Inositol Hexaphosphate (IP6) and Colon Cancer: From Concepts and First Experiments to Clinical Application.

Multiple human health-beneficial effects have been related to highly phosphorylated inositol hexaphosphate (IP6). This naturally occurring carbohydrate and its parent compound, myo-inositol (Ins), are abundantly present in plants, particularly in certain high-fiber diets, but also in mammalian cells, where they regulate important cellular functions. However, the striking and broad-spectrum anticancer activity of IP6, consistently demonstrated in different experimental models, has been in a spotlight of the scientific community dealing with the nutrition and cancer during the last several decades. First experiments were performed in colon cancer 30 years ago. Since then, it has been shown that IP6 reduces cell proliferation, induces apoptosis and differentiation of malignant cells with reversion to normal phenotype, affecting several critical molecular targets. Enhanced immunity and antioxidant properties also contribute to the tumor cell destruction. Although Ins possesses a modest anticancer potential, the best anticancer results were obtained from the combination of IP6 + Ins. Here we review the first experimental steps in colon cancer, when concepts and hypotheses were put together almost without real knowledge and present clinical studies, that were initiated in colon cancer patients. Available as a dietary supplement, IP6 + Ins has been shown to enhance the anticancer effect of conventional chemotherapy, controls cancer metastases, and improves quality of life in cancer patients. Emerging clinical and still vast amount of experimental data suggest its role either as an adjuvant or as an "alternative" to current chemotherapy for cancer.

Incarcerated Inguinal Hernia Mesh Repair: Effect on Testicular Blood Flow and Sperm Autoimmunity.

BACKGROUND The aim of our study was to determine an influence of incarcerated inguinal hernia mesh repair on testicular circulation and to investigate consequent sperm autoimmunity as a possible reason for infertility. MATERIAL AND METHODS This prospective study was performed over a 3-year period, and 50 male patients were included; 25 of these patients underwent elective open mesh hernia repair (Group I). Group II consisted of 25 patients who had surgery for incarcerated inguinal hernia. Doppler ultrasound evaluation of the testicular blood flow and blood samplings for antisperm antibodies (ASA) was performed in all patients before the surgery, on the second day, and 5 months after. Main outcome ultrasound measures were resistive index (RI) and pulsative index (PI), as their values are inversely proportional to testicular blood flow. RESULTS In Group I, RI, and PI temporarily increased after surgery and then returned to basal values in the late postoperative period. Friedman analysis showed a significant difference in RI and PI for all measurements in Group II (p<0.05), with a significant decrease between the preoperative, early, and late postoperative periods. All final values were within reference range, including ASA, despite significant increase of ASA in the late postoperative period. CONCLUSIONS Although statistically significant differences in values of testicular flow parameters and immunologic sensitization in observed time, final values remained within the reference ranges in all patients. Our results suggest that the polypropylene mesh probably does not cause any clinically significant effect on testicular flow and immunologic response in both groups of patients.

Antisperm antibodies and testicular blood flow after inguinal hernia mesh repair.

BACKGROUND: Testicular flow studies after hernia mesh repair mostly showed different outcomes. The reason of infertility in some men after hernia repair is immunological factors. Aim of the study was to investigate the influence of mesh hernia repair on antisperm antibodies production and testicular blood flow and a connection among these parameters. MATERIALS AND METHODS: A prospective interventional longitudinal cohort study was made on 82 male patients without exclusion criteria who had an inguinal hernia. Patients underwent laparoscopic TAPP or open tension-free hernia repair. Vascular ultrasound and antisperm antibodies were measured in the preoperative and postoperative periods. Main outcome measures were resistive index (RI), peak systolic velocity (PSV) cm/s, and end-diastolic velocity (EDV) cm/s in testicular blood flow measurement and the quantitative value of antisperm antibodies (ASA) in serum (IU/ml). RESULTS: ASA significantly increased postoperatively only in patients who underwent open tension-free hernia repair (p < 0.001). ASA stayed in normal range in all patients except the one with postoperative complication. Friedman analysis showed significant change of the RI only on intratesticular (p < 0.001) and capsular artery level (0.02) in patients who underwent laparoscopic technique. PSV significantly changed on intratesticular (p < 0.001) and capsular artery level (p = 0.015) in the laparoscopic hernia repair. PSV showed significant change on intratesticular (p < 0.001) and testicular artery levels (p < 0.001) in the open tension-free hernia repair. EDV showed significant change only on testicular artery level (p = 0.032) in the patients who had open tension-free hernia repair. These blood flow parameters significantly increased in the early postoperative period and returned on basal value in the late postoperative period. Parameters of flow did not show any significant correlation with ASA. CONCLUSION: Mesh hernia repairs without complication caused only a transitory change in testicular blood flow and no clinical significant autoimmune reaction.

