Horizontal Transfer of Malignant Traits and the Involvement of Extracellular Vesicles in Metastasis.

Metastases are responsible for the vast majority of cancer deaths, yet most therapeutic efforts have focused on targeting and interrupting tumor growth rather than impairing the metastatic process. Traditionally, cancer metastasis is attributed to the dissemination of neoplastic cells from the primary tumor to distant organs through blood and lymphatic circulation. A thorough understanding of the metastatic process is essential to develop new therapeutic strategies that improve cancer survival. Since Paget's original description of the "Seed and Soil" hypothesis over a hundred years ago, alternative theories and new players have been proposed. In particular, the role of extracellular vesicles (EVs) released by cancer cells and their uptake by neighboring cells or at distinct anatomical sites has been explored. Here, we will outline and discuss these alternative theories and emphasize the horizontal transfer of EV-associated biomolecules as a possibly major event leading to cell transformation and the induction of metastases. We will also highlight the recently discovered intracellular pathway used by EVs to deliver their cargoes into the nucleus of recipient cells, which is a potential target for novel anti-metastatic strategies.

New dosimetric parameters to predict ano-rectal toxicity during radiotherapy treatment.

PURPOSE: Radiotherapy is essential in the treatment of locally advanced rectal cancer. Side effects of radiotherapy in the treatment of rectal cancer have a great effect on quality of life. The aim of this retrospective study is to evaluate the correlation between dosimetric parameters and acute toxicity in rectal cancer patients. METHODS: We analyzed the Dose Volume Histogram parameters for both the target structures and the Organs at risk of 89 patients. A dedicated statistical analysis was performed for all the acute toxicities showing a frequency rate higher than 20%. A linear logistic regression model was elaborated using the variable showing the highest level of significance at the univariate analysis. RESULTS: The occurrence of proctitis was significantly correlated with three dosimetric parameters: D98% of low ano-rectum, D98% and Dmean of low ano-rectum wall. A predictive linear logistic regression model reports that the D98% of the wall of the low ano-rectum must be < 38.5 Gy to decrease the rate of proctitis. A general analysis on grade 2 acute toxicity occurrence reported that it was correlated with D98% of low ano rectum. CONCLUSIONS: Two dose constraints were elaborated: D98%<33.5 Gy for low ano rectum to prevent grade 2 acute toxicity and D98%<25 Gy for low ano-rectum wall to prevent proctitis (grade 1 or superior).

An Unusual Presentation of Crohn's Disease Diagnosed Following Accidental Ingestion of Fruit Pits: Report of Two Cases and Review of the Literature.

The clinical course of Crohn's disease (CD) is often complicated by intestinal strictures, which can be fibrotic, inflammatory, or mixed, therefore leading to stenosis and eventually symptomatic obstruction. We report two cases of subclinical CD diagnosed after fruit pit ingestion, causing bowel obstruction; additionally, we conducted a narrative review of the scientific literature on cases of intestinal obstruction secondary to impacted bezoars due to fruit pits. Symptoms of gastrointestinal bezoars in CD patients are not diagnostic; and the diagnosis should be based on a combined assessment of history, clinical presentation, imaging examination and endoscopy findings. This report corroborates the concept that CD patients are at a greater risk of bowel obstruction with bezoars generally and shows that accidental ingestion of fruit pits may lead to an unusual presentation of the disease. Therapeutic options in this group of patients differ from the usual approaches implemented in other patients with strictures secondary to CD.

Oncosuppressor-Mutated Cell-Based Diagnostic Platform for Liquid Biopsy Diagnoses Benign Head and Neck Masses and Predicts Malignancy in Thyroid Nodules: Results from a Consecutive Cohort of Patients.

