Hypersensitivity to platinum salts according to BRCA status in ovarian cancer: A retrospective analysis of clinical outcomes and systematic review of literature.

BACKGROUND: Hypersensitivity reactions (HSRs) to platinum are an important issue in the treatment of patients (pts) with ovarian cancer (OC). Germline BRCA mutations have been proposed as a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum in OC pts. with known BRCA status. PATIENTS AND METHODS: We retrospectively analyzed 432 pts. from 5 Italian Centers. In addition, we performed a systematic review and meta-analysis of published series. RESULTS: Four hundred nine pts. received at least one prior platinum-based treatment line: 314 were BRCA wild type (77%) and 95 were BRCA mutated (23%). There was no statistical difference in exposure to platinum. Incidence of any grade HSRs was higher among BRCA mutated pts. [9% vs 18%, p = 0.019] and the time-to-HSRs curves show that the risk increases with the duration of platinum exposure, in BRCA mutated pts. more than in BRCA wild type. A multivariable analysis showed that harboring a germline BRCA mutation was related to a higher incidence of HSRs (HR: 1.84, 95% CI 1.00-3.99, p = 0.05) while having received pegylated liposomal doxorubicin (PLD) was related to a lower incidence of HSRs (HR: 0.03 95% CI 0.004-0.22, p = 0.001). The systematic review confirmed the higher incidence of HSRs in BRCA mutated pts., though heterogeneity among series was significant. CONCLUSIONS: In OC pts. with BRCA mutations, there is a significantly higher incidence of HSRs to carboplatin, not justified by longer drug exposure. On the other hand, PLD exerted a protective role in our series.

Exercise-induced GH secretion is related to puberty.

PURPOSE: Exercise represents a physiological stimulus that initiates the coordinated responses of hypothalamic-pituitary axis and sympathetic nervous system. Aims of the study were: 1) to analyze the response of GH, cortisol and prolactin to acute exercise in healthy children with normal GH response to stimulation tests 2) to evaluate the reliability of physical exercise as a screening test for GH secretion. METHODS: Forty-four children (mean age 9.35 ± 2.69 years, range 4-13.7) underwent standardized Bruce's test on treadmill. Twenty-nine children were pre-pubertal (nine females and 20 males) and 15 children were pubertal (ten females and five males). RESULTS: Exercise elicited a peak secretion of all the analyzed hormones. GH showed the highest mean percentage increase (558%), followed by prolactin (178%) and cortisol (23%). In 19/44 children (43.2%), GH peak did not reach the cut-off level of 8 ng/ml, considered as the normal GH response to stimulation tests. Despite a wide inter-individual variability, both GH peak and GH increase from baseline were higher in pubertal children than in pre-pubertal ones (GH peak: 13.49 ± 10.28 ng/ml versus 6.6 ± 4.09 ng/ml-p < 0.001; GH increase: 12.02 ± 10.30 ng/ml versus 5.28 ± 3.97 ng/ml-p < 0.001). The impact of puberty on both GH peak and GH increase was independent of sex, age, BMI SDS and VO2max. No differences related to sex or pubertal status were found in cortisol and prolactin responses. CONCLUSION: Exercise-induced GH secretion should not be considered a valuable screening tool in the diagnostic work-up of GH deficiency, due to the wide inter-individual variability in GH response. As described for standard GH stimulation tests, puberty represents the key factor that enhances GH secretion in healthy children.

No thyroid abnormalities in patients submitted to cardiac catheterization in the first eighteen months of life.

BACKGROUND: No data are available about the risk of thyroid disturbance after exposure to low-dose radiation due to the use of cardiac catheterization in the first years of life. AIM: To determine the risk of functional and morphological thyroid abnormalities in a homogeneous cohort of patients who underwent diagnostic low-dose radiation for heart catheterization during the first 18 months of life. SUBJECTS AND METHODS: Fifty-five patients, submitted to cardiac catheterization during the first 18 months of life, underwent evaluation of the thyroid function and structure after a median period of 13 yr since the first radiation exposure. Sixty-eight unexposed controls matched for age and sex, underwent the same protocol. Twenty-two patients were then re-evaluated after a median period of 22 yr. RESULTS: Thyroid function resulted normal in both patients and controls. The prevalence of small thyroid nodules and inhomogeneous structures in ultrasound study was not augmented in irradiated patients compared to controls. No thyroid tumors or reduced thyroid volume were observed. CONCLUSIONS: Neither functional nor morphological disorders of the thyroid gland were demonstrated after a period up to 24 yr in patients exposed to diagnostic ionizing radiation for cardiac catheterization during the first 18 months of life.

