Comprehensive genomic profiling by liquid biopsy captures tumor heterogeneity and identifies cancer vulnerabilities in patients with RAS/BRAFV600E wild type metastatic colorectal cancer in the CAPRI 2-GOIM trial.

BACKGROUND: Emerging evidence supports tumor tissue-based comprehensive genomic profiling (CGP) in metastatic colorectal cancer (mCRC). Data on liquid biopsy-based circulating tumor DNA (ctDNA) CGP are scarce and mainly retrospective. Prospective comparison between the two tests is not currently available. METHODS: The CAPRI 2-GOIM trial investigates efficacy and safety of ctDNA-driven, cetuximab-based, sequence of three treatment lines in patients with RAS/BRAFV600E wild type (WT) mCRC, as determined by local laboratory. Before first-line therapy, CGP is performed with FoundationOne (F1) CDx and F1 Liquid (F1L) CDx (324 genes) on tumor tissue DNA and plasma ctDNA, respectively. RESULTS: For 2/207 (0.96%) patients, no ctDNA was detected by F1L CDx. No patient displayed tumor fraction (TF) below 1%, whereas elevated ctDNA (TF≥10%) was detected among 140/205 (68.3%) patients. 1013 genomic variants were identified. F1L CDx found KRAS, NRAS or BRAFV600E alterations in 19 patients, whose tumors were classified as RAS/BRAFV600E WT by local laboratory. Both F1 CDx and F1L CDx were available for 164/205 (80%) patients. Concordance of 61.4% between the two tests was observed. Concordance increased to 72.7% for F1L CDx with TF ≥10%. Concordance for genes potentially involved in anti-epidermal growth factor receptor (EGFR) resistance was found in 137/164 (83%) patients, increasing to 91.5% for F1L CDx with TF ≥10%. A higher number of genomic alterations was detected by F1L CDx compared with F1 CDx, including 6 cases with KRAS and NRAS alterations. Overall, 109/205 (53.2%) patients displayed at least one actionable genomic alteration (I to IIIB), according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). CONCLUSION: Baseline liquid biopsy-based CGP is feasible, it has high concordance with tumor tissue-based CGP, it could better recapitulate tumor heterogeneity, and it is clinically informative by identifying additional actionable genomic alterations in approximately half of RAS/BRAFV600E WT mCRC patients.

Perceived social support attenuates increased hostile reactions to traumatic threat.

OBJECTIVE: Extant literature has seldom examined the naturalistic role of reaction to threat on downstream emotional distress while also considering buffers, such as perceived social support, to acute negative mental health outcomes. The present study examined how trauma symptoms, in reaction to a global stressor, predicted increased psychological distress via elevated emotional hostility and whether perceived social support modified such effects. We predicted a priori that increased exposure to trauma would be associated with increased hostility and global psychological distress, but that this path would be attenuated by greater levels of perceived social support, as individuals who report greater support exhibit greater emotional coping. METHODS: We recruited 408 adults from a large university in the Midwestern United States to participate in a survey assessing past-week trauma, hostility, distress, and perceived social support following the initial COVID-19 lockdown. The survey was conducted in March 2020, directly after strict shelter-in-place orders were locally mandated. To test our hypotheses, we employed a moderated mediation analysis approach. RESULTS: Results demonstrate that higher trauma predicted increased hostility, which in turn predicted increased distress, and trauma predicted distress via hostility (an indirect effect). As hypothesized, higher perceived social support attenuated the association between trauma and hostility. CONCLUSION: Results support a hostile emotional pathway that may increase distress in the context of increased traumatic impact; however, social support likely buffers these effects, particularly in the face of new or novel threats and stressors. Findings suggest broad application for understanding the relation between the introduction of stressors, psychological distress, and social support.

Morphological and Elastic Transition of Polystyrene Adsorbed Layers on Silicon Oxide.

