Average treatment effect of hepatic resection versus locoregional therapies for hepatocellular carcinoma.

BACKGROUND: When comparing the efficacy of surgical and non-surgical therapies for hepatocellular carcinoma (HCC), a major limitation is the causal inference problem. This concerns the impossibility of seeing both outcomes of two different treatments for the same individual at the same time because one is inevitably missing. This aspect can be addressed methodologically by estimating the so-called average treatment effect (ATE). METHODS: To estimate the ATE of hepatic resection over locoregional therapies for HCC, data from patients treated in two tertiary care settings between August 2000 and December 2014 were used to obtain counterfactual outcomes using an inverse probability weight survival adjustment. RESULTS: A total of 1585 patients were enrolled: 815 underwent hepatic resection, 337 radiofrequency ablation (RFA) and 433 transarterial chemoembolization (TACE). The option of operating on all patients who had tumour ablation returned an ATE of +9·8 months for resection (effect size 0·111; adjusted P = 0·064). The option of operating on all patients who had TACE returned an ATE of +27·9 months (effect size 0·383; adjusted P < 0·001). The ATE of surgery was negligible in patients undergoing ablation for very early HCCs (effect size 0·027; adjusted P = 0·627), independently of albumin-bilirubin (ALBI) grade; or in patients with ALBI liver function grade 2 (effect size 0·083; adjusted P = 0·213), independently of tumour stage. In all other instances, the ATE of surgery was notably greater. Operating on patients who had TACE with multinodular HCC beyond the Milan criteria resulted in a mild ATE (effect size 0·140; adjusted P = 0·037). CONCLUSION: ATE estimation suggests that hepatic resection is a better treatment option than ablation and TACE in patients with HCC.

The Italian Register of Biological Prostheses.

BACKGROUND: A wide variety of meshes are available for surgical treatment of abdominal wall defects. These meshes are constructed with different materials with different biological properties. METHODS: A prospective database was instituted (January 2009-December 2010) to register biological prostheses (BPs) implanted in Italy. RESULTS: A total of 193 cases were registered. The mean age of the patients was 53.1 years (SD ±7.4). The ratio of males to females was 1.3 to 1. The mean body mass index was 28.2 (SD ±4.1). The breakdown of American Society of Anesthesiologists (ASA) scores was as follows: ASA I, 35.7%; ASA II, 27.5%; ASA III, 31.6%, and ASA IV, 5.2%. For ventral-incisional hernias, the mean duration of surgery was 101.1 min (SD ±25.3), while for inguinal-femoral hernias it was 49.2 min (SD ±19.1). The rate of urgent procedures was 36.7%. The surgical field was clean in 57.4% of cases, clean-contaminated in 21.3%, contaminated in 12.3% and dirty in 9%. Techniques used for inguinal-femoral hernias were as follows: Lichtenstein in 66.7%, plug and mesh in 3.8%, transabdominal-preperitoneal in 25.7% and intraperitoneal onlay mesh in 3.8%. The following prostheses were used: swine intestinal submucosa in 54.9%, porcine dermal collagen in 39.9% and bovine pericardium in 5.2%. In 45.1% of cases the prostheses were cross-linked. Techniques used for ventral-incisional hernias were as follows: onlay in 3.6%, inlay in 5.5%, sublay in 62.7% and underlay via laparoscopy in 28.2%. The mean overlap was 4.1 cm (SD ±1.2). No intestinal anastomosis was necessary in 65.3% of cases; however, small/large bowel resection and anastomoses were necessary in 22.3 and 12.4% of cases, respectively. Intraoperative blood transfusion was necessary in 10.4% of procedures. The skin was completely closed in 84% of procedures. At the 1-month follow-up, there were no complications in 54.4% of cases. Among the cases with complications, 10 patients (5.8%) experienced recurrence, and the postoperative readmission rate was 12.9%. The average visual analog scale (VAS) score for pain was 2.9 (SD ±1.2) at rest. At the 1-year follow-up, there were no complications in 96.4% of cases. Two patients experienced recurrence, and the postoperative readmission rate was 3.6%. The average VAS score for pain was 1.8 (SD ±0.8) at rest. CONCLUSIONS: This register shows that BPs are highly versatile and can be used in either open or laparoscopic surgery in all kinds of patients and in contaminated surgical fields. However, due to the very good outcomes of synthetic meshes and the high costs of BPs, the latter should only be used in selected cases.