Local excision with adjuvant imatinib therapy for anorectal gastrointestinal stromal tumors.

Rectal gastrointestinal stromal tumors (GISTs) are uncommon, and the role of local excision versus a more extensive resection after the advent of effective targeted chemotherapy with imatinib is not known. Our aim is to present two cases of large anorectal GIST treated with local excision through a new anterolateral trans-sphincteric approach followed by adjuvant therapy with imatinib. Two patients (both males, 68 and 63 years old) presented at our institution with anorectal GIST in the period October-November 2010. Their medical records, pathology results, and imaging studies were retrospectively reviewed. Both patients presented with an anterior perianal mass. Imaging studies were characteristic of GIST originating in the lower rectum, circumscribed by a pseudocapsule, and protruding into the ischiorectal fossa. Both patients underwent local excision via an anterolateral trans-sphincteric approach. Both tumors were removed intact, with microscopically negative margins. The maximum tumor diameter was 8 and 9 cm, and the diagnosis of GIST was confirmed by positive CD117 and CD34 staining in both cases. Both tumors had a high (>5/50HPF) mitotic index. The patients had an uneventful postoperative course and were discharged on days 5 and 6. Both patients were started on imatinib 400 mg bid postoperatively. Postoperative magnetic resonance imaging and positron emission tomography computed tomography were carried out at 12 months and did not reveal any signs of recurrence. The patients are currently disease-free at 24 and 23 months of follow-up. In selected cases, complete excision of rectal GIST with negative margins is feasible via a trans-sphincteric approach. With the use of adjuvant therapy, which is currently advocated in all high-risk cases, it is possible that local excision with its reduced morbidity may become a viable alternative, especially in patients who would otherwise require abdominoperineal excision such as the two presented here. Prospective studies with longer follow-up are needed to confirm adequate oncologic results.

Is subclinical adrenal failure in adrenoleukodystrophy/adrenomyeloneuropathy reversible?

BACKGROUND: X-linked adrenoleukodystrophy/adrenomieloneuropathy (ALD/AMN) is a progressive neurodegenerative disorder due to mutations in the ABCD1 gene encoding the ABC transporter ALDP. Mutations in ALDP impair peroxisomal ß-oxidation of very long chain fatty acids (VLCFA), resulting in elevated levels of VLCFA in plasma, nervous system, and adrenals. Lorenzo's oil, combined with VLCFA- poor diet, normalizes plasma VLCFA within 1 month, but it does not prevent the progression of pre-existing neurological symptoms. No previous study analyzed the effect of Lorenzo's oil therapy on adrenal function. AIM: To investigate short-term effects of Lorenzo's oil, combined with VLCFA- poor diet, on adrenal function of AMN patients with early subclinical signs of adrenal failure. SUBJECTS AND METHODS: Seven AMN subjects underwent VLCFA-restricted diet combined with Lorenzo's oil (45 ml/day po), without steroid therapy, for 6 months. RESULTS: All patients had elevated ACTH at baseline, and a significant reduction was evident after 6 months (median ACTH at baseline: 1300 pg/ml, range: 720- 2100; median ACTH at 6 months: 186 pg/ml, range: 109-320, p: 0.0156). Cortisol was normal both at baseline and after 6 months. VLCFA dropped in all patients during the 6- month follow-up, and no patient required glucocorticoid replacement therapy. CONCLUSIONS: Adrenal insufficiency in ALD/AMN is probably due to a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of the adrenal cell membrane functions. In an early phase, Lorenzo's oil therapy may be able to improve VLCFA clearance and restore a normal ACTH receptor activity, and hypoadrenalism may be potentially reversible.

Pre-diabetes in Italian obese children and youngsters.