Herein we present a study on the formation of irreversibly adsorbed layer of polystyrene molecules on silicon oxide surfaces. Various scanning probe microscopy techniques have been employed to study both the morphology and the mechanical properties of these self-assembled thin polymeric layers. More in detail, standard contact mode, force versus distance spectroscopy and ultrasonic force microscopy have been employed to obtain spatially-resolved maps and, thus, observe the physisorption of polystyrene on native silicon oxide substrate in function of time. Thick films, spin coated from a toluene solution, have been annealed at a temperature above the glass transition for increasing time intervals, and finally thoroughly rinsed in toluene. We have found that isolated islands of adsorbed chains are already present after an annealing time of half an hour. Prolonged annealing determines a progressive increase of the covered areas, whereas the formation of a complete flat layer requires 24 h. The pattern observed is in line with expected evolution of an unstable system, corresponding to the phenomenon of spinodal dewetting. Adhesion measurements show that the films present a reduced snap-off and the formation of a meniscus between tip and surface for annealing time up to 8 h. On the other hand, elastic measurements allow us to observe a progressive increase of the elastic modulus, with a complete transition for annealing time above 20 h. This is indication that a dense packing of the polystyrene molecules occurs, in line with the predictions of current models on the kinetics of irreversible adsorption. LAY DESCRIPTION: Herein we present a study on the formation of irreversibly adsorbed layer of polystyrene molecules on silicon oxide surfaces. Various scanning probe microscopy techniques have been employed to study both the morphology and the mechanical properties of these self-assembled thin polymeric layers. Thick polystyrene films, spin coated from a toluene solution, have been thermally annealed at a temperature above the glass transition for increasing time intervals, and finally thoroughly rinsed in toluene. We have found that isolated islands of adsorbed chains are already present after an annealing time of half an hour. Prolonged annealing determines a progressive increase of the covered areas, whereas the formation of a complete flat layer requires twenty-four hours. The adsorption pattern observed is in line with expected evolution of an unstable system, corresponding to the phenomenon of spinodal dewetting. Adhesion and elastic measurements have allowed us to observe a progressive increase of the packing density of the polystyrene molecules, in agreement with the predictions of current models on the kinetics of irreversible adsorption.

Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.

BACKGROUND: Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. PATIENTS AND METHODS: We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. RESULTS: Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. CONCLUSION: These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.

Recurrent esophageal stricture from previous caustic ingestion treated with 40-year self-dilation: case report and review of literature.

BACKGROUND: Corrosive esophageal strictures are common. The severity of the strictures depends on type, quantity, duration of contact and concentration of the caustic substance ingested. Endoscopic balloon dilation and endoscopic bougienage are a cornerstone in the management of the benign esophageal strictures and are the most widely used treatments, but are expensive and invasive procedures. CASE PRESENTATION: We report the case of an 82-year-old patient with a corrosive esophageal stricture treated for over 40 years by means of home self-bougienage. The procedure has been carried out for the longest lapse of time described in literature, with an excellent control of symptoms. In the case reported, after being carried out for more than 40 years, self-dilation allowed good quality of life and symptoms management, ensuring an excellent nutritional status. CONCLUSIONS: Following an adequate patient training, self-dilatation can be a safe and effective option of treatment, avoiding frequent expensive hospital admissions for endoscopic esophageal dilatation.

Anisakis simplex hypersensitivity is associated with chronic urticaria in endemic areas.

BACKGROUND: Chronic urticaria (CU) may affect up to 1% of the general population. Anisakis simplex hypersensitivity is frequent in areas where raw fish is consumed and A. simplex allergy represents a relevant cause of acute urticaria. We assessed the possible association between CU and A. simplex sensitization in an area where marinated fish is very frequently eaten. METHODS: A thorough history of CU was sought in 919 adults seen at the Allergy Center, Bari. CU patients and 187 controls underwent skin-prick testing with a commercial extract of A. simplex, and reactors were recommended a 6-month raw-fish-free diet regimen. Responders were followed after a further 3 months. RESULTS: Of 919 subjects, 213 (23%) met the criteria for CU and 106/213 (49.7%) were sensitized to A. simplex with a significant difference between patients aged >65 or <65 years (56 vs. 41%, respectively; p < 0.05). All patients hypersensitive to A. simplex were regular consumers of marinated fish. In a control population without CU, the prevalence of A. simplex sensitization was 16% (p < 0.001). The 6-month diet regimen led to the disappearance of urticaria in 82/106 cases (77%) versus 1/42 (2%) subjects who did not change their dietary habits (p < 0.001). All nonresponders were sensitized to house-dust mites. Of 75 responders who were followed-up after 3 months, CU relapsed in 88% of those who had reintroduced raw fish versus 14% of those who were still on the diet (p < 0.001). CONCLUSION: In areas where raw or marinated fish is frequently eaten, A. simplex hypersensitivity is a frequent cause of CU.