Impact of primary cancer features on behaviour of colorectal liver metastases and survival after hepatectomy.

Background: Markers of tumour biology may be valuable prognostic indicators after hepatic resection of colorectal cancer liver metastases (CRLMs). Identification of the aggressiveness of these metastases might inform the appropriateness of hepatic surgery. Methods: Patients undergoing liver resection for CRLMs between January 2001 and July 2013 in four tertiary hospitals were reviewed. A mathematical model to estimate CRLM doubling times was constructed for patients with metachronous metastases. Tumour doubling time was investigated in relation to the features of colorectal cancer, including KRAS status. The hazard rate for recurrence and death following hepatectomy was explored through the Kernel-smoothed estimator. Results: Of 1063 patients undergoing liver resection for CRLMs, 361 with metachronous metastases undergoing single-stage hepatectomy were analysed. The mean doubling time in patients not receiving chemotherapy between surgery for colorectal cancer and CRLM was 71·4 days. Tumour doubling time was shorter in patients with more advanced primary tumour stages, with mutant KRAS and in those who did not receive chemotherapy. For fast-growing CRLMs (doubling time less than 48 days), the risk of recurrence was highest within the first postoperative year, and was about 7 per cent per month. Conclusion: Primary features of colorectal cancer were linked to aggressiveness of CRLMs as measured by doubling time.

Neoadjuvant systemic treatment for breast cancer in Italy: The Italian Society of Surgical Oncology (SICO) Breast Oncoteam survey.

The Italian Society of Surgical Oncology (SICO) Breast Oncoteam developed a survey to explore the state of the art of neoadjuvant treatment for breast cancer in Italy, specifically focusing on cases treated during the two-year period 2014-2015. A questionnaire was sent to Italian Breast Units with a minimum of 150 new breast cancer cases treated/year according to the Senonetwork directory and to the SICO Breast Oncoteam Breast Unit network. A total of 23/107 Breast Units submitted the survey, reporting a total amount of 20156 cases of breast carcinoma (17241 invasive, 2915 in situ) treated in the biennium, corresponding approximately to 20% of newly diagnosed breast cancers in Italy. In the United States, medical treatment before surgery for breast cancer is indicated in about 22.7% of newly diagnosed cases according to the National Cancer Database, while a German study reported approximately 20% of cases treated with neoadjuvant therapy. In our survey, a total of 1673/17241 cases (9.7%) were treated with neoadjuvant therapy, ranging from 2.9% to 23.6% according to different centres, showing heterogeneity in neoadjuvant treatment indications, even in multidisciplinary breast units. Better resources should be engaged to achieve a standardised quality indicator for neoadjuvant treatment, and this indicator could be included among the European Society of Breast Cancer Specialists (EUSOMA) quality indicators. In the near future, we plan to develop a second survey to better test improvements in the employment of neoadjuvant therapy after the expiry of the 2016 European Parliament deadline and after the 2017 St. Gallen Conference recommendations.

The impact of field cancerization on the extent of duct carcinoma in situ (DCIS) in breast tissue after conservative excision.