Comparison of thermal damage of the internal thoracic artery using ultra high radiofrequency and monopolar diathermy.

BACKGROUND: The internal thoracic artery (ITA) has been accepted worldwide as a first choice conduit for myocardial revascularisation. It still remains questionable what is the best method for ITA harvesting in a skeletonized fashion according to structural integrity of artery, as a risk factor of early and late graft failure. The purpose of this study was to determine the impact of the ultra-high radiofrequency energy used for ITA harvesting on arterial structural integrity, in particular on the endothelial layer. METHODS: Seventy-four ITA specimens were divided into two groups depending on device used for harvesting (radiofrequency-knife (RF) or electrocauter (EC)). Thermal damage on arterial structural integrity was measured using light microscope, morphometric imaging analysis and immunohistochemical methods. RESULTS: Thermal damage of endothelium was 2.8 times higher in EC than in RF group (p = 0.041) and 5 times higher in patients older than 66 years of age (p = 0.002). Extent of endothelial damage (graded from 0 to 3) was significantly higher in EC group (p = 0.03). Also, in EC group, in patients older than 66 years of age higher proportion of extent of endothelial damage was found (p = 0.027). CONCLUSIONS: The endothelial damage was more often in EC than in RF group as in the patients older than 66 years of age. Demonstrated results suggest that the radiosurgery in comparison to conventional electrocautery is safe and effective method, and significantly reduces thermal damage to endothelial layer of artery.

Analysis of endoloops and endostaples for closing the appendiceal stump during laparoscopic appendectomy.

PURPOSE: An inadequate closure of the appendiceal stump can lead to intra-abdominal surgical site infections. The aim of this study was to assess the efficiency of different closure techniques by focusing on the intraoperative and postoperative complications versus cost. METHODS: From June 2011 to June 2013, 333 patients from two different hospitals undergoing laparoscopic appendectomy were included in this study. The patients were divided into two groups based on the technique used for appendiceal stump closure: there were 104 patients in the stapler group and 229 in the loop group. RESULTS: Among the 333 patients who underwent laparoscopic appendectomy, there were two (0.6%) intraoperative complications and 22 (6.6%) postoperative complications. There were no significant differences between the groups with respect to the intraoperative and postoperative complications. The length of the operation was 7 min shorter when the endoloop was used (p = 0.014). The mean costs of the operation were significantly lower when the loop was used ( 554.93) compared to the stapler ( 900.70) (p = 0.000). CONCLUSIONS: There is no clinical evidence supporting the routine use of endoscopic staplers. The appendiceal stump can be secured safely with the use of endoloops in the majority of patients. Surgeons have to be more selective when choosing how to perform closure, and an endostapler should be used only in cases where it is clinically indicated.

Peutz-Jeghers syndrome complicated with intussusception: enteroscopic polyps resections through laparotomy.

Peutz-Jeghers syndrome is an autosomal dominant inherited disorder characterized by intestinal hamartomatous polyps in association with mucocutaneous pigmentations. Here we present a case of a 30-year-old woman who was hospitalized and underwent diagnostic procedures because of crampy abdominal pain. Physical examination on admission revealed pigmented spots around lips and on the oral mucosa. Multiple polyps were found in stomach, small and large intestine, with signs of initial ileo-ileal intussusception. After endoscopic removal of achievable polyps, we applied gastroscope through laparotomy and enterotomy and removed total number of 34 polyps from small bowel. The polyps were found to be mostly hamartomatous at histological examination. This procedure can provide removal of the most polyps, which are potentially premalignant, also with less complicationes than after multiple intestinal resectiones.

Prognostic value of MVD, LVD and vascular invasion in lymph node-negative colon cancer.

