Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation.

Background: Non-randomized studies showed that temozolomide (TMZ) achieves an average 10% response rate in heavily pretreated metastatic colorectal cancer (mCRC) patients with promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). In this phase II trial, irinotecan and temozolomide (TEMIRI) combination regimen was assessed in irinotecan-sensitive, MGMT methylated/microsatellite stable (MSS) pretreated mCRC patients. Patients and methods: Key inclusion criteria were centrally confirmed MGMT methylation by methylation-specific PCR, MSS mCRC, progression after at least two prior chemotherapy regimens for advanced disease and irinotecan-free interval >3 months. TEMIRI (TMZ 150 mg/m2 on days 1-5 plus irinotecan 100 mg/m2 on days 1, 15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary end point was overall response rate (ORR). Exploratory translational analyses included MGMT immunohistochemistry (IHC) and methyl-BEAMing (MB). Results: Between December 2014 and June 2017, 25 patients were enrolled. The primary end point was met, since six patients achieved a partial response [ORR 24%, 95% confidence interval (CI) 11% to 43%]. At a median follow-up of 15.6 months, median progression-free survival (mPFS) and overall survival (mOS) were 4.4 and 13.8 months, respectively. Only four (16%) patients had ≥ grade 3 (CTCAE 4.0) adverse events. All patients whose cancer was MGMT-positive IHC were non-responders. Consistently, patients with MGMT-negative/low tumors had a significantly longer mPFS than others (6.9 versus 2.0 months; hazard ratio = 0.29, 95% CI 0.02-0.41; P = 0.003) and a non-significant trend for longer mOS. MB testing showed similar accuracy. Conclusions: TEMIRI regimen is a safe and active option in pre-treated, irinotecan-sensitive mCRC patients with MGMT methylation.

Colorectal cancer: an update on the effects of lycopene on tumor progression and cell proliferation.

Colorectal cancer (CRC) is one of the most common cancers worldwide. Various factors, including oxidative stress, where excessive productions of reactive oxygen species (ROS) and reactive nitrogen species (RNS) occur, contribute to its pathogenesis. Numerous studies have investigated the effect of antioxidant substances derived from food such as fruits and vegetables; however, data on Lycopene are still rare. Studies on HT-29 colorectal cancer cells and on animal models have shown that lycopene has effects on cell proliferation and on the progression of the CRC by interacting with various cellular signaling pathways. This analysis of the literature focused on the antioxidant effect of lycopene, a substance that is found in the tomato.

Pelvic lymphedema in rectal cancer: a magnetic resonance feasibility study: a preliminary report.

BACKGROUND: Functional pelvic disorders in patients undergoing conservative surgical approach for rectal cancer are considered a major public health issue and represent one third of cost of colorectal cancer. We investigated the hypothesis that lymphadenectomy, involves the pelvic floor results in a localized hides or silent pelvic lymphedema characterized by symptoms without signs. PATIENTS AND METHODS: We examined 13 colo-rectal cancer patients: five intra-peritoneal adenocarcinoma: 1 sigmoid and 4 upper third rectal cancer (1 male and 3 female) and 9 extra-peritoneal adenocarcinoma: 3 middle and 5 lower third rectal cancer (4 male and 5 female) using 1.5-T magnetic resonance, one week before and twelve months after discharged from hospital. RESULTS: Lymphedema was discovered on post-operative magnetic resonance imaging of all 9 patients with extra-pertitoneal cancer, whereas preoperative magnetic resonance imaging as well as a post-operative examination of 4 intra-peritoneal adenocarcinoma, revealed no evidence of lymphedema. Unlike the common clinical skin signs that typify all other sites of lymphedema, pelvic lymphedema is hides or silent, with no skin changes or any single symptom manifested. Magnetic resonance imaging showed that pelvic illness alone is accompanied by lymphedema related exclusively to venous congestion, and accumulation of liquid in adipose tissue or lipedema. CONCLUSIONS: Alteration of the pelvic lymphatic network during pelvic surgery can lead to lymphedema and, pelvic floor disease. Patients should be routinely examined for the possibility of developing this post-surgical syndrome and further studies are needed to establish diagnosis and to evaluate treatment preferences.