Cetuximab as third-line rechallenge plus either irinotecan or avelumab is an effective treatment in metastatic colorectal cancer patients with baseline plasma RAS/BRAF wild-type circulating tumor DNA: Individual patient data pooled analysis of CRICKET and CAVE trials.

The rechallenge strategy is based on the concept that a subset of patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) could still benefit of epidermal growth factor receptor (EGFR) inhibition, after progression to an anti-EGFR based-therapy. We performed a pooled analysis of two-phase II prospective trials to determine the role of rechallenge in third-line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from CAVE and CRICKET trials that received as third-line therapy cetuximab rechallenge were collected. Overall survival (OS), Progression-free survival (PFS), Overall response rate (ORR), Stable disease (SD) >6 months were calculated. Adverse events were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95% Confidence Interval, CI 3.0-4.9) with median OS (mOS) of 16.9 months (95% CI 11.7-22.1). For CRICKET patients, mPFS was 3.9 months (95% CI 1.7-6.2); mOS was 13.1 months (95% CI 7.3-18.9) with OS rates at 12, 18, and 24 months of 62%, 23%, and 0%, respectively. For CAVE patients, mPFS was 4.1 months (95% CI 3.0-5.2); mOS was 18.6 months (95% CI 11.7-25.4) with OS rates at 12, 18, 24 months of 61%, 52%, 21%, respectively. Skin rash was more frequently reported in CAVE trial (87.9% vs. 30.8%; p = 0.001), whereas a increased incidence of hematological toxicities was observed in CRICKET trial (53.8%% vs. 12.1%; p = 0.003). Third-line cetuximab rechallenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy.

Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics. MATERIALS AND METHODS: We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping. RESULTS: A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX-bevacizumab and mitomycin-capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab-second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy. CONCLUSIONS: Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.

An approach to urticaria in the elderly patients.

The guidelines for the management of urticaria in adults and children have been published in outstanding position papers. By contrast, the onset of urticaria in the elderly has not yet had a clear definition. In order to approach diagnosis and treatment in a population of elderly patients, we have performed an epidemiological study on a population of elderly people observed in the Immuno Allergology Unit in Bari University Hospital. The patients underwent skin prick test for food allergy and laboratory and instrumental tests. From the data it resulted that 49% of cases have had urticaria because of adverse drug reactions (ADRs), 16% of cases were positive to food, while in 21% of cases systemic and metabolic diseases (SMDs) have been diagnosed. If we consider the young controls, urticaria for ADR was present in 48% of cases; however, in 28% it was possible to make the diagnosis of food allergy, 12% cases had a SMD. Our results show that the main cause of urticaria in the elderly is related to drug assumption because of the high number of drugs taken, followed by internal pathologies correlated to the typical immune and metabolic changes of the elderly. Furthermore, from the observation of our data it was possible to give guidelines for the treatment of urticaria in geriatric age.

Long-term outcomes following "presumed" total parathyroidectomy for secondary hyperparathyroidism of chronic kidney disease.