BACKGROUND/AIMS: To clarify the influence of microvessel density (MVD), lymphangiogenesis (LVD), and vascular invasion on prognosis in lymph node-negative colon cancer. METHODOLOGY: We performed immunohistochemical analysis from 152 Duke's B colon carcinomas, CD34 and LYVE-1 antibodies. Carcinomas were graded as low or high grade. χ2 test was used to examine their relationships and correlations with clinicopathological parameters. Survival time was analyzed and the differences between groups were assessed. RESULTS: A statistically significantly correlation was found between increasing MVD with age >60 years, tumor size >4cm, and poor tumor differentiation (χ2=40.018, p<0.001). The increase in MVD was associated with shorter DFS (p<0.001) and shorter OS in patients with colon cancer (p<0.001). LVD was statistically significantly associated with increasing the number of newly created blood vessels (χ2=96.6, p<0.001), low degree of tumor differentiation (χ2=96.6, p<0.001), and vascular invasion (χ2=51.8, p<0.001) in colon cancer. Log rank analysis showed that positive staining for MVD and LVD, high histological grade, vascular invasion, male gender, and age >60 years were connected with shorter survival of patients with Dukes B colon cancer 45 vs. 100 months (p=0.016 to <0.001). CONCLUSIONS: Positive expression MVD and LVD was significantly correlation with survival time and with high tumor grade and vascular invasion in patients with Dukes B colon cancer. The correlation of MVD and LVD with vascular invasion in Dukes B colon cancer indicates the need for further confirmation as a possible predictive marker.

Squamous metaplasia of the peritoneum: report of a case.

The ability of the peritoneum to undergo metaplasia, especially to Müllerian-type epithelium has been recognized for a long time. The ability of mesothelial cells to modulate cytoskeletal filaments and shape is provided through the distinct form of subserosal cells, called multipotential subserosal cells, that have the function of replicative cells that differentiate into surface epithelium when affected by various stimuli. Rare forms of peritoneal metaplasia include squamous and cartilaginous metaplasia. This report presents a case of fully developed, mature peritoneal squamous metaplasia in an 85-year-old woman who underwent surgery because of small bowel perforation leading to diffuse peritonitis. This rare incidental finding almost always occurs in the background of chronic peritoneal irritation as a response to mesothelial injury. Squamos peritoneal metaplasia should not be interpreted as metastatic squamous cell carcinoma. The most important distinguishing criteria are the lack of nuclear atypia, mitoses, necrosis, and desmoplastic stromal response.

Differentiation of inflammatory from non-inflammatory causes of acute scrotum using relatively simple laboratory tests: prospective study.

OBJECTIVE: The differential diagnosis of an acute scrotum is of great importance in clinical practice and may be difficult in some cases. The aim of this study was to differentiate inflammatory from non-inflammatory causes of acute scrotum using relatively simple laboratory tests which can be performed quickly and easily outside a hospital setting. PATIENTS AND METHODS: From 2007 to 2010, 85 boys with acute scrotum were included in this prospective study. There were 28 boys with inflammatory and 57 with non-inflammatory causes. We investigated the role of erythrocyte sedimentation rate, C-reactive protein, leukocyte, white blood cell differential count, alkaline phosphatase, creatine kinase and child's age in differential diagnosis of the acute scrotum, differentiating inflammatory from non-inflammatory causes of the disease. We used receiver operating characteristics (ROC) analysis and logistic regression analysis. RESULTS: Statistically significant parameters in accurate differentiation between inflammatory and non-inflammatory causes of the acute scrotum were C-reactive protein (p = 0.001) and child's age (p < 0.001). These two parameters yielded the probability of an inflammatory outcome in the etiology of acute scrotum with sensitivity of 75% and specificity of 69.1%. CONCLUSION: C-reactive protein and child's age are helpful in differentiating inflammatory from non-inflammatory causes of the acute scrotum.

Comparison of lateral thermal damage of the human peritoneum using monopolar diathermy, Harmonic scalpel and LigaSure.