BACKGROUND AND AIM: Metabolic characteristics and rate of progression to overt Type 2 diabetes (T2D) in low-risk European obese children are not well documented. Aim of the study was to investigate differences in insulin sensitivity and secretion in Italian obese children and youngsters with pre-diabetes. METHODS: Ninety-six obese children and youngsters with pre-diabetes, pair-matched with individuals with normal glucose tolerance (NGT) were included in the present study. Participants were screened by oral glucose tolerance. Pre-diabetes was classified as impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and combined IFG-IGT. Homeostasis model assessment of insulin resistance (HOMA-IR), 2-h insulin, insulin sensitivity index (ISI) and disposition index (DI) were calculated to estimate fasting, peripheral and whole body insulin sensitivity and capacity of pancreatic islets to compensate for lower insulin sensitivity, respectively. One-way analysis of variance was used to compare groups. RESULTS: Eleven subjects had IFG (11.5%), 79 IGT (82.3%), 6 combined IFG-IGT (6.3%). Individuals with IFG showed the highest HOMA-IR (p=0.0007), those with IGT the highest 2-h insulin (p<0.0001), those with IFG-IGT the lowest ISI (p<0.0001), with severely reduced DI (p=0.0003). Compared with NGT, DI was 60% lower in those with IFG-IGT. CONCLUSION: IFG is linked primarily to fasting insulin resistance, IGT to peripheral insulin resistance. IFG-IGT is hallmarked by reduced whole body insulin sensitivity and an additional severe defect in DI. Further longitudinal studies are needed to understand whether the different categories of pre-diabetes in European obese adolescents represent real pre-diabetic alterations.

Emerging molecular alterations leading to histology-specific targeted therapies in ovarian cancer beyond PARP inhibitors.

After more than 30 years of a one-size-fits-all approach in the management of advanced ovarian cancer, in 2018 the SOLO1 trial results have introduced a new era of personalized medicine. A deeper knowledge of ovarian cancer biology and the development of new drugs targeting specific molecular pathways have led to biomarker-driven phase 3 trials with practice changing results. Thereafter, platinum-based combinations are no longer the only therapeutic options available in first line setting and poly-ADP ribose polymerase inhibitors maintenance therapy has become the mainstay in patients with tumor harboring a homologous recombination defect. However, most of the recent therapeutic breakthroughs regard high grade serous carcinoma, the most frequent ovarian cancer subtype, and only few improvements have occurred in the management of less common histotypes. Moving towards the next challenges, we aimed to investigate and review new potential molecular targets in ovarian cancer, according to histotype, starting from promising molecular drivers and matched drugs that have been investigated in early and late-stage clinical trials or conceptualized in preclinical studies.

A bump in the neck. Myositis ossificans of the omohyoid muscle: Imaging findings.

Myositis ossificans is a benign ossifying soft-tissue mass that occurs in muscle. In the majority of cases it is related to trauma but rarely observed in the neck. A 54 year-old-man with history of minor trauma and anticoagulant drug assumption for V Leiden mutation, was referred to our institution for a painless mass in the right supraclavicular fossa. On CT plan study a mass with negative attenuation values located in the posterior triangle of the neck, into the inferior belly of the right omohyoid muscle was evident. On MRI the lesion appears as an ovalar mass, with smooth borders, isointense to muscles on T1 images, isointense to fat on T2 images, intensely enhancing after i.v. Gd administration. After surgical removal the pathologist concluded for the nature of myositis ossificans. This is the first case, as far as we know, reported in the literature of a myositis ossificans arising in the inferior belly of the omohyoid muscle in a patient treated with dicumarol.

Cytoreductive surgery (cs) and hyperthermic intraperitoneal chemotherapy (hipec) in treatment of peritoneal surface malignances: report of a phase II clinical study.

Peritoneal surface malignancy is the expression of a spectrum of disease involving the peritoneum primary or secondary to gastrointestinal and gynecological neoplasms. Even if intraperitoneal therapy has now been demonstrated in multiple randomized trials to improve the outcome of chemotherapy for patients with optimally debulked or small volume ovarian carcinoma, it is believed that peritoneal carcinomatosis is considered an advanced stage of disease; for this reason, it is treated with systemic chemotherapy and surgery plays only a palliative role (1). In the last twenty years, some centres have developed surgical treatment of peritoneal carcinomatosis that involves aggressive cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy. This treatment has improved and prolonged survival, despite the associated high morbidities and mortalities (3-14).