AIM: The most efficacious surgical treatment for renal hyperparathyroidism is still subject of research. Considering its low incidence rate of long-term relapse, "presumed" total parathyroidectomy without autotrasplantation (TP) may be indicated for secondary hyperparathyroidism (2HPT) in patients with chronic kidney disease (CKD), not eligible for kidney transplantation. The aim of this study was to analyse the TP long-term results in 2HPT haemodialysis (HD) patients. METHOD: Between January 2004 and October 2009, 25 2HPT HD patients, not eligible for kidney transplantation, underwent TP of at least four parathyroid glands. Clinical status and intact parathyroid hormone (iPTH) serum levels were assessed intraoperatively and during a 36-month follow-up. RESULTS: TP improved the typical clinical symptoms and a significant reduction of iPTH serum levels was achieved in each patient. Aparathyroidism was never observed; in case of severe postoperative hypocalcemia, hypocalcemic seizures were never reported and the long-term recurrence rate was 8%. Only one patient received a kidney transplantation. Postoperative cardiovascular events (hypertension, peripheral artery disease, arrhythmia, coronary or cerebrovascular disease) were observed in 32% of cases and mortality rate was 16%. CONCLUSIONS: Considering its low long-term relapse rate and the absence of postoperative aparathyroidism, TP may still be considered the treatment of choice in patients with aggressive forms of 2HPT or of advanced dialytic vintage, with no access to renal transplantation. In case of postoperative hypoparathyroidism, hypocalcaemia can be effectively managed by medical treatment.

Surgical treatment of papillary thyroid carcinoma without lymph nodal involvement.

BACKGROUND: In the treatment of differentiated thyroid cancer (DTC), in absence of enlarged lymph nodes, the role of routine central lymph node dissection (RCLD) remains controversial. The aim of this study is to analyze data resulting from total thyroidectomy (TT) not combined with RCLD in the treatment of DTC. METHODS: We retrospectively evaluated the clinical records of 80 patients treated between January 1996 and December 2003 with TT without RCLND, in absence of suspected enlarged lymph nodes at preoperative ultrasonography and intraoperatively during neck exploration. In this series, 75 patients (93.7%) underwent radioiodine (RAI) ablation, followed by Thyroid Stimulating Hormone (TSH) suppression therapy. In case of locoregional lymph nodal recurrence, a central (VI) and ipsilateral (III-IV) selective lymph node dissection was performed. RESULTS: Incidence of permanent hypoparathyroidism (iPTH < 10 pg/ml) and unilateral temporary vocal fold paralysis were respectively 2.55% and 2.55%. Locoregional recurrence, with positive cervical lymph nodes, after a 10.3 ± 4.7 years mean follow-up was observed in 3 patients (3.75%). They were submitted to a central (VI) and ipsilateral (III-IV) selective neck dissection without significant complications. CONCLUSIONS: In our series, TT not combined with RCLD was associated to a low locoregional recurrence rate, even if the lack of a control group treated with RCLD does not allow any generalized assumption. RCLD may be indicated in high risk patients, in whom lymph nodal recurrence is more frequent. More prospective randomized studies are needed to better define the role of RCLD and postoperative radioiodine ablation.

Clinical efficacy of sequential treatments in KRASG12C-mutant metastatic colorectal cancer: findings from a real-life multicenter Italian study (CRC-KR GOIM).

BACKGROUND: The presence of KRASG12C mutation in metastatic colorectal cancer (mCRC) correlates with poor outcome. Although different selective inhibitors are under clinical development, the optimal treatment remains uncertain. Thus, we conducted a retrospective analysis in a large cohort of patients with KRASG12C mCRC treated in 12 Italian oncology units. PATIENTS AND METHODS: Patients with unresectable mCRC harboring KRASG12C mutation receiving a first-line chemotherapy doublet or triplet between 2011 and 2021 were included in the study. Evaluation of overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) analysis was carried out. RESULTS: A total of 256/6952 (3.7%) patients with mCRC displayed KRASG12C mutation; of these, 111 met the inclusion criteria. The ORR of first-line therapy was 38.7% (43/111). Median PFS (mPFS) was 9 months [95% confidence interval (CI) 7.5-10.5 months]. After progression, only 62% and 36% of the patients are fit to receive second or third lines of treatment, with limited clinical benefit. Median OS (mOS) was 21 months (95% CI 17.4-24.6 months). In patients receiving first-line triplet chemotherapy, ORR was 56.3% (9/16), mPFS was 13 months (95% CI 10.3-15.7 months) and mOS was 32 months (95% CI 7.7-56.3 months). For irinotecan-based doublets, ORR was 34.5 (10/29), mPFS was 9 months (95% CI 6.4-11.6 months) and mOS was 22 months (95% CI 16.0-28.0 months). With oxaliplatin-based doublets ORR was 36.4% (24/62), mPFS was 7 months (95% CI 4.6-9.4 months) and mOS was 18 months (95% CI, 13.6-22.4 months). CONCLUSION: Patients with KRASG12C-mutant mCRC had a disappointing response to standard treatments. Within the limitations of a retrospective study, these results suggest that first-line chemotherapy intensification with FOLFOXIRI is a valid option in fit patients.