AIM: Aim of the present study is to evaluate the risk of residual neoplastic foci, in patients treated with breast conservative surgery, based on duct carcinoma in situ (DCIS) grading. MATERIALS AND METHODS: The study is based on a retrospective analysis of 419 resection specimens relative to 161 patients. All these patients underwent surgical re-excision when the first specimen had shown one or more margins involved by DCIS. Margins were oriented and the side of margin involved was recorded. Clonal analysis, using the mitochondrial DNA (mtDNA) technique, was obtained in selected cases. RESULTS: Residual neoplastic foci were found in 145 out of 419 (34.6%) re-excised specimens. Specifically, residual foci of DCIS grade 2 and 3 were found more frequently in the margin facing the nipple (33.3% and 51.6%, respectively). On the contrary foci of DCIS grade 1 did not show any specific distribution. Clonal mt DNA analysis evidenced that DCIS grade 3 foci present in the re-excision specimens were genetically similar to the tumor removed in the first specimen, while DCIS grade 1 foci were not clonally related each other. CONCLUSIONS: The present data further confirm that DCIS grade 3 is characterized by a circumscribed neoplastic process extending along the large ducts probably of a single mammary lobe. On the contrary DCIS grade 1 is characterized by multiple independent neoplastic foci, dispersed through several lobes indicating a field where multiple independent foci of cancer harbor.

Blood noradrenaline and 5-HT levels in depressed women during amitriptyline or lithium treatment.

Noradrenaline levels and platelet and free serotonin concentrations were studied in depressed women in-patients (n=78) before and during amitriptyline (n=41) or lithium treatment (n=37). Pronounced monthly differences in platelet serotonin level have been shown in these subjects before treatment. In all clinical subgroups (neurotic, involutional, manic-depressive patients) a significant fall in platelet serotonin level was observed with amitriptyline medication while an increase was noted with lithium. No significant correlations between serotonin concentrations and clinical outcome were found. Amitriptyline treatment also produced a decrease in peripheral noradrenaline concentration in all subgroups, while an increase was observed with lithium. Some correlations between noradrenaline level and degree of depression were noted in patients treated with amitriptyline or lithium. A more extended analysis of blood amine levels could supply meaningful information on the peripheral action of antidepressive drugs on noradrenaline and serotonin concentrations in depression.

Aspects of amitriptyline and nortriptyline plasma levels monitoring in depression.

Fifty-nine depressed female inpatients were treated with 100 mg amitriptyline (AMT) IM for 4 weeks. Depression ratings and determinations of the parent drug and nortriptyline (NT) were performed weekly. No direct relationship between plasma AMT + NT concentrations and therapeutic response was apparent, but beneficial therapeutic responses and significantly lower side-effect scores were more frequently noted in subjects with concentrations in the 100-200 ng/ml range. AMT + NT concentrations were significantly correlated with age. No significant difference was found in the number of responders between younger and older subjects with two clinical improvement criteria; however, a significant difference emerged when a third more restrictive clinical outcome criterion was adopted. The implications of the present findings for patient treatment and for the interpretation of previous studies are discussed. The data collected point to a possible usefulness of monitoring AMT and NT plasma levels, even if further investigations are needed.

A sensitive fluorimetric method for determination of platelet-bound and plasma free serotonin.

A sensitive and specific fluorimetric assay for blood platelet-bound and plasma free serotonin is described. Serotonin is concentrated and purified on Amberlite CG-50 resin, eluted by 0.15 mol/l HCl and its native fluorescence is read at 295/350 nm. The good recovery (90% about), reproducibility and sensitivity (the smallest amount detectable is 5 ng) make the assay particularly useful for the detection of free serotonin in plasma. The whole procedure is rapid enough to permit the analysis of 15--20 samples within one working day and thus the method is suitable for routine determination of serotonin in biological specimens.

Histochemical and biochemical research on the pallial gland of Lithophaga (Lithodomus) lithophaga L.

Histomorphological staining demonstrated 2 types of cells in the pallial gland of the mantle of Lithodomus lithophaga: gland cells containing glycolipoprotein and interstitial cells, containing lipid droplets. Biochemical analysis aiming at separate and evaluate lipidic and peptidic components were carried out by lipid extraction, T.L.C. separation and colorimetric assays. Phospho- and sulfolipids were separated from non-polar lipids. Sialo-cerebrosides (gangliosides) are missing. Hydrophobic peptide component was extracted and aminoacid analysis was made. The presence of acid (phosphate) group in the gland secretion is discussed in relation to the function of the secretion (Ca uptake and rock boring). The prominent glycogen storage is considered as an important energy source to be used for osmotic work and to synthesize glycosidic stones for glycolipo-protein secretion.