Stem cells based therapy in high grade glioma: why the intraventricular route should be preferred?

AIM: Mesenchymal stem cells (MSCs) migrate in response to chemokines and possess extensive tropism for experimental glioma. Antitumor effects have been reported following intracranial and intravenous administration of gene-modified MSCs. Among the different routes for cell transplant, the intraventricular (IV) approach found very little employment in comparison with intraparenchymal, intratumoral and intravenous administration protocols. Nevertheless, IV transplantation offers advantages in terms of cells viability and distribution toward target sites, opening interesting opportunities for its clinical application. METHODS: Using a rat glioma model, we investigated migratory capacity, tumor tropism, distribution and differentiation of MSCs following IV administration. RESULTS: Transplanted MSCs create niches of viable cells in the subventricular zone and can be stimulated to migrate to sites of tumor infiltration. MSCs seemed not to be involved in tumor growth and angiogenesis. CONCLUSION: We speculate that the IV route can be used to achieve a kind of reservoir of self-renewal cells, potentially active against the spread of cancer cells. Further studies are needed to shed light on MSCs distribution close to the ventricular wall, in order to define their lifespan and their capacity to migrate towards new-enhancing foci time after implantation.

Small bowel occlusion due to giant perineal hernia: abdominal approach with plastic perineal reconstruction.

A perineal hernia is defined as a protrusion of peritoneal or extraperitoneal content through a pelvic floor defect. A 64-year-old woman with a bowel occlusions due to a giant postoperative perineal hernia was admitted to our hospital. We describe abdominal approach with plastic perineal reconstruction.

Delayed and occult splenic rupture: a diagnostic puzzle.

Splenic rupture is a common complaint encountered in emergency surgery. Trauma is the most common cause of splenic rupture, while non-traumatic or occult splenic rupture (OSR) is a rare condition. The differential diagnosis weighs on treatment that ranges between close monitoring, splenorrhaphy, splenic conservation and splenectomy. We report a case of an 63-year-old man presenting with acute atraumatic left upper quadrant pain. Preliminary diagnosis was subsequently determined to be a hematoma secondary to OSR. More accurate detailed history revealed a previous trauma, which occurred more than one year before and mimicked an OSR. Delayed and occult splenic rupture are as different diagnosis as different treatment. Even in emergency surgery, the key for a target therapeutic strategy should consider an accurate diagnostic time.

Preliminary results of a program for the implementation of laparoscopic colorectal surgery in an Italian comprehensive cancer center during the COVID-19 pandemic.

Despite operative benefit and oncological non-inferiority, videolaparoscopic (VLS) colorectal surgery is still relatively underutilized. This study analyzes the results of a program for the implementation of VLS colorectal surgery started in an Italian comprehensive cancer center shortly before COVID-19 outbreak. A prospective database was reviewed. The study period was divided in four phases: Phase-1 (Open surgery), Phase-2 (Discretional phase), Phase-3 (VLS implementation phase), and Phase-4 (VLS consolidation phase). Formal surgical and perioperative protocols were adopted from Phase-3. Postoperative complications were scored by the Clavien-Dindo classification. 414 surgical procedures were performed during Phase-1, 348 during Phase-2, 360 during Phase-3, and 325 during Phase-4. In the four phases, VLS primary colorectal resections increased from 11/214 (5.1%), to 55/163 (33.7%), 85/151 (57.0%), and 109/147 (74.1%), respectively. The difference was statistically significant (P < 0.001). All-type VLS procedures were 16 (3.5%), 61 (16.2%), 103 (27.0%), and 126 (38.6%) (P < 0.001). Conversions to open surgery of attempted laparoscopic colorectal resections were 17/278 in the overall series (6.1%), and 12/207 during Phase-3 and Phase-4 (4.3%). Severe (grades IIIb-to-V) postoperative complications of VLS colorectal resections were 9.1% in Phase-1, 12.7% in Phase-2, 12.8% in Phase-3, and 5.3% in Phase-4 (P = 0.677), with no significant differences with open resections in each of the four phases: 9.4% (P = 0.976), 11.1% (P = 0.799), 13.8% (P = 1.000), and 8.3% (P = 0.729). Despite the difficulties deriving from the COVID-19 outbreak, our experience suggests that volume of laparoscopic colorectal surgery can be significantly and safely increased in a specialized surgical unit by means of strict operative protocols.