How we treat locoregional melanoma.

Cutaneous melanoma is the most lethal form of skin cancer and its incidence has been increasing in the past 30 years. Although this is completely resectable in most cases, thicker melanoma and those with regional lymph-node involvement are at a high risk of relapse. In recent years, the management of locoregional disease has drastically changed. In particular, in the 8th Edition of the American Joint Committee on Cancer (AJCC), subgroup classification of TNM (tumor-node-metastasis) has been modified, with the addition of the IIID stage. Furthermore, in recent randomized trials, completion lymph node dissection in case of sentinel lymph node biopsy positivity has not been shown to offer any improvement in overall survival versus observation. Consequently, radical dissection has been recommended as the standard treatment, but only in patients with palpable nodal metastases. However, the major novelty in the treatment of locally advanced melanoma has been the introduction of drugs, already used for metastatic disease, that have also shown clinical efficacy in the adjuvant setting. In fact, immunotherapies and, in the case of BRAF V600E/K-mutated melanoma, combination treatment of BRAF and MEK inhibitors have improved recurrence-free survival in these patients. In this paper, we will describe the current management of a patient with radically resectable melanoma and discuss the key points in light of the latest scientific evidence.

Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression.

BACKGROUND: Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance. METHODS: We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance. RESULTS: The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models. CONCLUSIONS: These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.

It is finally time for adjuvant therapy in melanoma.

Although melanoma is amenable to early detection, there has been no decline in the mortality rate of this disease and the prognosis of patients with high-risk primary melanoma or with macroscopic nodal involvement remains poor. The best option for patients with higher-risk melanoma is to receive effective adjuvant therapy in order to reduce their chances of recurrence. Multiple systemic therapeutic agents have been tested as adjuvant therapy for melanoma with durable benefits seen only with interferon- to date. More recently ipilimumab at the high dose of 10 mg/kg has shown a significant improvement in terms of Relapse free survival and Overall survival for stage III melanoma patients but at a significant cost in terms of immune-related toxicities. More recently, novel treatment options have emerged. The results from the latest trials with immunotherapy (PD-1 inhibitors) and molecular targeted therapy (BRAF inhibitor + MEK inhibitor) have revolutionized the management of adjuvant treatment for melanoma. As the results from these trials will mature in the next years, a change in the landscape of adjuvant treatment for melanoma is expected, resulting in new challenges in treatment decisions such as optimizing patients' selection through predictive and prognostic biomarkers, and management of treatment related adverse events, in particular immune related toxicities.

[Diagnostic and therapeutic guidelines for entero-cutaneous fistulas. Personal experience and literature review]. / Orientamenti diagnostico-terapeutici nel trattamento delle fistole enterocutanee: esperienza personale e review della letteratura.

