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.

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.

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.

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.

Surgical resection for neuroendocrine tumors of the pancreas: a fourteen years single institutional observation.

OBJECTIVE: Pancreatic neuroendocrine tumors (PNETs) are a rare entity that can present with symptoms of hormone overproduction with surgical resection being the only chance for cure despite the poorly defined tumor behavior. Their management involves a variety of therapies which require a well coordinated multidisciplinary team with the effort to optimize outcomes. PATIENTS AND METHODS: A retrospective analysis of 25 consecutive patients was performed by means of our single institution prospectively maintained database. All patients' files from 1999 to 2013, with histologically proven neuroendocrine tumors of the pancreas, were reviewed for clinical presentation, functional status, treatment, postoperative morbidity and mortality. RESULTS: Of 25 patients a total of 22 patients (11 females, 11 males, average age 49.7 years) underwent surgery with curative intent. We had 3 female patients that underwent palliative surgery because of unresectable disease. Nineteen of the 25 were not functional tumor. For the resected patients the overall morbidity was 38.8%. The 30-day mortality rate was zero. The overall median length of hospital stay was 10.4 days (range 4-23 days). CONCLUSIONS: Surgical resection with regional lymph node dissection is the only potentially curative therapy for patients with localized PNETs with the exceptions of most insulinomas where simple enucleation may be the standard of treatment. The anatomic considerations for determining the resecability are the same as those for pancreatic adenocarcinomas. Careful follow-up after surgery is essential because up to 50% of patients who undergo complete resection develop metachronous liver metastasis. Distant metastatic disease should be resected if possible.

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.

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.

Serum insulin-like growth factor-I (IGF-I) reference ranges for chemiluminescence assay in childhood and adolescence. Data from a population of in- and out-patients.

BACKGROUND: Insulin-like growth factor I (IGF-I) measurement is widely used for the diagnosis of disorders of GH secretion and sensitivity, and for monitoring of both GH and IGF-I replacement therapies. However, the lack of appropriate reference values obtained from large and representative samples undermines its practical utility. OBJECTIVE: To establish IGF-I reference values for a commonly used enzyme-labeled chemiluminescent immunometric assay in a large population of children aged 0 to 18 years. DESIGN: Cross-sectional analysis of serum IGF-I levels from samples collected in the two major Italian Children's Hospitals. SUBJECTS AND METHODS: IGF-I was measured using a solid-phase, enzyme-labeled chemiluminescent immunometric assay in 24403 children (50.6% girls) aged 0 to 18 years. Quantile regression coupled to multivariable fractional polynomials was used to produce age- and sex-specific reference values. MAIN OUTCOME MEASURE: Age- and sex-specific IGF-I reference values. RESULTS AND CONCLUSION: Reference values for immunometric assay of IGF-I were produced in a large sample of children and adolescents. Prediction equations were provided to automatize their calculations.

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.

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.

Serous cystadenocarcinoma of the pancreas with portal thrombosis.

Serous cystadenocarcinoma of the pancreas is a rare entity. We report on a primary tumor of the pancreas in a 74-year-old male. Computerized tomography showed an abdominal mass within pancreatic head, portal vein infiltration and absence of metastatic lesions. Patient underwent Whipple's procedure and portal vein thrombectomy. Pathologic examinations of the specimen showed it to be serous cystadenocarcinoma. To the knowledge of the authors, serous cystic neoplasms of the pancreas have been uniformly benign in biologic behaviour. However, serous cystadenocarcinoma of the pancreas has been reported as a new entity. The current report is the fi rst among 22 cases described to present portal vein thrombosis and might support the local malignant behaviour of this controversial class of tumours.

Laparoscopic enucleation of a jejunal mesenteric cyst: a case report.

Mesenteric cysts (MC) are a rare surgical condition occurring approximately in 1/200.000-350.000. The aetiology is unknown and the rarity of the tumor has led to confusion about their nature and classifi cation. They can be uni- or multi-locular, and are mostly benign. Approximately 830 cases have been reported in the literature and only four of them were found to be malignant. Cysts are usually diagnosed during routine abdominal examinations, they can present with various signs, such as acute abdominal pain, chronic abdominal pain, nausea and vomiting, or change in bowel habit. Although rare, shock due to rupture or bleeding of the cyst, intestinal obstruction secondary to external compression and volvulus or torsion of the cyst have been reported. Defi nitive treatment requires complete surgical resection of the cyst and is indicated when the lesion causes symptoms. We report a case of calcifi ed MC which was completely excised using the laparoscopic approach.

