Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity.

Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T cells against leukemia and lymphoma with promising clinical results. Extending this approach to allogeneic T cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen-specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy. We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with marked prolongation of survival in a xenograft Raji lymphoma murine model. Interleukin-15 (IL-15) production by the transduced CB-NK cells critically improved their function. Moreover, iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. In conclusion, we have developed a novel approach to immunotherapy using engineered CB-derived NK cells, which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. This approach should greatly improve the logistics of delivering this therapy to large numbers of patients, a major limitation to current CAR-T-cell therapies.

Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway.

Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naïve chronic lymphocytic leukemia (CLL). Besides directly inhibiting BTK, ibrutinib possesses immunomodulatory properties through targeting multiple signaling pathways. Understanding how this ancillary property of ibrutinib modifies the CLL microenvironment is crucial for further exploration of immune responses in this disease and devising future combination therapies. Here, we investigated the mechanisms underlying the immunomodulatory properties of ibrutinib. In peripheral blood samples collected prospectively from CLL patients treated with ibrutinib monotherapy, we observed selective and durable downregulation of PD-L1 on CLL cells by 3 months post-treatment. Further analysis showed that this effect was mediated through inhibition of the constitutively active signal transducer and activator of transcription 3 (STAT3) in CLL cells. Similar downregulation of PD-1 was observed in CD4+ and CD8+ T cells. We also demonstrated reduced interleukin (IL)-10 production by CLL cells in patients receiving ibrutinib, which was also linked to suppression of STAT3 phosphorylation. Taken together, these findings provide a mechanistic basis for immunomodulation by ibrutinib through inhibition of the STAT3 pathway, critical in inducing and sustaining tumor immune tolerance. The data also merit testing of combination treatments combining ibrutinib with agents capable of augmenting its immunomodulatory effects.

The prevalence and distribution of the atherosclerotic plaques in the abdominal aorta and its branches.

BACKGROUND: The aim of our study was to determine the existence, distribution, type and burden of the atherosclerotic plaques which are found in the abdominal aorta, its branches and the branching points. MATERIALS AND METHODS: Two hundred and sixty-one patients (117 female, 144 male; mean age 53.34 ± 16.02, range 12-84) who underwent dual-source computed tomography angiography (CTA) were retrospectively analysed. The prevalence and distribution of the plaques in the proximal, middle and distal parts of abdominal aorta and its branches; coeliac trunk, superior and inferior mesenteric arteries, renal arteries, splenic artery and common, external and internal iliac arteries and in the aortic orifices, the type and severity of these plaques and their relations with age and gender were studied. RESULTS: In our study, 69.3% of the patients had atherosclerotic plaques, mostly at the distal part of abdominal aorta. The existence of the plaques increased with age. The types of these plaques were mixed (43%), calcified (24%) and soft (3%). Mixed and calcified plaques were more common in the abdominal aorta and its branches, respectively. All of the arteries except for inferior mesenteric artery mostly had mild plaques. The plaques at the branching points, which were most frequently localised in the aortic bifurcation, were found in the 41.8% of the patients. The plaques in the branches were usually accompanied by atherosclerosis of abdominal aorta. CONCLUSIONS: Dual-source CTA enables mapping of atherosclerotic burden in abdominal arteries. Knowing the localisation, type and severity of the atherosclerotic plaques can be important to predict the clinical results and choose the proper treatment.

A combined anatomical variation of inferior epigastric vessels.

During the routine gross anatomical dissection of the right inguinal region of a 45-year-old male cadaver, a variation was observed both in the inferior epigastric artery and the inferior epigastric vein. In this case, the right inferior epigastric artery originated from the femoral artery 13 mm inferior to the inguinal ligament. Additionally, in this cadaver, the single right inferior epigastric vein drained into femoral vein 8 mm inferior to the inguinal ligament. The distal origin of the inferior epigastric artery from the femoral artery and the lower drainage of the single inferior epigastric vein to the femoral vein must be taken into consideration by surgeons.

Accurate course and relationships of the transverse facial artery in human cadavers.

Both the course and localization of the transverse facial artery are described, based upon the bilateral dissection of heads from 20 human cadavers. Its anatomical relationships with the mandibular fossa, the articular tubercle, the zygomatic arch, the parotid duct and the maxillary artery are studied and morphometric features are calculated. Furthermore, the transverse facial territory was examined. This territory was supplied by a single perforating branch in 28 cases, by two perforating branches in 10 and by three perforating branches in 2. Knowledge of the course and relationships of the transverse facial artery should help to protect this artery from the risk for transection. However, the variable course of the transverse facial artery must always be taken into consideration by the clinicians during surgical procedures.