The entero-cutaneous fistulas (ECF) are abnormal communications between intestine and abdominal skin. They can occur spontaneously, or after an injury or a surgical procedure. They are associated with a high rate of morbidity and mortality. Spontaneous fistulas can mainly occur in patients affected by cancer, inflammatory bowel disease, diverticulitis, appendicitis, as a result of radiotherapy or injuries. Surgical procedures, carried out in case of neoplastic diseases, inflammatory bowel disease, adhesions removal, represent the primary cause in the development of a postoperative fistulas. Malnourishment, poor general conditions of the patient, high output fistula along with anatomical site of development, and the presence of abscesses, represent the negative factors influencing the spontaneous healing of fistulas. The experience reported here is about three ECF cases occurred after surgery and treated only with medical therapy. The first case is a woman in good general conditions who underwent surgery to remove a recurrent retroperitoneal myxoid liposarcoma situated in the right lower quadrant. The patient had never undergone surgery for an intestinal resection. The other two patients analyzed were affected by sepsis and metabolic unbalance and had developed a fistula after colonic resection. Fluids and electrolytes adjustments and sepsis management have preceded any other kind of therapy. Continuous infusion with somatostatin, fast, proton pump inhibitors and loperamide have been taken up to decrease secretions and intestinal motility. Total parenteral nutrition has been essential to recover nutritional status and improve patients' general conditions. In order to heal and protect peri-fistula skin we have used sterile washing solutions, absorbable ionic exchange resin, silver and polyurethanes based medications and colostomy bags adhesive systems. Since surgical treatment of ECF is associated with high rates of morbidity and mortality, conservative treatment should always be taken into consideration. When conservative treatment fails, delayed surgical intervention has been related to a higher rate of success. The purpose of this study is to describe diagnostic and therapeutic guidelines to general surgeons, like ourselves, whenever they have to deal with ECF cases.

[The gold standard in the treatment of haemorrhoidal disease. Milligan-Morgan haemorrhoidectomy vs Longo mucoprolapsectomy: comparing techniques]. / Il gold standard nel trattamento della malattia emorroidaria. Emorroidectomia secondo Milligan-Morgan vs mucoprolassectomia secondo Longo. Tecniche a confronto.

AIM: Although mucosectomy according to Longo was a real revolution in the treatment of haemorrhoidal disease, Milligan-Morgan haemorrhoidectomy, maintaining the characteristics of a technique which is physiopathologically efficacious and easily performed, is still the procedure of choice in some clinical conditions. The aim of this study was to evaluate which of the two techniques, Milligan-Morgan haemorrhoidectomy and Longo mucoprolapsectomy, could be considered the gold standard in the treatment of haemorrhoidal disease. METHODS: From March 2002 to October 2006, in the VII Department of General Surgery of SUN, we compared two groups of 26 patients each: one treated with Milligan-Morgan haemorrhoidectomy, the other one with Longo mucoprolapsectomy. Among the patients treated with traditional technique, 16 were suffering from grade III haemorrhoids and prolapse, while the other 10 from grade IV haemorrhoids and prolapse. The group treated with stapler was composed of 10 patients affected by grade III haemorrhoids and prolapse, while the other 16 were patients complaining for grade IV haemorrhoids and prolapse. For both groups of patients the follow-up lasted 12 months; they were controlled at 1 week, 1 month, 6 months and 1 year after the operation. RESULTS: The level of pain measured with a visual analogue scale (VAS) was always higher in the group treated with traditional technique. In 69% of the patients treated with stapler and in 59% of those treated with open technique there was the first defecation within postoperative day 2. The return to normal activity was earlier in patients who underwent Longo technique. Among the patients treated with traditional technique, 7.7% had postoperative bleeding, 15.4% at the 6-month control, suffered from anal fissure with associated high pressure of anal sphincter and tenesmus and 7.7% showed a recurrence after 1 year. In the group treated with Longo technique, 11.54% of the patients had a postoperative haemorrhage at the 6-month control, 7.7% showed substenosis, 3.84% of the patients felt tenesmus; in 3.84% of the cases a perianal extra-sphincteric fistula was evident. At 1 year control, 11.54% of the patients showed recurrences. CONCLUSION: The conclusion is drawn that it does not exist any indication for the Longo technique; however, it seems to give the best results in grade III haemorrhoids with prolapse, without sphincteric implications.