BACKGROUND: New hemostatic technologies are often employed in open and laparoscopic surgery to reduce duration of surgery and complications. Monopolar diathermy, Harmonic scalpel and LigaSure are routinely used in open and laparoscopic surgery for tissue cutting and hemostasis. We compared lateral thermal damage following in vivo application of 3 commonly used instruments. METHODS: We used monopolar diathermy, Harmonic scalpel and LigaSure to coagulate and divide the peritoneum of patients who underwent median laparotomy. After anesthesia, median supraumbilical laparotomy was performed, and the peritoneum of each patient was coagulated using different devices. Using light microscopy and morphometric imaging analysis, the width of tissue lateral thermal damage was measured from the point of the peritoneal incision. RESULTS: We included 100 patients in our study. After a peritoneal incision, the mean lateral thermal damage of monopolar diathermy, Harmonic scalpel (output power 3), Harmonic scalpel (output power 5) and LigaSure were 215.79 µm, 90.42 µm, 127.48 µm and 144.18 µm, respectively. CONCLUSION: The degree of lateral thermal spread varied by instrument type, power setting and application time. LigaSure and Harmonic scalpel were the safest and most efficient methods of tissue coagulation. Monopolar diathermy resulted in the greatest degree of thermal damage in tissues.

Percutaneous embolization of persistent low-output enterocutaneous fistulas.

OBJECTIVES: To present and retrospectively evaluate the technique of percutaneous embolization of chronic enterocutaneous fistulas (ECFs) using n-butyl-2-cyanoacrylate and Lipiodol under fluoroscopic guidance. METHODS: Six patients with a total of seven post-operative low-output ECFs of the large intestine were treated. After fistulography a hydrophilic guide wire and a catheter were advanced through the ECF into the intestine. After dilation of the bowel with saline and contrast medium, the catheter was withdrawn into the enteric orifice and glue together with Lipiodol was injected while simultaneously pulling the catheter. RESULTS: Complete closure of all seven fistulas was achieved. There were no peri-procedural complications. In one patient 1 month following embolization a low-output enteric discharge was observed, but the ECF spontaneously healed 5 days later. In one patient 18 months after the embolization a new perforation due to diverticulitis close to the embolization site occurred and resection of the sigmoid colon was performed. One patient needed reoperation due to a recurrence of rectal carcinoma. CONCLUSIONS: In our series of patients, the presented technique of percutaneous embolization proved to be efficacious and easy to perform. It may have potential as a first-line treatment of low-output ECFs but a prospective study with a larger series of patients and a longer follow-up is required.

Formation of adhesions at surgical meshes in a rat experimental model.

Abdominal wall hernias are surgical problem that are easily solved with laparoscopic surgery. The determining factor for the success of the operation is the right choice and use of surgical mesh as the support material. The most common complication of surgical mesh placement is the formation of adhesions. Aim of this paper is to determine whether there is a statistic difference in formation of adhesions between different surgical meshes in lab environment. Wistar rats were used as the experimental model. After the anaesthesia a 1x1 cm defect of the abdominal wall was made, but the skin was left intact. The mesh was placed directly on the internal organs. The experiment considered four different mesh types. After set time periods of one, two or four weeks the animals were sacrificed and the amount of formed adhesions were evaluated based on the modified Diamond scale. Immediately after the first week we found a statistically significant difference in the adhesion occurrence rate between compared materials. The smallest amount of adhesions was caused by polypropylen + polydoksanon mesh, and the most by polypropilen mesh. Polypropylen + polyglactin mesh showed significant reduction of adhesion formation between the tested weeks. We can conclude that polypropylen + polydoxanon meshes are superior for ventral hernia operation, because those defects are in close contact with the internal organs and it is very important to have the smallest amount of adhesions.

Preperitoneal approach for femoral hernia repair.

BACKGROUND/AIMS: Although Lichtenstein's procedure is the standard procedure in surgical hernia treatment, and the role of laparoscopic hernia repair is constantly increasing, preperitoneal approach for femoral hernia repair should be equally considered. METHODOLOGY: After the horizontal incision of transversal fascia, preperitoneal space is visualized. The hernial sac is opened and its content is placed in the abdominal cavity, or if there is a need, resection is performed. Once the peritoneum is sutured, the iliopubic tract and Cooper's ligament are bridged with two or three sutures in the medial portion of the femoral ring. RESULTS: From 1998 to 2008, 94 patients were treated for femoral hernia using the preperitoneal approach. Out of 94 participants, 86 were female. Intestinal obstruction was present in 48 cases. Resection of the small intestine or omentum was performed in 40 patients. There was no perioperative mortality. We observed early postoperative complications in 4 patients. Following the procedure, there was no recurrence of the femoral hernia. CONCLUSIONS: We found that preperitoneal repair is the method of choice in surgical treatment of femoral hernia. The surgical technique is simple and feasible, while fully acknowledging the functional anatomy of the inguinofemoral region and the etiology of the condition.