A study of variations of transverse foramens of cervical vertebras in human: accessory foramina in shape and number.

Transverse foramens of 250 cervical vertebras were examined. There were accessory foramina and variations in shape and number in 10 out of 250 cervical vertebras. Since such a variation of foramens, through which the vertebral artery passes, has not been detected in the literature, these ten cases are to be considered.

A connecting branch between the musculocutaneous nerve and the median nerve.

We report here a connecting branch between the musculocutaneous and the median nerves in a 42 years old male cadaver. The connecting branch was 8 cm in length and 3 mm in width. One of the brachial veins and the brachial artery were located between the roots of the median nerve and the second brachial vein was present between the connecting branch and the median nerve. These kinds of variations may effect the venous return and may cause edema in the upper extremities. Additionally, variations of these nerves have an importance during operations of this region.

Relation of the radial nerve with the sulcus nervi radialis: a morphometric study.

The radial nerve's course from the axillary region, branch patterns and the relation of the nerve to fixed anatomical landmarks in the arm region were studied in 27 embalmed intact cadavers. The radial nerve and its relation with the sulcus nervus radialis (SNR) was analyzed. The direct contact of the nerve with humerus in SNR was observed during the dissections. The following measurements were made: the total length of the humerus (the palpable uppermost point of the tuberculum majus and the lateral epicondyle); proximal safe zone (the tuberculum majus and the proximal beginning of the SNR); distal safe zone (the intercondylar axis and the middle of SNR); lateral safe zone (the lateral epicondyle and the distal end of SNR). In conclusion, it was aimed to correlate the osseus palpable landmarks of humerus with the course of the radial nerve for a safe surgery as the sulcus nervi radialis region is one of the main risky areas for the radial nerve palsies.

The comparison of the incidence of horseshoe kidney in autopsy cases versus urologic patient population.

This study was applied on 9665 cases between January 1993 and October 1998. Of these, 6985 (72.3%) were urologic patients and 2680 (27.7%) were autopsy cases. The patients having urinary complaint investigated by urine analysis and kidney-ureter-bladder film (KUB), routinely. In all patients who have pathological urine, ultrasonography exam was done and in all patients who established an abnormality on ultrasonography, intravenous pyelography (IVP) was taken, also. We established the horseshoe kidney in 23 of patients (1/304) and in 6 of autopsy cases (1/447) with overall incidence 1/333. There were 21 male and 8 female with horseshoe kidney (male/female = 2.6/1). Abdominal discomfort with lower lumbar pain and Rovsing's sign were seen in 56.5% and in 65.2% of patients respectively. We concluded that horseshoe kidney incidence is almost the same as reported in the literature, although its clinical appearance is higher in our urologic patient population. In the urological out-patient evaluation, at least Rovsing's sign should be applied to all patients with lower lumbar pain with vague abdominal discomfort and an abdominal ultrasonographic exam should be applied, if this sign is positive.

Frequency of septum pellucidum anomalies in non-psychotic population: a magnetic resonance imaging study.

This prospective MRI investigation was performed to investigate septum pellucidum (SP) anomalies in 505 (242 male, 263 female) non-psychotic persons. The mean age of the population was 39.179 +/- 0.904 (40.461 +/- 1.395 male, 38 +/- 1.166 female). There was no significant difference between the means of age in the male and female groups (t-test, DF = 479, p > 0.05). The SP anomalies were classified as cavitation anomalies (Type I) and absence of the SP (Type II). Type I anomalies were subdivided into four groups as isolated cavum septi pellucidi (Ia), cavum septi pellucidi et cavum vergae (Ib), anterior small triangular cavities (Ic), and cysts of the SP (Id). The incidences of the anomalies (Type I + Type II) were 17.31%, 1.89%, 7.55%, 3.53%, 7%, 4.55%, 4.76% and 6.06% for the age groups of 0-9, 10-19, 20-29, 30-39, 40-49, 50-59, 60-69 and 70-79 years respectively. The anomalies were very significantly more frequent in the 0-9 years age group than in the other age groups (chi 2 = 9.7858, DF = 1, p < 0.05). The incidences of the anomalies (Type I + Type II) were 6.34%, 5.37%, 7.22% for the whole, male, and female populations, respectively. These values were 1.39%, 1.65% and 1.14% for Type Ia, 2.77%, 2.89% and 2.66% for Type Ib, and 1.78%, 0.83% and 2.66% for Type Ic. Both Type Id and II anomalies were determined in only one case for each group in females (0.2%). There was no significant difference between the incidences of the anomalies in both sexes (chi 2 = 0.45, DF = 1, p > 0.05).