[Elective laparoscopic cholecystectomy: the limit of a dream become true]. / La colecistectomia videolaparoscopica elettiva: i limiti di un sogno ormai realtà.

Laparoscopic technique in elective cholecystectomy is the last step in an evolutive time to minimize the abdominal access. From 1st January 2004 to 31th December 2006 we analyzed 5515 cholecystectomy procedures: 4877 laparoscopic cholecystectomy, 635 open cholecystectomy. Complications and supplementary diagnosis have been identified in SDO Lombardia's country database. Morbidity occurred in 82 patients (12.9%) with open technique and 109 patients (2.23%) with laparoscopic technique; mortality occurred in 11 patients (1.73%) with open technique and 1 patient (0.02%) with laparoscopic technique. Mean hospital stay are 14.40 days with open technique and 4.75 with laparoscopic technique. Morbidity in open technique is 6 fold more than laparoscopia technique. The difference between the two technique is present in literature and it's the result of non invasive technique compared with the incision of the laparoscopia technique. This is the critical point in the difference of hospital stay between the two technique all to the good of laparoscopy. The high mortality ratio is due to the selective criteria in laparoscopic technique. First remark is the high quality of our hospital care, compared with hospital teaching in the word. In this hospital the laparoscopic cholecystectomy is the gold standard in cholelitiasis treatment. The second remark is the limit of the open technique in severe cholelitiasis with evidence in high ratio of hospital stay, morbidity and mortality.

Quality of life in parents of children with cerebral palsy: is it influenced by the child's behaviour?

The aims of the present study were: to examine the quality of life (QOL) of parents of children with cerebral palsy (CP) and to establish the possible effect of behaviour problems on their QOL. One-hundred children with CP, aged between 4 and 10 years, and both their parents were included in the study. Both parents completed the WHOQOL-BREF, to assess their QOL. A sample of 60 parents of healthy children was used as control group. The primary caregiver also completed the CHILD BEHAVIOUR CHECKLIST (CBCL). Parents of children with CP showed lower scores on physical and psychological domains than the control group on QOL. In the psychological domain the mothers of children with hemiplegia had the lowest scores. The mothers reported lower scores than the fathers for the physical domain in the group of children with diplegia and quadriplegia and for the psychological domain in the group of children with hemiplegia. Children with hemiplegia showed externalizing scores at CBCL higher than the other groups, that could explain the poorer QOL scores of their mothers. In conclusions our results provide useful information on the QOL in families with different forms of CP, useful in planning interventions for the family of children with CP.

Quantitative and qualitative characterization of plasma DNA identifies primary and recurrent colorectal cancer.

Because plasma DNA may be a useful tool for cancer detection, we screened primary tumors and related multiple plasma samples at the time of surgery and during the follow-up period for plasma DNA level as well as for K-Ras mutations and p16INK4a promoter hypermethylation in colorectal cancer patients. At the time of surgery, DNA levels were higher in tumor patients than in healthy donors, and K-Ras and p16INK4a alterations were detected in 7 and 11 cancers respectively, and in all related plasma samples. During the follow-up, plasma DNA levels decrease progressively but rapidly increased when a relapse occurred, whereas K-Ras and p16INK4a alterations were detected only in relapsed patients. Therefore, combined quantitative and qualitative analyses of plasma DNA confirm the presence of colorectal cancer, define disease-free status and indicate the presence of relapse.

Hyperhomocysteinemia is associated with cognitive impairment in multiple sclerosis.