Cyclooxygenase-2 in Dukes B colon cancer.

BACKGROUND/AIMS: To demonstrate immunohistochemical expression of COX-2 protein in Dukes B colon cancer and to establish a correlation with clinicopathological parameters such as: age, gender, gradus, presence of vascular invasion and patient's overall survival. METHODOLOGY: We performed immunohistochemical analysis of formalin-fixed, paraffin embedded specimens form 152 Dukes B colon carcinomas, using the COX-2 monoclonal antibody. Immunohistochemical results were scored semi-quantitatively. Carcinomas were graded as low or high grade. Survival time was analyzed by Kaplan-Meier method, and the log-rank test was used to assess the differences between groups. For multivariate analysis, Cox proportional hazard regression model was used to examine several parameters simultaneously. RESULTS: Univariate analysis showed that positive staining for COX-2, high histological grade; vascular invasion; male gender and age over 60 years, were connected with shorter survival of patients with Dukes B colon cancer (0.023< p<0.001). However, multivariate analysis have shown that the high COX-2 expression in Duke's B colon cancer was unrelated to overall patient survival (RR=1.4; p=0.311). CONCLUSION: Expression of COX-2 in tumor epithelial cells does not seem to be related to survival in patients with colon cancer Dukes B.

Laparoscopic transabdominal preperitoneal approach for inguinal hernia repair: a five-year experience at a single center.

PURPOSE: Laparoscopic hernia repair has emerged as an effective alternative method for treating inguinal hernias. It has several significant advantages over the tension-free open repair now in use. In this report we summarize our laparoscopic hernia repair results and recommendations. METHODS: The transabdominal preperitoneal (TAPP) procedures for groin hernias performed between January 2003 and January 2008 at a single center were analyzed retrospectively. Individual surgeon performances were compared to determine whether the rates of complications were related to the level of surgeon experience. RESULTS: A total of 312 TAPP procedures were reviewed, and 284 (91%) of the patients were followed retrospectively. There were 266 (85.25%) males and 46 (14.75%) females. The average age was 57.4 years. The mean length of hospital stay was 2.1 days. The mean duration of surgery was 35 min. Six (1.92%) intraoperative and seven (2.24%) postoperative complications were noted. Two recurrences occurred (0.70%). CONCLUSIONS: Laparoscopic TAPP hernia repair has proven to be an efficient method for the treatment of groin hernias at our institution. Most patients can be treated as day-cases, namely they are hospitalized for 1 day, and they demonstrate a low recurrence rate (0.70%). Such low morbidity makes TAPP an attractive method for the routine treatment of groin hernias.

Torsion of epiploic appendage mimic acute appendicitis.

Epiploic appendagitis is a rare cause of focal abdominal pain which, depending on its localisation, can mimic a variety of abdominal diseases. We report a case of 36-year-old woman who presented with a classic signs of acute appendicitis. On examination, the obese, afebrile, and had very strong right iliac fossa tenderness and guarding. The white cell count was 12.82 x 10(9)/L, and C reactive protein count was 15.13MG/DL. She underwent emergency laparoscopic procedure after the acute appendicitis diagnosis has been established. Laparoscopic exploration of the abdominal cavity showed vermiform, no inflamed, appendix and necrotic appendix epiploica of the caecum. The treatment consisted of typical laparoscopic appendectomy and laparoscopic resection of the necrotic appendix epiploica. The patient made rapid recovery and was discharged from the hospital on second day after the operation. Histological investigation of the appendix epiploica revealed gangrenous epiploic appendage.

[Clinical recommendations for diagnosis, treatment and monitoring of patients with colorectal cancer]. / Klinicke upute za dijagnozu, lijecenje i pracenje bolesnika oboljelih od kolorektalnog raka.