Unusual branching in lumbar plexus: case report.

This article describes a complex bilateral variation in the formation of lumbar plexus in a 32 year old male cadaver. On the left side the plexus was postfixed and located posterior to the psoas major muscle. The femoral nerve was formed by the union of anterior rami of the second, third, fourth and fifth lumbar spinal nerves. On the right side, the lumbar plexus was prefixed. The lateral cutaneous nerve of the thigh was formed by the union of the anterior rami of the first and second lumbar spinal nerves. The femoral nerve formed by branches from the first, second, third and fifth lumbar spinal nerves while the obturator nerve was formed by the union of the first, second and third lumbar spinal nerves. The right lumbar plexus was located in the substance of the psoas major muscle. In the present case, the formation of branches of the lumbar plexus were different from the previous data present in the literature.

Histopathological changes and nitric oxide synthase activity in corpus cavernosum from rats with neurogenic erectile dysfunction.

OBJECTIVE: To investigate changes in histology and nitric oxide synthase (NOS) activity in cavernosal tissues from rats with neurogenic erectile dysfunction induced experimentally. MATERIALS AND METHODS: Twenty-four adult male Sprague-Dawley rats were divided equally into three groups and underwent a sham operation (control, group 1), unilateral (group 2) or bilateral (group 3) cavernosal nerve resection. Three months later they were killed and the cavernosal tissues analysed histologically by light and transmission electron microscopy, with NOS activity detected using an NADPH-diaphorase staining technique. RESULTS: On light and electron microscopy, while penile nerves and cavernosal smooth muscle cells had a normal morphological appearance in the eight control rats, there were degenerative changes of the myelinated penile nerves and axonal fibrosis in groups 2 and 3. However, these changes were not significant. Using NADPH-diaphorase staining, NOS activity was detected in all three groups in endothelial cells and cavernosal structures. However, the staining was more intense in endothelial cells and cavernosal muscles of rats in group 2 than in the other groups. CONCLUSION: NOS activity was increased in the cavernosal tissue after cavernosal denervation, but the pharmacological action of nitric oxide may be impaired.

Electron microscopic findings of penile tissues in veno-occlusive dysfunction: is penile biopsy necessary?

In this study, we examined the biopsy patterns of penile tissues taken during operation from patients subjected to surgical treatment for veno-occlusive dysfunction, and evaluated the importance of penile biopsy. We evaluated the findings from 17 patients with venous impotence. Fourteen of them underwent total vein ligation and the rest penile prosthesis implantation. Tissue specimens taken from superficial and deep dorsal veins, tunica albuginea and corpus cavernosum during operation were examined under electron microscope. Tissue specimens taken from 3 cadavers were used as the control group. Although the deep and superficial vein specimens of all patients did not show significant differences, oedema and increase of fibroblasts in collagen fibres of the corpus cavernosum and tunica albuginea were demonstrated. We concluded that penile biopsy as an invasive method does not give enough information about the choice of treatment for erectile dysfunction.

Comparative study between corpus cavernosum-electromyography findings and electron microscopy of cavernosal muscle biopsies in erectile dysfunction patients.

