months the ferritin values which initially lay around the lower limiting value of 20 or 10 mg/l in men or women had doubled.

[Are our blood donors in danger of iron deficiency?]. / Sind unsere Blutspender durch den Eisenmangel gefährdet?

In blood donors the question arises for eventual endangering by iron deficiency. The results of this work show that ferritin determinations for blood donors will indicate a latent, in some cases a manifest iron deficiency. The examination of testing components such as PVC, MCH, Fe i. S., transferrin and transferrin saturation produced no special advantages concerning sensitivity and specificity, in terms of ferritin determination. It is indispensable, however, to know the ferritin value because the control of the Hb value prior to blood donation will usually characterize the blood donor's situation in a sufficient manner. For control purposes it is possible to use capillary or venous blood. It is only in general, but particularly in special clinical situations that you have to be aware of the blood donor's condition concerning his/her Fe-metabolism.

[Expectations between the clinic and the clinical laboratory]. / Erwartungen zwischen Klinik und klinischem Laboratorium.

A considerable part of the paraclinical diagnostics and therapy control takes place in the clinical laboratory. The readiness for achievements of the clinical laboratory also depends on the responsible acquaintance with the demands of the laboratory and the observance of certain rules. The increasing number of possible test components and their peculiarities render possible their appropriate interpretation, also taking into consideration possible factors which have influence on the representance. A reasonable cooperation between laboratory and clinic is suitable to optimize and to realize the mutual expectations.

Fibrin monomer complexes (SFMC) after substitution of antithrombin III (AT III) in consumption coagulopathy.

The report refers to substitution therapy of 33 patients who suffered consumption coagulopathy. Various blood coagulation and fibrinolytic variables were measured. After successful AT III donation to patients suffering DIC, soluble fibrin monomer complexes (SFMC) disappeared within 0.5-12 hours. If AT III decreases SFMC proves positive again. In addition to analysis of AT III we recommend to analyse SFMC to detect thrombin induced consumption reaction (DIC). Furthermore we found the fibrin split product D-dimer was a particularly sensitive indicator of DIC in case of hyperfibrinolysis (D-dimer was analysed in six patients). The reactions of fibronectin and SFMC proved inversely proportional.

Attenuation of the virulence of the M strain of Plasmodium cynomolgi during prolonged multiplication in splenectomized rhesus monkeys.

The primary data in this report showed that prolonged multiplication of the M strain of Plasmodium cynomolgi in splenectomized rhesus monkeys led frequently to emergence of parasites whose virulence for monkeys with intact spleens was markedly attenuated while that for splenectomized monkeys was unimpaired. Expressions of attenuation regularly included reductions in the height of the peak parasitemia and in some instances failure to induce infection with inocula 1,000-fold those infective for splenectomized monkeys. Attenuation of virulence, once established, was maintained through as many as 17 serial passages in intact monkeys and more than 100 such transfers in splenectomized monkeys. Not only asexual blood stages, but also sexual stages (gametocytes) carried the attenuated characteristic, as indicated by its ready passage through mosquitoes. Studies in monkeys with sporozoite-induced infections showed that the persisting exoerythrocytic stages did not participate in the attenuation phenomenon; for when erythrocytic parasites of reduced virulence were cleared from the blood by either immune processes or chemotherapy, they were replaced upon relapse with parasites of unimpaired virulence. A major effort to determine whether splenectomized monkeys carried plasma or erythrocyte factors responsible for displays of attenuated virulence was nonproductive. An intact spleen was the essential element in these displays, for they disappeared immediately upon removal of this organ. The attenuation phenomenon probably reflects selection of spontaneously occurring mutants with limited capacity to escape normal splenic clearance mechanisms and unimpaired or even enhanced capacity to multiply in splenectomized monkeys.

Compatibility of relapse patterns of Plasmodium cynomolgi infections in rhesus monkeys with continuous cyclical development and hypnozoite concepts of relapse.