BACKGROUND: We reported that a novel oncosuppressor-mutated cell (OMC)-based platform has the potential for early cancer detection in healthy individuals and for identification of cancer patients at risk of developing metachronous metastases. OBJECTIVE: Herein, we sought to determine the diagnostic accuracy of this novel OMC-based platform in a consecutive cohort of patients operated for suspicious head and neck masses. METHODS: OMCs (BRCA1-deficient fibroblasts) were exposed to blood serum from patients with head and neck nodules before surgical removal. These cells were analyzed for their proliferation and survival. Treated OMCs were inoculated subcutaneously in NOD/SCID mice, and tumor growth was monitored over time. RESULTS: OMCs exposed to serum from patients with malignant lesions displayed increased proliferation compared to those exposed to serum from patients with benign lesions. Only OMCs exposed to serum from patients diagnosed with malignant thyroid neoplasia generated a cancerous mass. The sensitivity of the test was 92%, with only 1 false negative out of 34 patients. Immunohistochemical staining showed that the cancerous masses were poorly differentiated adenocarcinomas with high proliferative index. CONCLUSIONS: These data show that liquid biopsy combined with an OMC-based in vivo platform has the potential to diagnose benign head and neck masses and predict whether a thyroid nodule is malignant. These results strengthen the concept that OMCs can be used to detect circulating malignant factors in cancer patients.

Itraconazole inhibits nuclear delivery of extracellular vesicle cargo by disrupting the entry of late endosomes into the nucleoplasmic reticulum.

Extracellular vesicles (EVs) are mediators of intercellular communication under both healthy and pathological conditions, including the induction of pro-metastatic traits, but it is not yet known how and where functional cargoes of EVs are delivered to their targets in host cell compartments. We have described that after endocytosis, EVs reach Rab7+ late endosomes and a fraction of these enter the nucleoplasmic reticulum and transport EV biomaterials to the host cell nucleoplasm. Their entry therein and docking to outer nuclear membrane occur through a tripartite complex formed by the proteins VAP-A, ORP3 and Rab7 (VOR complex). Here, we report that the antifungal compound itraconazole (ICZ), but not its main metabolite hydroxy-ICZ or ketoconazole, disrupts the binding of Rab7 to ORP3-VAP-A complexes, leading to inhibition of EV-mediated pro-metastatic morphological changes including cell migration behaviour of colon cancer cells. With novel, smaller chemical drugs, inhibition of the VOR complex was maintained, although the ICZ moieties responsible for antifungal activity and interference with intracellular cholesterol distribution were removed. Knowing that cancer cells hijack their microenvironment and that EVs derived from them determine the pre-metastatic niche, small-sized inhibitors of nuclear transfer of EV cargo into host cells could find cancer therapeutic applications, particularly in combination with direct targeting of cancer cells.

Uveal Melanoma-Derived Extracellular Vesicles Display Transforming Potential and Carry Protein Cargo Involved in Metastatic Niche Preparation.

Extracellular vesicles (EVs) carry molecules derived from donor cells and are able to alter the properties of recipient cells. They are important players during the genesis and progression of tumors. Uveal melanoma (UM) is the most common primary intraocular tumor in adults and is associated with a high rate of metastasis, primarily to the liver. However, the mechanisms underlying this process are poorly understood. In the present study, we analyzed the oncogenic potential of UM-derived EVs and their protein signature. We isolated and characterized EVs from five UM cell lines and from normal choroidal melanocytes (NCMs). BRCA1-deficient fibroblasts (Fibro-BKO) were exposed to the EVs and analyzed for their growth in vitro and their reprograming potential in vivo following inoculation into NOD-SCID mice. Mass spectrometry of proteins from UM-EVs and NCM-EVs was performed to determine a protein signature that could elucidate potential key players in UM progression. In-depth analyses showed the presence of exosomal markers, and proteins involved in cell-cell and focal adhesion, endocytosis, and PI3K-Akt signaling pathway. Notably, we observed high expression levels of HSP90, HSP70 and integrin V in UM-EVs. Our data bring new evidence on the involvement of UM-EVs in cancer progression and metastasis.

Biomechanical characterization of a chronic type a dissected human aorta.

Aortic dissection is one of the most lethal cardiovascular diseases. A chronic Type A (Stanford) dissected aorta was retrieved for research from a 73-year-old male donor without diagnosed genetic disease. The aorta presented a dissection over the full length, and it reached a diameter of 7.7 cm in its ascending portion. The descending thoracic aorta underwent layer-specific quasi-static and dynamic mechanical characterizations after layer separation. Mechanical tests showed a physiological (healthy) behavior of the intima and some mechanical anomalies of the media and the adventitia. In particular, the static stiffness of both these layers at smaller strains was three times smaller than any one measured for twelve healthy aortas. When the viscoelastic properties were tested, adventitia presented a larger relative increase of the dynamic stiffness at 3 Hz with respect to most of the healthy aortas. The loss factor of the adventitia, which is associated with dissipation, was at the lower limit of those measured for healthy aortas. It seems reasonable to attribute these anomalies of the mechanical properties exhibited by the media and the adventitia to the severe remodeling secondary to the chronic nature of the dissection. However, it cannot be excluded that some of the mechanical anomalies were present before remodeling.