Young elite athletes of different sport disciplines present with an increase in pulsatile secretion of growth hormone compared with non-elite athletes and sedentary subjects.

Acute exercise is a well-known stimulus for GH secretion but the effect of chronic training on GH secretion still remains equivocal. The aim of our study was to analyse spontaneous pulsatile GH secretion (during a period of 2 hours in the morning) in a group of young elite athletes (EA) compared with non-elite athletes (NEA), and sedentary subjects (SS). Mean and peak GH levels proved significantly higher in EA than in NEA and SS (p=0.0004 and p<0.0001, respectively). The same differences in mean and peak GH levels were also demonstrated in males and females when considered separately (males: p=0.0062 and p=0.0025; females: p=0.0056 and p=0.0032). In addition, GH levels (mean and peak) were higher in females than in males in SS while no differences were demonstrated between the 2 sexes in the EA and NEA groups. IGF-I levels were within the normal range for age in all the subjects with no difference between the 3 groups. Body mass index (BMI) exhibited no difference between groups, while EA showed higher lean mass (p=0.0063) and lower fat mass (p=0.0139) than NEA and SS measured by dual-energy x-ray absorptiometry. A strong positive correlation between GH levels (mean and peak) and hours of training a week was demonstrated (p=0.0101; r2=0.1184; p=0.0022; r2=0.1640, respectively). In conclusion, GH levels were higher in EA than NEA and SS without any modification of IGF-I levels; a strong positive correlation was present between GH levels and intensity of training. An increase in the knowledge of the effect of chronic training on GH secretion could improve the training programme to elicit the greatest exercise- induced GH response.

Oral etoposide in heavily pre-treated metastatic breast cancer: A retrospective series.

BACKGROUND: Patients with metastatic breast cancer (MBC) can derive clinical benefit from several subsequent lines of chemotherapy. However, in heavily pre-treated patients, agents with clinical activity, a favourable side effects profile and a convenient administration modality are preferred. PATIENTS AND METHODS: We retrospectively analyzed 110 patients with previously treated MBC, who received oral etoposide at the dose of 50 mg/day for 20 days in 28 days cycles, between 2003 and 2017. Because this was not a prospectively planned study, to describe the clinical performance of oral etoposide we adopted the approach suggested by Dzimitrowicz and colleagues (J Clin Oncol. 2016; 34:3511-17); Tumour Response (TR) was defined as the proportion of physician-reported clinical or imaging response; Prolonged Duration on Therapy (PDT) as the proportion of non-progressing patients whose treatment lasted more than 6 months. Furthermore, we evaluated median duration on therapy (TD) and median Overall Survival (OS) by the Kaplan Meier method. RESULTS: The median number of previous chemotherapy lines was 5 (range 2-8). TR, PDT, median TD and median OS were 6.4%, 18.2% 4 (range 3.5-4.5) and 10.6 (range 8.4-12.8) months respectively. Interestingly, etoposide activity was unrelated to the number of previous lines and type of metastatic involvement. Oral etoposide was well tolerated with only two patients discontinuing therapy due to toxicity. CONCLUSIONS: In this large, single Institution, real practice analysis oral etoposide is a valuable and safe option for pre-treated metastatic breast cancer patients and might be considered in patients failing other approaches, but still suitable for chemotherapy.

Mechanism of calcium oscillations in migrating human astrocytoma cells.

