Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment-naïve advanced TC. They received ramucirumab, carboplatin and paclitaxel for six cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Centralized radiologic review was carried out. RESULTS: From November 2018 to June 2023, 52 patients were screened and 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. The Eastern Cooperative Oncology Group performance status was 0 in 68.5% and 1 in 31.4% of patients. At the present analysis carried out some months after the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95% confidence interval (CI) 63.1% to 91.6%]. At the centralized radiological review of 33/35 assessable patients, ORR was 57.6% (95% CI 39.2% to 74.5%). After a median follow-up of 31.6 months, median PFS was 18.1 months (95% CI 10.8-52.3 months) and median OS was 43.8 months (95% CI 31.9 months-not reached). Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE ≥ grade 3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

Affinity purification and partial characterization of the zonulin/zonula occludens toxin (Zot) receptor from human brain.

The intercellular tight junctions (TJs) of endothelial cells represent the limiting structure for the permeability of the blood-brain barrier (BBB). Although the BBB has been recognized as being the interface between the bloodstream and the brain, little is known about its regulation. Zonulin and its prokaryotic analogue, zonula occludens toxin (Zot) elaborated by Vibrio cholerae, both modulate intercellular TJs by binding to a specific surface receptor with subsequent activation of an intracellular signaling pathway involving phospholipase C and protein kinase C activation and actin polymerization. Affinity column purification revealed that human brain plasma membrane preparations contain two Zot binding proteins of approximately 55 and approximately 45 kDa. Structural and kinetic studies, including saturation and competitive assays, identified the 55-kDa protein as tubulin, whereas the 45-kDa protein represents the zonulin/Zot receptor. Biochemical characterization provided evidence that this receptor is a glycoprotein containing multiple sialic acid residues. Comparison of the N-terminal sequence of the zonulin/Zot receptor with other protein sequences by BLAST analysis revealed a striking similarity with MRP-8, a 14-kDa member of the S-100 family of calcium binding proteins. The discovery and characterization of this receptor from human brain may significantly contribute to our knowledge on the pathophysiological regulation of the BBB.

[Leiomyosarcoma of the mesenteric root. A case report]. / Leiomiosarcoma della radice del mesentere. Presentazione di un caso clinico.

Although smooth muscle tumors are the most common mesentery neoplasms, they are lesions of infrequent occurrence. The main clinical features of these malignancies are an insidious onset and an aspecific symptomatology, usually presenting themselves as quite large masses. The preoperative diagnosis is difficult, but selective angiography and CT scan may be of great value for this purpose. Since these malignancies are usually not responsive either to radiotherapy or chemotherapy, once diagnosed, the only hope of cure lies in surgical resection. The authors report case of leiomyosarcoma of the mesentery root, treated with radical surgery and still alive and disease free 12 months after resection.

Vulvo-vaginitis and reproduction.

The main micro-organisms able to interfere with the reproductive function have been considered. In particular, the problems concerning the vaginal environment and its interactions with spermatozoa, immunological aspects and contraception. Lastly, reference has been made to methods of prevention and study in the field of diagnostics and of clinical management.

[The efficacy of the hysteroscopic treatment of menorrhagia associated with uterine fibromyomas]. / Efficacia del trattamento per via isteroscopica della menorragia associata con fibromiomi uterini.

Objective of our study was to determine the effectiveness of hysteroscopic surgery in the treatment of menorrhagia associated with uterine myomas. 25 women with clinical and ultrasonographic diagnosis of intramural or submucous myomas were treated for menorrhagia by hysteroscopic surgery: 9 by resection and 16 by resection and endometrial ablation. In both groups there was a significant decrease of dysmenorrhea. The mean number of pads used during the heaviest day of menses decreased significantly from 19.5 to 7.4 in women undergoing resection only, and from 20.8 to 2.9 in women treated by resection and endometrial ablation. 2 women of 9 became amenorrheic and no one underwent hysterectomy. 12 of 16 became amenorrheic and 2 underwent hysterectomy. Our study show that menorrhagia can be treated by hysteroscopic surgery of uterine myomas in some selected women.