Hyperhomocysteinemia (HHcy) has been associated with cognitive impairment in various neurological diseases. Cognitive impairment occurs early in multiple sclerosis (MS). Conflicting data have been reported regarding plasma total homocysteine (tHcy) levels in MS patients, and the impact of HHcy on cognitive impairment in MS is not known. This study investigated whether plasma total homocysteine levels are increased in MS and if HHcy is associated with cognitive impairment in MS. We compared tHcy levels in 94 patients with MS and 53 healthy age-matched controls. We used a neuropsychological test battery that included the Raven's Coloured Progressive Matrices, the Visual Search Test, the Trail Making Test A and B, the Immediate and Delayed Recall of a Short Story, the 30 Paired Word Associates, the Rey-Osterrieth Complex Figure Test, and the Semantic and Verbal Fluency Tests. Clinical (sex, age, type of MS, relapse, disease duration, coexisting disease, smoking habit, and physical disability) and laboratory variables (HHcy, low serum levels of folate and vit.B12, MTHFR genotype) were evaluated for their ability to predict cognitive impairment. The mean tHcy was higher in patients (13.19 micromol/L, SD5.58) than in controls (9.81 micromol/L, SD2.53; p < 0.001). Univariate analysis determined the following factors to be associated with cognitive impairment: higher age at observation, chronic progressive course of disease, longer disease duration,moderate or severe physical disability, and frequency of HHcy. With multivariate regression analysis, there remained a significant association only between frequency of HHcy and cognitive impairment (beta 0.262, p = 0.01). We conclude that tHcy levels are increased in MS and that HHcy is associated with cognitive impairment in this disease.

Solid lipid micro-particles carrying insulin formed by solvent-in-water emulsion-diffusion technique.

The study aimed to produce solid lipid insulin-loaded micro-particles by the solvent-in-water emulsion-diffusion technique, using isobutyric acid as solvent phase, glyceryl monostearate or cetyl palmitate as lipid, soya lecithin and taurodeoxycholate as emulsifiers. Isobutyric acid, a partially water-miscible solvent with low toxicity, was used due to its high insulin-solubilization capacity. Solid lipid micro-particles of spherical shape were prepared by simple dilution of the emulsion with water. To increase the lipid load the process was conducted at 50 degrees C, and in order to reach sub-micron size, a high-shear homogeniser was used. Insulin encapsulation efficiency was about 80%. Analysis of microsphere content after processing showed that insulin did not undergo any chemical modification within the micro-particles. The in vitro release of insulin from the micro-particles was very low, and an initial burst effect of 20% of the dose was observed. After treatment of the solid lipid micro-particles with pepsin solution, an insulin loss of about 24% of the total englobed insulin was observed. The solid lipid micro-particles appear to have interesting possibilities as delivery systems for oral administration of insulin.

The impact of EUS to predict lymph node metastasis in patients with rectal cancer: a difficult challenge.

OBJECTIVE: Current trends in the management of rectal cancer, identify accurate local assessment of positive lymph nodes (LN), as the strongest predictor for stratifying patients who would benefit from preoperative therapy. We a present retrospective analysis of a prospective data collection, to determine the clinical concordance between the suspicious LN at the pre-operative EUS (uN) and a post-operative EUS detection (pN). PATIENTS AND METHODS: From March 2009 to March 2011, 31 patients with suspicious LNs at EUS (uN positive) were enrolled. The surgeon performed pre-operative EUS and directly in the operating room, an ex vivo EUS of the specimen. The immediate mesorectal LN sampling by the surgeon was delivered to the pathologist. Endosonographic staging was compared to postoperative pathological staging. RESULTS: Preoperative EUS identified 67 suspicious LN. The LN medium size was 6.8 mm. We repeated the EUS after surgery. The pathologist found 41 positive LN. The definitive LN medium size was 6.3 mm. Eleven LN presented the same size between ultrasound and pathological examination, 11 LN a smaller size and 41 a bigger size, the remnants 4 were not discovered. EUS LN staging presented 83.9% in overstaging and 3.2% in understaging. Although endo ultrasonography (EUS) is a very effective method for assessing LN metastasis, this is still a difficult challenge. Inaccurate assessment of LNs can conceivably lead to either under-staging or over-staging. The present study indicates that the clinical concordance between the suspected metastatic LN at the pre-operative EUS (uN) and a post-operative (ex-vivo) ultrasound LN detection, is moderate. CONCLUSIONS: We should re-consider all this strategy: we need to switch from morphological information to biological behavior.