Simultaneous measurement of total catecholamines and metanephrines in human urine by liquid chromatography with coulometric detection.

A simple routine method is described for simultaneous assay of total urinary norepinephrine, epinephrine, dopamine, normetanephrine and metanephrine. An internal standard of 3,4 dihydroxybenzylamine is added to the diluted urine and acidic hydrolysis of the conjugates is followed by reverse-phase HPLC separation and coulometric detection in the redox mode. The method is rapid and precise and it has a broad linear working range for all substances making it suitable for clinical analysis. Examples are shown of excretion patterns of catecholamines and metanephrines for healthy subjects and depressed patients.

[The laparoscopic treatment of common bile duct lithiasis]. / Trattamento laparoscopico della litiasi della via biliare principale.

Nowadays the laparoscopic cholecystectomy has become the main surgical therapy in the treatment of cholecysto-lithiasis. At the beginning the treatment of cholecysto-choledochal lithiasis was the sequential endoscopic-laparoscopic therapy. In fact, the endoscopic sphincterotomy allows transpapillary ablation of Common Bile Duct (CBD) stones, and the laparoscopic cholecystectomy completes the therapy. Recently we have brought the full-laparoscopic of CBD lithiasis. This has become possible on account of an improved intraoperative laparoscopic diagnostics and a better technical experience of the laparoscopic surgeon. Intraoperative examination of CBD requires suitable instruments: cholangiography is still a basic examination and now is easily performed in laparoscopy without a considerable increase of the surgical time; choledochoscopy allows an intraluminal inspection of completes the examination, supplying further detailed information. Afterwards the laparoscopic approach allows the transcystic ablation of stones, using a Dormia probe or through a choledochotomy, but is previously required for the surgeon a high-level operative and technical ability about laparoscopic surgery, in order to perform an excellent preparation of the CBD and precise stitches, making knots with extra corporeal or intra-abdominal technique. Clinical results in patients until now fully-laparoscopic treated are quite good and encourage the CBD lithiasis therapy by a mini-invasive approach, which has the advantage that's not requested the sacrifice of a sound papilla.

[Nodular hyperthyroidism: surgical experience and hypothesis of carcinogenic correlations]. / Ipertiroidismo nodulare: esperienze chirurgiche ed ipotesi di correlazioni oncogenetiche.

In a retrospective study 109 patients operated for nodular toxic goiter from 1984 to may 1988 are examined. Clinical feature, diagnosis and surgical approach are analyzed; the follow-up of the patients is reported as well. Some results are really interesting: 1) the incidence of hyperthyroidism in a nodular goiter (toxic multinodular goiter, solitary or multiple Plummer's nodes) is higher in the females; 2) most of the patients with solitary or multiple nodes are middle-young-aged; 3) prevalence of autonomous toxic adenomas; 4) relapses are higher (76%) in young patients with thyroid nodes operated with lobectomy and isthmectomy in pre-toxic stage (multifocality of the disease). Basedowified goiter, on the contrary, is present in old females with a long history of goiter. In these cases, subtotal thyroidectomy is often curative. The association with cancer is a fearful event to remember.

Cytological features of nipple adenoma in scraping smears.

INTRODUCTION: Nipple adenoma (NA) is a benign epithelial lesion of the breast that can clinically simulate Paget's disease or invasive ductal carcinoma. Therefore, correct pre-operative diagnosis is important for appropriate management. METHODS: Cytological samples may be obtained by different methods such as fine needle aspiration, nipple discharge or nipple scraping. Herein, the cytological features of three cases of NA are described in which samples were derived from nipple scraping. RESULTS: In all three cases, patients were adult females presenting with a sub-areolar nodule, showing skin ulceration in 2 of 3 cases. The nipple scraping cytological smears were characterised by a bloody background with epithelial cells arranged in clusters or singularly, showing an irregular nuclei profile. These features could simulate a malignant process. However, at higher magnification, fine nuclear chromatin with inconspicuous nucleoli and presence of myoepithelial cells were helpful to exclude malignancy. DISCUSSION: NA may present "worrisome" cytological features on smears derived from nipple scraping. Therefore, knowledge of the cytological spectrum of this lesion is important to avoid misdiagnosis.

