Adapter CAR T cells to counteract T-cell exhaustion and enable flexible targeting in AML.

Although the landscape for treating acute myeloid leukemia (AML) patients has changed substantially in recent years, the majority of patients will eventually relapse and succumb to their disease. Allogeneic stem cell transplantation provides the best anti-AML treatment strategy, but is only suitable in a minority of patients. In contrast to B-cell neoplasias, chimeric antigen receptor (CAR) T-cell therapy in AML has encountered challenges in target antigen heterogeneity, safety, and T-cell dysfunction. We established a Fab-based adapter CAR (AdCAR) T-cell platform with flexibility of targeting and control of AdCAR T-cell activation. Utilizing AML cell lines and a long-term culture assay for primary AML cells, we were able to demonstrate AML-specific cytotoxicity using anti-CD33, anti-CD123, and anti-CLL1 adapter molecules in vitro and in vivo. Notably, we show for the first time the feasibility of sequential application of adapter molecules of different specificity in primary AML co-cultures. Importantly, using the AML platform, we were able to demonstrate that chronic T-cell stimulation and exhaustion can be counteracted through introduction of treatment-free intervals. As T-cell exhaustion and target antigen heterogeneity are well-known causes of resistance, the AdCAR platform might offer effective strategies to ameliorate these limitations.

Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder.

BACKGROUND: Proinflammatory cytokines have been reported to be elevated in individuals experiencing chronic stress as well as in those with major depressive disorder. Much less is known about cytokines in anxiety disorders such as posttraumatic stress disorder (PTSD) and panic disorder (PD). We hypothesized that PD and PTSD would be associated with a generalized proinflammatory cytokine signature. METHOD: We utilized Luminex technology to examine 20 cytokines and chemokines in serum from 48 well-characterized individuals with a primary DSM-IV PD or PTSD diagnosis, and 48 age- and gender-matched healthy controls. We conservatively employed a Bonferroni correction for multiple testing (alpha=.05/20=.0025). RESULTS: Individuals with primary PTSD or PD had significantly elevated median peripheral cytokine levels for 18 of 20 different cytokines compared to age- and gender-matched healthy controls (all P<.0025). To assess for the presence of a generalized proinflammatory state, we also examined the proportion of subjects with detectable levels of at least six of nine common proinflammatory cytokines and chemokines (IL-6, IL-1alpha, IL-1beta, IL-8, MCP-1, MIP-1alpha, Eotaxin, GM-CSF, and IFN-alpha). For men and women, 87% of anxiety patients had six or more detectable levels of these proinflammatory cytokines, compared with only 25% of controls (Fisher's Exact Test (FET) P=.000). Confirmatory analysis of the subset of individuals without current psychiatric medication use or comorbid depression was of comparable significance. CONCLUSIONS: These findings suggest that a generalized inflammatory state may be present in individuals with PD or PTSD.

Massive intrahepatic hemorrhage as first manifestation of polyarteritis nodosa.

A case of an acute abdomen caused by a massive intrahepatic hemorrhage in a 77-year old man is presented. The hemorrhage was the first manifestation of an underlying polyarteritis nodosa which had not been diagnosed prior to the event. The diagnosis was suspected after a preoperatively performed angiography, surgical treatment was required to control the bleeding. This case demonstrates the differential diagnosis of acute intrahepatic hemorrhage which includes rare causes of vasculitis.

[Sclerotherapy of the internal spermatic vein in varicocele. Significance of normal anatomical variants]. / Sklerotherapie der Vena spermatica interna bei Varikozele. Bedeutung der anatomischen Normvarianten.

During a period of four years, 386 patients with left sided varicoceles were treated by sclerotherapy of the left internal spermatic vein. This was successful in 93.8%. The most common complication was perforation of the vein in 6.2%. Technical success and complications depended on anatomical variations. Of particular significance was Bähren type IVb (competent main vein, incompetent collaterals) which occurred in 18.9%. This accounted for 66.5% of all perforations and 54.2% of unsuccessful interventions. The recurrence rate was 3.8%.

[A comparison of color duplex sonography with selective penile DSA in assessing erectile dysfunction]. / Vergleich der Farbduplexsonographie mit der selektiven penilen DSA bei der Abklärung der erektilen Dysfunktion.