This report encompasses the results of two studies on the relapse patterns of infections with the B strain of Plasmodium cynomolgi treated repetitively with chloroquine. One study of sizeable dimensions dealt primarily with relapses that occurred within 120 days of onset of patency in infections induced with inocula of 10(5) to 7 X 10(6) sporozoites. The second study, of more limited dimensions, dealt with relapses that occurred over a 689-day period after inoculation with 5 X 10(0) to 5 X 10(6) sporozoites. Both studies showed that with few exceptions relapses occurred at relatively regularly spaced intervals. The second study showed that frequency of relapse was related directly to the size of the sporozoite inoculum and inversely to the age of the infection; also that an inoculum larger than the minimum infective dose was required for relapse. Attempted correlation of these observations with the new and generally accepted hypnozoite concept of relapse uncovered two areas of serious incompatibility and numerous defects in the experimental base of this conceptualization. With limited provisos, the relapse patterns of infections with P. cynomolgi are fully compatible with the older cyclical development concept. The results of this study argue for caution in discarding this concept and for continuation of efforts to determine the genesis of the extended post-primary attack latent period that characterizes infections with the majority of strains of P. vivax.

Antimalarial activities and subacute toxicity of RC-12, a 4-amino-substituted pyrocatechol.

RC-12 [1,2-dimethoxy-4-(bis-diethylaminoethyl)-amino-5-bromobenzene] was evaluated for prophylactic, radical curative, and suppressive activities against infections with Plasmodium cynomolgi and subacute toxicity in rhesus monkeys. Applied as a prophylactic agent, RC-12, administered in doses of 6.25 to 25.0 mg/kg daily throughout the incubation period, provided near-complete to complete protection against 10(5) to 10(6) times the minimum infective dose of sporozoites. Applied as a suppressive agent, daily doses of 100.0 mg of RC-12 per kg did not eradicate blood schizonts regularly; hence, the need for concomitant administration of a blood schizonticide, such as chloroquine, in assessments of radical curative activity. In such appraisals, daily doses of 6.25 to 25.0 mg of RC-12 per kg for 14 days, in combination with 2.5 mg of chloroquine per kg daily for 7 days, effected cure of 69 and 93% of established infections, respectively. The curative activity of RC-12 was related to the total dose and could be achieved with a regimen as brief as 4 days. With respect to outward expressions of toxicity, daily doses of 50.0 mg/kg or lower for 15 to 225 days evoked no reactions. Doses of 100.0 or 200.0 mg/kg, scheduled for 15 days, evoked convulsions and depression and were, respectively, lethal to 4 of 17 and 7 of 7 recipients. Doses of 25.0 mg/kg or lower evoked no discrete reactions. Doses of 50.0 mg/kg and higher evoked hepatomegaly, vacuolation of hepatocytes, and elevations of glutamic oxalacetic and glutamic pyruvic transferase activities in serum, reactions related in intensity to dose but not duration of dosage.

Enhancement of the curative activity of primaquine by concomitant administration of mirincamycin.

Mirincamycin, a lincomycin derivative with unequivocal but limited activity against the pre-erythrocytic and persisting exoerythrocytic stages of Plasmodium cynomolgi, has been evaluated for capacity to enhance the radical curative potential of the conventional primaquine-chloroquine combination. Established infections with sporozoites of the above plasmodium in rhesus monkeys served this evaluation. The results showed that the dose of primaquine required for cure of 50% of active infections was reduced by one-half to two-thirds by coadministration with 2.5 mg of mirincamycin per kg, 1/16 the 50% curative dose of this lincomycin derivative when used in a mono-drug regimen. The dimensions of the enhancement of the curative activity of primaquine were inversely related to the size of the sporozoite inoculum. The smallest dose of mirincamycin productive of enhancement was 2.5 mg/kg; whether doses larger than 2.5 mg/kg would have been more effective was not determined. There is much to be done before it is known whether a mirincamycin-primaquine combination is useful for suppressive cure or radical cure of the human malarias. Irrespective of that result, the current study serves to focus attention on a somewhat novel approach to the development of more effective and better-tolerated regimens for radical cure, an alternative to the empirical chemical synthesis and screening approach that has dominated searches heretofore.