Induction therapy with alemtuzumab (campath) in combined liver-kidney transplantation: University of Bologna experience.

BACKGROUND: Combined liver-kidney transplantation (LKT) is considered to be a safe procedure, but the appropriate immunosuppressive regimen is unclear. PATIENTS AND METHODS: Between January 1997 and October 2011, 55 patients were listed for LKT: 45 (82%) were effectively transplanted, 5 (9.2%) died whereon here the waiting list, 3 (5.5%) temporarily out of waiting list, 1 (1.8%) was on waiting list and 1 (1.8%) refused LKT. Five LKTs treated with cyclosporine (CyA) were excluded from the analysis. Mean recipient age was 50.32 ± 10.32 years (14-65), MELD score at time of LKT was 19.22 ± 4.69 (8-29), mean waiting list time was 8.14 ± 9.50 months (0.1-35.76), and follow-up, 4.09 ± 3.02 years (0.01-10.41). Main indications for LKT were policystic disease (n = 15; 37%), hepatitis virus C (HCV)-related cirrhosis (n = 9; 22%) metabolic disease (n = 5; 13%), hepatitis virus B (HBV) cirrhosis (n = 4; 10%), alcoholic cirrhosis (n = 4; 10%), and cholestatic disease (n = 3; 8%). Immunosuppressive regimen was based on tacrolimus and steroids in 40 cases with induction therapy with alemtuzumab (Campath; 0.3 mg/kg) in 13 of 40 instances cases administered on day 0 and day 7. RESULTS: Postoperative mortality was 2.5%. Acute cellular rejection episodes were biopsy-proven in 2 (5%) cases, post-LKT infections developed in 17 cases (42.5%), and de novo cancer developed in 3 (7.5%) cases. Similar 5-year overall survivals were obtained irrespective of the LKT indication: 100% in cholestatic and alcoholic cirrhosis patients, 86% in policystic disease, 75% in metabolic disease and HBV patients, and 66% in HCV cirrhosis. Overall survivals for the alemtuzumab vs without-induction therapy groups at 1, 3, and 5-years were 100%, 85.7%, and 85.7% vs 76%, 76%, and 70%, respectively (P = .04). CONCLUSION: An immunosuppressive regimen based on tacrolimus and steroids with induction therapy with alemtuzumab was safe, with excellent long-term results for combined LKT.

Primary sarcoidosis of the breast: case description and review of the literature.

Sarcoidosis is a systemic granulomatous disease of unknown aetiology. The breast is involved in less than 1% of cases. Breast can be either a primary or a secondary site of presentation. Breast sarcoidosis often mimics carcinomas at clinical examination. We report a case of breast sarcoidosis detected during screening mammography in a 57-year-old woman. The lesion presented as a 1.4 cm nodule located in the right breast. On histology, it was characterized by non-caseating giant cell granulomas. Differential diagnoses included idiopathic granulomatous mastitis, tuberculosis, fungal infection, cat-scratch disease and sarcoid-like reactions to cancer. Further clinical and laboratory investigations were consistent with a diagnosis of sarcoidosis. Specifically, serum levels of angiotensin-converting enzyme (ACE) were elevated and a CT scan showed small bilateral pulmonary nodules distributed along the pleura and bronchovascular bundles (perilymphatic pattern), as well as enlarged bilateral hilar and mediastinal lymph nodes. The patient received corticosteroid treatment, and is presently asymptomatic. Breast involvement by sarcoidosis, although rare, should be considered when dealing with granulomatous lesions of the breast.