Interpretation of postmortem vaginal acid phosphatase determinations.

Identification of evidence indicative of sexual assault, including elevated levels of acid phosphatase (AP) in the vagina, is an important part of the investigation of female homicidal deaths. In this study, vaginal AP levels in 43 female homicide victims, determined using sodium thymolphthalein as the substrate, were retrospectively correlated with semiquantitative assessment of spermatozoa in vaginal smears. The results were then compared with those from a prospectively studied age-matched group of controls. AP determinations ranged from 0 to 6,000 units (U)/L in the homicide group and from 1 to 726 U/L in the control group. In both groups, the majority of the AP values (homicide, 65%; and controls 85%) were < 100 U/L. Spermatozoa were identified on vaginal smears from 30% of the homicide victims and 17% of the controls. The spermatozoa-positive cases had AP levels that ranged from 2 to 6,000 U/L. In both groups, an AP value of > or = 400 U/L was always associated with the presence of spermatozoa on the vaginal smear. Intermediate AP values (100-399 U/L) were associated with the presence of spermatozoa in 60% of the control group and 22% of the homicide group; 18% of the homicide group and 3% of the control group were positive for spermatozoa despite AP values of < 100 U/L. In the absence of spermatozoa on a vaginal smear, an AP value of > 400 U/L strongly suggests the presence of semen that is either oligo- or aspermic. A low or intermediate AP determination, however, does not exclude the presence of semen and hence a careful search for spermatozoa on the vaginal smear is indicated, regardless of the AP value obtained.

Variability of human coronary artery geometry: an angiographic study of the left anterior descending arteries of 30 autopsy hearts.

A computer-based system is described to measure objectively the geometric parameters of arteries from pairs of projection angiograms. This technique, which employs back-projection to define the vessel axes in 3-D space, was used to obtain selected parameters of coronary artery geometry from radiographic images of autopsy hearts. Results of the first 30 cases are presented, focussing on the distribution of the geometric parameters of the left anterior descending coronary artery (LAD) and its first two major branches. The derived parameters include the angle between the left circumflex artery and the LAD; the angles between the LAD and its early diagonal and septal perforator branches; distances between branch points; and tortuosity. The geometric parameters vary considerably, presumably contributing to a corresponding variability in local hemodynamic and mechanical stresses. Most parameters are uncorrelated. One exception is the angle at the origin of the second diagonal branch, which is positively correlated (p < 0.01) with the distance between the ostia of the first two diagonal vessels; this correlation could reflect the existence of "target" perfusion regions. No relation between geometric parameters and age or gender was seen. In this sample, blacks had a larger angle at the left main bifurcation than whites (p < 0.05).

Postmortem viability and early changes in organ culture of human and rabbit aortic endothelial cells.

In order to understand the role of the postmortem interval (PMI) on endothelial cell changes both in human and rabbit aortas, we have examined the ultrastructural cytomorphologic alterations of these cells. Human aorta (HA) and rabbit aorta (RA) were maintained in calcium-free, glucose-supplemented Hank's balanced salt solution (HBSS). Rabbit endothelial cells (REC) on the aorta (organ culture) assayed morphologically survive for at least 12 h in culture solution. The predominant morphological change in the RA was the formation of multiple subendothelial vacuoles (SEV). These vacuoles may form as the results of increased permeability of endothelial cells to ions and fluid or cell contraction. Cell to cell connection remained intact. Individual and dispersed endothelial cells were observed 8 h after removal from the animal when incubated in calcium-free HBSS. These necrotic endothelial cells were scattered among viable endothelial cells. Human aortic endothelial cells were also well preserved in the same media for periods of 6-8 h postmortem. Increased extracellular calcium (1.3 mM) in the incubation media caused accelerated cell death. These findings suggest that aortic endothelial cells can be preserved for longer periods of postmortem time than would be expected and that the use of calcium-free HBSS media supplemented with glucose improves endothelial cell viability in vitro.