42 patients with suspected vasculogenic impotence were examined via colour duplex sonography. Penile vascular anatomy was mapped and peak velocity was determined in both cavernous arteries before and after intracorporeal injection of 15 mg papaverine and 0.5 mg regitine. In all patients the results could be compared with selective penile pharmacoangiography as the gold standard. In 34/42 patients colour Duplex sonography and angiography led to an identical evaluation of penile blood supply. 4 patients were classified false-negative and 4 patients false-positive. Sensitivity and specificity were calculated for each side separately. Sensitivity was 82.4% for left side angiogram and 83.3% for right side angiogram. Specificity was 88% for left side angiogram and 87.5% for right side angiogram. Peak flow velocity was significantly diminished in pathological angiograms.

[The value of computed tomography in the diagnosis of the local and lymph node recurrences of head and neck tumors]. / Wertigkeit der Computertomographie bei der Diagnose von Lokal- und Lymphknotenrezidiven von Kopf-Hals-Tumoren.

544 CT studies of 231 patients were evaluated retrospectively to assess the role of CT in posttherapeutic monitoring of patients with head and neck tumours. CT (80%) was inferior to clinical evaluation (87%) in diagnosing recurrent malignancy due to a lack of specificity (76 vs. 92%). With CT small recurrencies were missed. Occasionally evaluation of the oral cavity was impaired by metal artifacts (dental fillings). However with larger recurrent tumours, CT offered important additional information regarding extent, infiltration of deeper compartments and bony destruction in 51% of the cases. CT (95%) was superior to clinical evaluation (80%) in diagnosing recurrent lymph node metastases. A baseline CT study at about 6-8 weeks after the end of therapy is of great importance for follow-up studies.

Is ultrasonography a reliable method for evaluation of fragment clearance after biliary ESWL? A prospective, blinded study of two independent ultrasound units.

Ultrasound is the preceding method for evaluation of fragmentation and subsequent fragment clearance from the gallbladder. Considering the methodological shortcomings of ultrasonography, this study was therefore designed to investigate the degree of conformity between two independent ultrasound units. In our protocol patients were evaluated for fragments two weeks and three, six, nine and twelve months after ESWL. A restricted number of experienced sonographers in two independent ultrasound units examined the patient without knowledge of the other unit's findings. A total of 62 examinations have been carried out so far. Complete or sufficient conformity with a difference in size of 0-3mm was achieved in 24 examinations. Seven examinations revealed differences of 4-13 mm. In 31 cases the diagnosis of a stone-free gallbladder has been made, but only in 25 cases this could be confirmed by the other ultrasound unit. In six examinations a small fragment of less than 5mm was found by the respective other sonographer. We conclude that the diagnoses of a stone-free gallbladder after ESWL should be reconsidered by a second independent and experienced sonographer.

[Color duplex sonography of the penis--examination technique and clinical results]. / Farb-Duplexsonographie des Penis--Untersuchungstechnik und klinische Ergebnisse.

40 patients with suspected vasculogenic impotence were examined with color duplex sonography. Penile vascular anatomy was mapped and peak velocity was determined in both cavernosal arteries before and after intracorporeal injection of 15 mg papaverine and 0.5 mg regitine. A peak velocity exceeding 25 cm/sec was considered normal. In 20 patients the results could be compared with internal iliac angiography as the gold standard. In 18 of 20 patients, color duplex sonography and angiography led to identical evaluation of penile blood supply. Two false-negative findings were due to significant lesions of the internal iliac and pudendal artery with extensive collaterals to the penile arteries. One color dulex finding was false positive. Color duplex sonography is a sensitive and non-invasive method for evaluation of arteriogenic impotence. Only angiography, however, can delineate proximal arterial lesions. It remains indispensible if revascularisation is planned.

[Technique and value of digital subtraction angiography in erectile dysfunction]. / Technik und Wertigkeit der DSA bei erektiler Dysfunktion.

Arteriography of penile arterial supply is of decisive importance in the diagnostic evaluation of arteriogenic impotence. Technique and results of penile arteriography by means of high-resolution DSA in 26 impotent men are reported. In comparison to direct serial angiography on large-scale films, high-resolution DSA with 1024(2)-matrix provides the advantages of reduced investigation-time and reduction of contrast media load. Additional detailed views in different projections can be easily obtained. In 15 of 26 patients (mean age 54.9 years) a total of 34 steno-occlusive vessel changes were found (57.7%). 65.4% showed anatomic variations. In all patients, DSA provided clear vascular diagnosis. Thus, additional large-scale serial filming never became necessary. Results are comparable to those reported by other authors. In conclusion, high-resolution DSA can completely replace large-scale serial angiography in the evaluation of penile arterial supply.