Ultrastructural studies on the myocardial capillaries of the experimentally lathyritic rat, protective effect of certain flavonoids.

The ultrastructure of rat myocardial capillaries was studied in the course of experimental lathyrism. Endothelial cells were hypertrophic, with a sinuous profile of the plasma membrane facing the lumen and with a consistent increase of pinocytotic vesicles; the nuclei were irregular in shape; ATPase activity was no more demonstrable. Therefore, various and well distinct structural endothelial mechanisms seem to be primarily involved, causing an alteration of the dynamics of transcellular exchanges and of the permeability of the vascular wall. Simultaneous treatment with certain flavonoids, (O-(beta-hydroxyethyl)-rutosides and Na(+)-epicatechin-2-sulfonate), resulted in a less pronounced alteration and a more rapid recovery. The possibility of the existence of a common site of action of lathyrogens and flavonoids is raised in the discussion.

Higher plasma catecholamine and metabolite levels in the early phase of nonsegmental vitiligo.

The etiology of vitiligo is still being debated, although neural factors seem to play a pivotal role in its pathogenesis. In our search for a link between vitiligo and the activity of monoaminergic systems, we used high-pressure liquid chromatography and electrochemical detector (HPLC-ED) methods to measure the plasma levels of the following substances in 35 healthy subjects and in 70 patients suffering from nonsegmental vitiligo at the different stages of the disease: catecholamines [norepinephrine (NE), epinephrine (E), and dopamine (DA)], their precursor 3,4-dihydroxyphenylalanine (DOPA), their metabolites [3-methoxy-4-hydroxyphenylglycol (MHPG), normetanephrine (NMN), metanephrine (MN), and homovanillic acid (HVA)], and 5-hydroxyindolacetic acid (5-HIAA) as the major metabolite of serotonin. We found that the levels of NE, E, NMN, MN, HVA, and 5-HIAA were significantly higher in patients compared to controls. The patients at an active phase of the disease (n = 49/70) showed significantly higher levels of NE, NMN, MHPG, and HVA than ones at a stable phase. The patients with progressive vitiligo and at its more recent onset (< 1 year) showed significantly increased levels of E, NE, and MN in comparison with longer-term sufferers. No significant differences were observed when the patients were subdivided according to the type of vitiligo or their age at its onset. The higher catecholamine and metabolite levels in the early phase of the disease may reflect increased activity by monoaminergic systems, probably due to stressful events, including the onset of vitiligo itself.

Normal-range plasma catecholamines in patients with generalized and acrofacial vitiligo: preliminary report.

BACKGROUND: There is a body of evidence that neutral factors may play a role in the pathogenesis of vitiligo. OBJECTIVE: We look for the existence of a relationship between vitiligo and monoaminergic systems. METHODS: We use high-pressure liquid chromatography to measure the plasma level of catecholamines, their precursor 3,4-dihydroxyphenylalanine and their metabolites 3-methoxy-4-hydroxy phenylglycol (MHPG), normetanephrine (NMN), metanephrine and homovanillic acid (HVA). Forty patients with the generalized (n = 31) and acrofacial (n = 9) types of vitiligo are studied. RESULTS: Significant differences are not found either between males and females or between the entire group of patients and the controls. HVA and NMN levels significantly correlate with age (r = 0.332, p < 0.05, and r = 0.331, p < 0.05, respectively). Significant correlations are also seen either between noradrenergic or between dopaminergic parameters (norepinephrine vs. MHPG, r = 0.326, p < 0.05; dopamine vs. HVA, r = 0.540, p < 0.01). When the patients are grouped on the basis of vitiligo type or age of disease onset, the plasma mean levels of the neural compounds are always nonsignificantly different from those of the controls. However, both catecholamines and metabolites show higher, although not significant, concentrations in patients with a shorter duration of disease. CONCLUSION: Monoaminergic systems seem unlikely to be related to vitiligo, at least to the generalized and acrofacial types. However, variations cannot be excluded in genetically predisposed individuals during the onset or the active phases of disease.