BACKGROUND: Biopsy and electrical activity recordings of the corpus cavernosum are 2 new diagnostic methods for the evaluation of impotent men. We evaluated the corpus cavernosum ultrastructure and electromyography (EMG) recordings from patients with erectile dysfunction. METHODS: Twenty erectile dysfunction patients with veno-occlusive dysfunction underwent a detailed history, physical examination, biochemical tests, hormonal analysis, injection of an intracavernous vasoactive agent (60 mg papaverine-HCl), color penile Doppler ultrasonography, cavernosometry/ cavernosography and corpus cavernosum electromyography (CC-EMG). Thirteen patients underwent total vein ligation and 7 had penile prosthesis implantations. Tissue samples were obtained during surgery from both corpora cavernosa and examined by transmission electron microscopy. Control corporal tissue samples were taken from 3 cadavers. RESULTS: In 15 patients, CC-EMG recordings were 15.6 +/- 0.65 microV in the flaccid state, which decreased in 13 patients after papaverine (5.61 +/- 0.25 microV; P < 0.001). Five patients with diabetes mellitus had low amplitudes in the flaccid state (5.26 +/- 0.45 microV), which did not vary significantly after a papaverine injection (4.99 +/- 0.75 microV). The pathology of the corpus cavernosum biopsy specimens revealed a smooth muscle cell thickened basal membrane, dilated rough endoplasmic reticulum, and increased numbers of fibroblasts, but ultrastructurally normal endothelial cells lining the sinusoids. There was no difference between samples from diabetic or nondiabetic patients, or from either side of the corpora cavernosa. The only pathologic change observed in the controls was mitochondrial swelling. CONCLUSION: CC-EMG is less invasive and a valuable method in patients with erectile dysfunction, whereas no specific findings were observed from penile biopsy specimens.

Unusual branching in lumbar plexus. Case report.

This article describes a complex bilateral variation in the formation of lumbar plexus in a 32 year old male cadaver. On the left side the plexus was postifixed and located posterior to the psoas major muscle. The femoral nerve was formed by the union of anterior rami of the second, third, fourth and fifth lumbar spinal nerves. On the right side, the lumbar plexus was prefixed. The lateral cutaneous nerve of the thigh was formed. By the union of the anterior rami of the first and second lumbar spinal nerves. The femoral nerve formed by branches from the first, second, third and fifth lumbar spinal nerves while the obturator nerve was formed by the union of the first, second and third lumbar spinal nerves. The right lumbar plexus was located in the substance of the psoas major muscle. In the present case, the formation of branches of the lumbar plexus were different from the previous data present in the literature.

A unique anomaly of the fibrous sling of the digastric muscle.

Anomalies of digastric muscle are not very rare. During a routine dissection, it was found on a cadaver that the digastric muscles on both sides had no fibrous slings. It was also observed that the two intermediate tendons crossed over the stylohyoid muscles. Such anomalies should be considered during the evaluation of the floor of the mouth after CT examination of MR imaging, and during surgical procedures as well.

Complex variation of the superficial palmar arch--case report.

This article describes a complex variation in the pattern of blood supply to the palm of the hand. In the present case; a) the superficial palmar branch of the radial a. coursed superficial to the thenar mm.; b) The princeps pollicis and radialis indicis aa. arose from the superficial palmar branch of the radial a.; c) The first and second common palmar digital aa. arose as a common trunk from the superficial palmar arch.

The marginal mandibular branch of the facial nerve.

The peripheral, extraparotid course and localisation of the marginal mandibular branch of the facial n. is described, with variations, based on the dissection of 40 cadaver half heads. Its anatomical relationships with the ramus of mandible and facial a. are studied and morphometric features are reported. Knowledge of the accurate course and relationship of the marginal mandibular branch should help to protect this nerve from surgical injury.

An unusual insertion of accessory biceps brachii muscle.

In the course of a routine dissection of the anterior region of the arm an accessory muscle was observed in the flexor aspect of the right arm of a 64-year-old male cadaver. This accessory muscle, which was considered to be the third head of the biceps brachii muscle originated from the inserting tendon of the deltoid muscle. The muscle gave rise to three tendons as it approached the cubital fossa. Two of these tendons inserted to the bicipital aponeurosis whereas the third tendon inserted to the ulnar head of the pronator teres muscle. Dissection of the forearm on both sides revealed that the palmaris longus muscles was absent bilaterally. Mechanical effects of the insertion tendons of the accessory head of the biceps brachii on the median nerve, especially during the supination of the forearm, are discussed. For radiodiagnostic procedures, MRI images of the accessory head were obtained in the coronal and axial planes.

Agenesis of the celiac trunk: an angiographic case.

In the angiography performed for a clinical diagnosis, a unique case of "agenesis of the celiac trunk" was encountered in a 42-year-old Turkish male. There was instead an artery which arose from the aorta at the level of the first lumbar vertebra, and supplied blood to the territory of both the celiac and superior mesenteric arteries by giving rise to the splenic, the jejunal, the ileal, the pancreaticoduodenal, the proper hepatic and the left gastric arteries, consecutively.