Systemic pseudallescheriasis in a patient with acute myelocytic leukemia.

Presented is a case of widely disseminated systemic pseudallescheriasis in a 41 year old male with acute myelocytic leukemia. The immediate cause of death appeared to be due to an extensive invasion of the lungs which showed massive intra-alveolar hemorrhages, congestion, mycotic thrombi, and multiple fungal lesions in all lobes. Pseudallescheria boydii was diagnosed histopathologically by virtue of its characteristic conidia present in miliary lesions throughout a wide range of host's tissues, including the brain and the thyroid. Three antemortem blood specimens cultured during the patient's final hospital stay were positive for the fungus. It was concluded the fungemia was responsible for the rapid and widespread dispersion of P. boydii in this debilitated patient who was granulocytopenic and immunosuppressed.

Morphology and dimensions of the thoracic cord by computer-assisted metrizamide myelography.

Computed tomographic (CT) measurements of the thoracic spine and its contents were obtained in 33 patients undergoing metrizamide myelography for various spinal disorders. Twenty-eight of these patients had symptoms referable to the cervical or lumbar region and form the basis of this study. Five patients had symptoms referable to the thoracic spine. Sagittal and coronal CT measurements of the thoracic cord and subarachnoid space were obtained in all cases. In addition, macroscopic measurements of the thoracic cord were obtained from 10 autopsies for correlation with the CT findings. The technical aspects of the measurements are discussed; the normal morphology of the thoracic cord and thecal sac is presented; and the metrizamide CT pattern associated with pathologic lesions involving the thoracic cord is analyzed.

Acute renal failure and renal tubular squamous metaplasia following treatment with streptozotocin.

Nephrotoxicity, in the form of transient proteinuria, azotemia, abnormalities of tubular function, and acute renal failure, is the major toxic condition following administration of streptozotocin. The renal morphologic and ultrastructural abnormalities associated with streptozotocin remain poorly defined. We describe a patient with metastatic islet cell tumor of the pancreas who was treated with 16 weekly courses of 1 g/m2 of streptozotocin without marked change in renal function. Following a six-week hiatus without change in renal function, a single course of 1 g/m2 of streptozotocin was administered and resulted in acute renal failure. Light microscopic examination of the kidneys showed irregularly dilated renal tubules lined by low cuboid epithelium. The cells were pleomorphic and showed some mitoses. Nuclei were irregular and variably hyperchromatic. Electron microscopic examination disclosed large aggregates of fine microfilaments in the proximal convoluted tubules and collecting ducts. Microfilament aggregates were both free in the cytoplasm and membrane bound. Microfilaments were proved to be tonofilaments by the demonstration of keratin within the epithelium, using the immunoperoxidase method. These data suggest that squamous metaplasia may be an important part of streptozotocin renal toxicity, and the suggestion is made that they may be an antecedent of neoplastic change.

Pathologists' assistant training programs: a report.

This report describes the training of pathologists' assistants in three training programs: at Duke University, at Quinnipiac College associated with Yale University, and at the University of Maryland School of Medicine. The role of this new health profession is described as well as the job situation, experience, and current status of accreditation.

Angioimmunoblastic lymphadenopathy. Its occurrence with meningeal involvement.

A case of angioimmunoblastic lymphadenopathy with involvement of the leptomeninges and the lumbosacral nerve roots was studied. This condition seems related to malignant lymphoma, and clinical improvement occurred with administration of systemic corticosteroids.

Congestive heart failure and endocardial fibroelastosis caused by chronic lymphocytic leukemia.

Endocardial fibroelastosis developed in the heart of a patient who had chronic lymphocytic leukemia. Leukemic infiltrates were found in the endocardial scar tissue, myocardium, coronary arteries, and other viscera. In view of the absence of any other known cause of endocardial fibroelastosis, it is postulated that endocardial fibroelastosis was caused by myocardial leukemic infiltration. This is the first reported case of endocardial fibroelastosis in a patient with chronic lymphocytic leukemia.