Numerous studies show that intracellular calcium controls the migration rate of different mobile cell types. We studied migrating astrocytoma cells from two human cell lines, U-87MG and A172, in order to clarify the mechanisms by which calcium potentially influences cell migration. Using the wound-healing model to assay migration, we showed that four distinct components of migration could be distinguished: (i) a Ca(2+)/serum-dependent process; (ii) a Ca(2+)-dependent/serum-independent process; (iii) a Ca(2+)/serum-independent process; (iv) a Ca(2+)-independent/serum-dependent process. In U-87MG cells which lack a Ca(2+)-dependent/serum-independent component, we found that intracellular Ca(2+) oscillations are involved in Ca(2+)-dependent migration. Removing extracellular Ca(2+) greatly decreased the frequency of migration-associated Ca(2+) oscillations. Furthermore, non-selective inhibition of Ca(2+) channels by heavy metals such as Cd(2+) or La(3+) almost completely abolished changes in intracellular Ca(2+) observed during migration, indicating an essential role for Ca(2+) channels in the generation of these Ca(2+) oscillations. However, specific blockers of voltage-gated Ca(2+) channels, including nitrendipine, omega-conotoxin GVIA, omega-conotoxin MVIIC or low concentrations of Ni(2+) were without effect on Ca(2+) oscillations. We examined the role of internal Ca(2+) stores, showing that thapsigargin-sensitive Ca(2+) stores and InsP(3) receptors are involved in Ca(2+) oscillations, unlike ryanodine-sensitive Ca(2+) stores. Detailed analysis of the spatio-temporal aspect of the Ca(2+) oscillations revealed the existence of Ca(2+) waves initiated at the leading cell edge which propagate throughout the cell. Previously, we have shown that the frequency of Ca(2+) oscillations was reduced in the presence of inhibitory antibodies directed against beta3 integrin subunits. A simple model of a Ca(2+) oscillator is proposed, which may explain how the generation of Ca(2+) oscillations is linked to cell migration.

Benign fibromatous tumor (fibroma) of the kidney: a case report.

Benign fibromatous tumor (fibroma) of the urogenital tract is a distinctive pathologic entity occurring in the testis, paratesticular structures and renal peripelvis. We report a well-circumscribed tumor replacing the cortex and the medulla of more than half of the upper kidney, radiographically thought to be renal cell carcinoma. Histologically, the tumor was characterized by a variable cellularity and was composed of bland spindle-shaped cells loosely dispersed in a fibromyxoid to densely fibrous stroma in which calcifications and chronic inflammation were not observed. Immunocytochemistry showed that cells were positive for vimentin and, only focally, stained positive for desmin and alpha-smooth muscle actin. Differential diagnosis included a wide spectrum of benign and malignant spindle cell tumors. The clinicopathologic features were consistent with benign fibromatous tumor (fibroma) of the kidney. To our knowledge, this is the first case of benign fibromatous tumor (fibroma) of the kidney reported in the English literature.

Effects of repeated, small aliquot, same donor transfusions of HL-A defined blood on prospective recipients.

A series of HL-A defined, nonrelated blood transfusions given in small aliquots from the same donor to prospective cadaveric and living-related donor recipients has been presented. The results to date show 100% kidney survival in this small series over a relatively short period of time. The rejections noted have been very mild, and easily reversed. Nonspecific antibodies appear to be produced by the recipients in response to the blood, and these antibodies seem to have no negative effect upon kidney survival. This method of small aliquot transfusion to produce the desired effect is cheaper, wastes less blood, is less likely to lead to a CMV or HAA infestation in the transfusion recipient, and appears to be a highly efficient method of producing the desired effect.

[Criteria for applying target biopsy and histological features in the diagnosis of gastric cancer in situ (author's transl)]. / Criteri applicativi della biopsia mirata ed aspetti istologici nella diagnosi del carcinoma gastrico in situ

A histological examination of samples of 131 chronic gastric ulcers, 9 polyps and 12 cases of mucosal atrophy taken by means of a endoscope showed 3 border-line lesions and 4 early gastric cancers. The histological patterns of these lesions are described and the difficulty of histological diagnoses in early malignancy are emphasized.

Gastroscopy and directed biopsy in the diagnosis of primary gastric lymphomas. Report of 16 personal cases.

The results of an endoscopic bioptic study of 16 cases of primary gastric malignant lymphoma are reported. Endoscopic observation suggested a diagnosis of malignant lymphoma in 50% of the cases, while directed biopsy gave a similar diagnosis in 75% of the cases. A correlation of the endoscopic and the histologic results gave a diagnostic reliability or 87.5% (14 of 16 cases). In order to obtain also in this group of neoplasms the diagnostic positivity already obtained in the epithelial forms, both improvement in the bioptic sampling technique and a better knowledge of the endoscopic morphology of the lesions must be achieved.