Percutaneous embolization of an isolated hypogastric artery aneurysm. A case report.

We describe a case of an isolated aneurysm of the left hypogastric artery which came under our observation because of a syndrome of compression on the homolateral iliac vein. Having excluded the presence of aneurysms in other sites, it was decided to perform a percutaneous embolization of the hypogastric aneurysm. The follow-up revealed the disappearance of the compression on the ipsilateral iliac vein and a 30% reduction in the diameter of the thrombosed aneurysm. The method limited invasiveness, the reduction in volume of the aneurysmal mass, the disappearance of compression problems, and the shortened hospitalization time support the choice of embolization treatment.

Our experience with the use of buflomedil chlorhydrate in a mixed population of vasculopathic patients.

In the Observation Department of S. Giacomo Hospital the authors carried out a study on 242 patients, in whom they found a latent vascular pathology in some cases and a manifest vascular pathology in other cases. The patients were divided into two groups: (a) patients at risk, (b) manifestly vasculopathic patients and they were then subdivided according to the compromised region. The subjects underwent sero-haematological and radiological tests, instrumental tests not involving operations such as Doppler ultrasonography and rheography, and tests involving operations such as angiography. Both medical and surgical therapeutic means were used. Then the authors carried out a therapeutic trial with buflomedil chlorhydrate on subjects with obliterative vasculopathy with different aetiologies.

A new rapid assembly dynamic synthesis device (CEB) for the treatment of lateral fractures of the femoral neck.

The authors present a new intramedullary dynamic synthesis device for the internal fixation of pertrochanteric fractures. The system, known as CEB, is constituted by two elements: a flexible intramedullary nail combined with a triflanged nail that penetrates into the cervicocephalic area. The essential objectives are the rationalization and simplification of intramedullary surgical methods currently in use, and, in particular, the desire to overcome the several drawbacks encountered in use of the gamma nail. A review of the first 120 cases revealed the ease and rapidity of the assembly of the components, and the totally satisfactory clinical and radiographic results.

Static assembly of the CEB system in per-subtrochanteric fractures.

The CEB surgical system constitutes a new means of intramedullary dynamic osteosynthesis for the surgical treatment of pertrochanteric fractures. The effectiveness of results obtained in more than 250 cases has encouraged use of the method for the treatment of fractures in the femoral subtrochanteric region, too, with a static assembly that involves a supplementary oblique distal screw. The distal screwing phase proved to be very easy; the authors recommend its use in all of cases of strongly unstable lateral fractures.

Five-centimeter superior mesenteric artery aneurysm. A case report.

An unusual large mesenteric artery aneurysm presented as "angina abdominis" and abdominal mass is described. Endoaneurismectomy with reverse end-to-end saphenous vein graft was performed. The incidence, pathogenesis and diagnosis are reviewed and the treatment is discussed.

Development of O/W nanoemulsions for ophthalmic administration of timolol.

After an initial screening of ingredients and production methods, nanoemulsions for ocular administration of timolol containing the drug as maleate (TM) or as ion-pair with AOT (TM/AOT) were prepared. The physico-chemical characterization of nanoemulsions, regarding mean diameter, pH, zeta potential, osmolarity, viscosity and surface tension, underlined their feasibility to be instilled into the eyes. Single components and emulsions were tested ex vivo on rabbit corneas to evaluate corneal irritation, that was measured according to opacity test. A marked decrease in corneal opacity was observed using the drug formulated in nanoemulsions rather than in aqueous solutions. Drug permeation and accumulation studies were performed on excised rabbit corneas. An increase in drug permeation through and accumulation into the corneas were observed using TM-AOT compared to TM due to an increase of lipophilicity of the drug as ion-pair. The introduction of chitosan (a positive charged mucoadhesive polymer) into emulsions allowed to increase TM permeation probably due to the interaction of chitosan with corneal epithelial cells.