Distal pancreatectomy with en bloc resection of the celiac axis for pancreatic adenocarcinoma.

Resection of celiac axis for gastric cancer was first performed by Appleby in 1953. Subsequently, Mayumi et al. and Kimura et al. adopted this approach for locally advanced adenocarcinoma of pancreatic body. We are here describing this technique in case of adenocarcinoma of pancreatic body with infiltration of celiac axis achieving also gastric preservation. Our patient presented with diabetes, back pain and weight loss. CT scan showed a 3 cm mass in the body of pancreas infiltrating the origin of celiac axis, causing obstructive atrophy of pancreatic tail. Bilirubin, transaminases, amylase and tumoral markers were in the normal range with the exception of CEA (34 ng/ml) and chromogranin (30 IU/l). Vascular reconstruction imaging indicated the feasibility of the procedure. Under intraoperative ultrasound guidance we clamped the common hepatic artery in order to check the gastric and hepatic blood flow. We then performed a distal pancreasectomy and splenectomy with "en bloc" resection of celiac axis and regional lymphadenectomy. Appleby operation can increase the resectability of locally advanced cancer of the body and tail of the pancreas and offers not only a better life quality for patients but also perfect pain relief. This technique demands a multidisciplinary approach with careful pre and intra operative vascular evaluation, which is mandatory in assessing candidacy for this procedure.

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).

Portal vein thrombosis following laparoscopic total mesorectal excision: case report.

Data continue to grow regarding the safety and technical feasibility of laparoscopically assisted total mesorectal excision (TME). As this minimally invasive alternative to open colonic resection becomes more popular, it is inevitable that information on the benefits and complications associated with it will continue to expand. Portal vein thrombosis (PVT) has been reported after a variety of laparoscopic procedures. We report a case of superior mesenteric, splenic and portal vein thrombosis following laparoscopically assisted TME. To our knowledge, this complication of laparoscopic TME has not been previously reported in the literature. PVT should be ruled out in patients who present with vague abdominal symptoms. The course of this complication, while potentially devastating, is usually benign and responds well to lysis and/or anticoagulation.

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.

Aggressive fibromatosis of the neck initiated after thyroidectomy.

We describe the case of a 44-yr-old woman, who 2 yr after thyroidectomy for a multinodular goiter with a follicular adenoma showed a rapidly growing mass of the neck causing dysphagia and moderate pain. Fine needle aspiration biopsy revealed the presence of fibroblast-like cells, partially with atypical features and no colloid: the cytological diagnosis was suspicious for an indeterminate (mesenchymal) neoplasm. Histological diagnosis, after extensive surgery, indicated aggressive fibromatosis. Immunohistochemistry was positive for vimentin and negative for thyroglobulin. After surgery, nuclear magnetic resonance showed a persistent mass of approximately 2 cm; dysphagia and pain persisted. Therefore, the patient received external radiation therapy (total dose 60 Gy) with clinical benefit. The patient is without symptoms 1 yr after surgery.

[Treatment of local recurrences of rectal cancer]. / Trattamento delle recidive locali del cancro del retto.

In this work we report the results of 27 patients who underwent a second surgical operation for local disease recurrence after colorectal surgery for cancer. We describe the different intervention we performed and for everyone of them we analyze intraoperative mortality and morbidity, long term survival and quality of life related.

[Multiple organ resection in advanced gastric carcinoma: experience of 7 years]. / Resezioni multiorgano nel carcinoma gastrico avanzato setti anni di esperienza.

In this work we report our experience on multiorgan resections (MOR) for local advanced gastric cancer. From 1998 to 2004 in our Department 79 patient underwent total or partial resection of stomach associated with removal of various other organs. The results we report come from the evaluation of perioperative mortality and morbidity rates and further analysis of median survival time and quality of residual life. In conclusion, we affirm the utility of major surgery in advanced gastric cancer only in conditions that guarantee an acceptable rate of major complications.