[1st case of extra-gastrointestinal anisakiasis in a human diagnosed in Italy]. / Primo caso di anisakiosi extragastrointestinale nell'uomo diagnosticato in Italia.

A case of extra-gastrointestinal infection by Anisakis in a woman living in Catania (Sicily, Southern Italy) is described. The patient complained of severe pain in the ileocecal region, and a diagnosis of acute appendicitis led to an appendectomy. During the intervention, a laparoscopic exploration showed a nodule on the large omentum that was surgically removed. Parasitological diagnosis was achieved on the basis of morphological observations carried out on the histological sections of the nodule.

[Changes in the lymphocyte subpopulations in a patient with orthotopic transplant of the liver]. / Variazioni delle sottopopolazioni linfocitarie in un paziente con trapianto ortotopico di fegato.

Earlier experimental studies have shown that the cyclosporin immunosuppressive effect (CsA) can be modulated by drug timing as well as dose. More specifically treatment during the night was constantly associated with a statistically significant improvement in the prevention or delay of allograft rejection. The present study reports on the circadian variations in T-lymphocyte subpopulations in the peripheral blood of a patient given an orthotopic liver allograft and treated with CsA and steroids. In particular, a statistically significant circadian rhythm (p = 0.012) was observed for the T-helper (OKT4) subset with a peak time (acrophase) occurring during the night at 4:27 A.M. In this patient, CsA treatment was, therefore, adapted to the T-helper cycle with the aim of marching CsA blood level variations to that curve. The results suggest that CsA timing can provide a tool for daily dose reduction and then improve the success rate of drug treatment.

[The clinico-instrumental assessment of the vascular status of the uremic patient for the making of a vascular access for hemodialysis]. / Valutazione clinico-strumentale del patrimonio vascolare del paziente uremico per la confezione di accesso vascolare per emodialisi.

For almost twenty years the Institute of General Surgery and Organ Transplant at Palermo Polyclinic has dealt with vascular problems arising during the preparation, monitoring and search for vascular access in uremic patients. For a number of years advantage has been taken of the vascular status in uremic patients; in fact, the possibility of creating a long-lasting and efficient vascular access also depends on the optimal use of the patient's vascular resources. The authors briefly describe the clinical and instrumental diagnostic strategy for the approach to a vascular access in uremic patients which must be correct and must respect the vascular resources of a "chronic" patient by definition, for whom hemodialysis is often the only prospect of therapy.

Laparoscopic robot-assisted right adrenalectomy and left ovariectomy (case reports).

BACKGROUND: Laparoscopic robot-assisted surgery has been created to reduce the patient risk of inappropriate scope movements by an assistant and to perform operations quicker and with greater ease. The Authors report their experience in laparoscopic robot-assisted right adrenalectomy for Conn's syndrome and right ovariectomy for benign ovarian mass. MATERIAL AND METHODS: Case 1. CT scan: solid right adrenal mass (diam. 2 cm). An anterior transperitoneal approach was used to perform the right adrenalectomy. The surgeon was placed at the ventral side of the patient and robotic-device was placed at the backside. HISTOLOGY: adrenocortical adenoma (diam. 3 x 2.5 x 1.5 cm). Case 2. CT scan: left iliac mass (diam. 3.5 cm) with origin in the left ovary. The patient was positioned in the gynecological position. The surgeon was positioned on right side of the patient and robot-device on left side. Left ovariectomy was performed. HISTOLOGY: ovarian serous cyst. RESULTS: Operating time was 180 min. for the adrenalectomy and 25 min. for the ovariectomy. No blood loss or complications for both operations were encountered. Image was steady and lens cleaning was unnecessary. CONCLUSIONS: The robot device (AESOP 2000) facilitated the procedures by enhancing stability of the image and reducing the need for lens cleaning. We believe that this method is feasible and could be advantageous especially for cholecystectomy, Nissen funduplication or ovariectomy but at the moment there are no comparative studies to establish the real value of this device.