Colorectal cancer is the third most common malignant tumour in males and the fourth most common malignancy in women in the Republic of Croatia. It is usually manifested as stool forming disorders, feeling that bowel does not empty completely, finding blood in the stool, weight loss and fatigue. In-time diagnosis, confirmed by pathohistological findings, is cornerstone of successful treatment. The decision about treatment is made based on clinical assessment of disease stage and other risk factors, after completion of the diagnostic process. Depending on that, treatment options include surgery, the application of systemic therapy (chemotherapy, immunotherapy) and radiotherapy. The following text presents the clinical guidelines in order to standardize procedures and criteria for the diagnosis, management, treatment and monitoring of patients with colorectal cancer in the Republic of Croatia.

New paradigm in training of undergraduate clinical skills: the NEPTUNE-CS project at the Split University School of Medicine.

Clinical skills' training is arguably the weakest point in medical schools' curriculum. This study briefly describes how we at the Split University School of Medicine cope with this problem. We consider that, over the last decades, a considerable advancement in teaching methodologies, tools, and assessment of students has been made. However, there are many unresolved issues, most notably: (i) the institutional value system, impeding the motivation of the teaching staff; (ii) lack of a strong mentoring system; (iii) organization, timing, and placement of training in the curriculum; (iv) lack of publications pertinent to training; and (v) unwillingness of patients to participate in student training. To improve the existing training models we suggest increased institutional awareness of obstacles, as well as willingness to develop mechanisms for increasing the motivation of faculty. It is necessary to introduce changes in the structure and timing of training and to complement it with a catalog, practicum, and portfolio of clinical skills. At Split University School of Medicine, we developed a new paradigm aimed to improve the teaching of clinical skills called "Neptune-CSS," which stands for New Paradigm in Training of Undergraduate Clinical Skills in Split.

Efficacy of IP6 + inositol in the treatment of breast cancer patients receiving chemotherapy: prospective, randomized, pilot clinical study.

BACKGROUND: Prospective, randomized, pilot clinical study was conducted to evaluate the beneficial effects of inositol hexaphosphate (IP6) + Inositol in breast cancer patients treated with adjuvant therapy. PATIENTS AND METHODS: Patients with invasive ductal breast cancer where polychemotherapy was indicated were monitored in the period from 2005-2007. Fourteen patients in the same stage of ductal invasive breast cancer were involved in the study, divided in two randomized groups. One group was subjected to take IP6 + Inositol while the other group was taking placebo. In both groups of patients the same laboratory parameters were monitored. When the treatment was finished, all patients have filled questionnaires QLQ C30 and QLQ-BR23 to determine the quality of life. RESULTS: Patients receiving chemotherapy, along with IP6 + Inositol did not have cytopenia, drop in leukocyte and platelet counts. Red blood cell counts and tumor markers were unaltered in both groups. However, patients who took IP6 + Inositol had significantly better quality of life (p = 0.05) and functional status (p = 0.0003) and were able to perform their daily activities. CONCLUSION: IP6 + Inositol as an adjunctive therapy is valuable help in ameliorating the side effects and preserving quality of life among the patients treated with chemotherapy.

Pelvic peritonization after laparoscopic abdominoperineal resection for low-rectal carcinoma treatment: surgical technique.

Abdominoperineal resection is a standard method of low-rectum carcinoma treatment. It is associated with significant morbidity and mortality rates, which decreased with the development of preoperative diagnostic procedures, new surgical techniques and new surgical instruments. In this article, laparoscopic pelvic peritonization was used after laparoscopic rectum amputation for low-rectum carcinoma treatment. Pelvic peritonization is performed after laparoscopic recto-sigmoid extirpation, using the extended absorbable intracorporeal suture with titanic clip application after every second suture. The role of titanic clip is to grasp the extended suture and to mark the postoperative irradiation field. Laparoscopic pelvic peritonization after laparoscopic abdominoperineal rectum amputation is a simple procedure with clinical importance in possible adhesion and postirradiatic enteritis prevention. This procedure can satisfy all oncological requirements and minimally invasive surgery principles and is acceptable for every patient in which rectum amputation is indicated.