Colorectal cancer-derived extracellular vesicles induce transformation of fibroblasts into colon carcinoma cells.

BACKGROUND: We reported that horizontal transfer of malignant traits to target cells is a potential pathway to explain cancer dissemination. Although these results were encouraging, they were never corroborated by data showing the molecular mechanisms responsible for the observed phenomenon. METHODS: In the present study, we exposed BRCA1-KO fibroblasts to extracellular vesicles (EVs) isolated from a colon cancer cell line (HT29) and from sera of patients with colorectal cancer. Three weeks after exposure, fibroblasts were injected subcutaneously into NOD-SCID mice. Whole genome sequencing, transcriptome analysis and RNA sequencing of cancer EVs and fibroblasts prior and after exposure to cancer EVs were performed. RESULTS: Phenotypical transformation of the fibroblasts into colon cancer cells was confirmed by histopathological study of the xenotransplants. We observed that EV-mediated transfer of cancer microRNAs was responsible for the transition from a mesenchymal to an epithelial phenotype (MET) in the treated fibroblasts as well as activation of cell cycle progression and cell survival pathways. DNA and RNA sequencing suggested that cancer DNA was transferred and possibly transcribed in target cells. Furthermore, injection of colon cancer EVs in the tail vein of NOD-SCID mice determined neoplastic transformation and metastases in the lungs of the mice confirming for the first time the hypothesis that transfer of malignant epithelial cancer traits to distant target cells is a concept applicable to in vivo models. CONCLUSIONS: These discoveries shed new light into the molecular mechanisms behind the horizontal transfer of malignant traits and confirm the notion that metastatic disease might be reproduced through transfer of circulating genetic material.

Oncosuppressor-Mutated Cells as a Liquid Biopsy Test for Cancer-Screening.

We reported on the ability of immortalized or oncosuppressor-mutated cells (OMCs) to uptake circulating cancer-factors and give tumors when transplanted into mice. This led to the first biological based liquid biopsy test, which we called MATER-D platform. In the present study, we showed for the first time that a different type of OMCs (PTEN-deficient human epithelial MCF10A cells) turn malignant when exposed to cancer patient's sera, confirming the concept that different cells with diverse oncosuppressor mutations can uptake cancer factors and be used in biological based liquid biopsy tests. Our observations were confirmed in a large variety of solid and haematological malignancies. This test was able to detect dysplasia and carcinomas in situ lesions in different organs and circulating factors in cancer patients years after the removal of their lesions. To our knowledge, this ability is unique and not shared by other liquid biopsy platforms. Immunohistochemistry analysis of the xenotransplants revealed identical patterns of differentiation regardless of the cancer type, showing that differentiation through horizontal transfer might be dependent on the nature of the target cells rather than the type of cancer factors. These data strengthen the notion that OMC-based liquid biopsy tests might be promising platforms for cancer screening.

Exosomes isolated from cancer patients' sera transfer malignant traits and confer the same phenotype of primary tumors to oncosuppressor-mutated cells.

BACKGROUND: Horizontal transfer of malignant traits from the primary tumor to distant organs, through blood circulating factors, has recently become a thoroughly studied metastatic pathway to explain cancer dissemination. Recently, we reported that oncosuppressor gene-mutated human cells undergo malignant transformation when exposed to cancer patients' sera. We also observed that oncosuppressor mutated cells would show an increased uptake of cancer-derived exosomes and we suggested that oncosuppressor genes might protect the integrity of the cell genome by blocking integration of cancer-derived exosomes. In the present study, we tested the hypothesis that cancer patients' sera-derived exosomes might be responsible for the malignant transformation of target cells and that oncosuppressor mutation would promote their increased uptake. We also sought to unveil the mechanisms behind the hypothesized phenomena. METHODS: We used human BRCA1 knockout (BRCA1-KO) fibroblasts as target cells. Cells were treated in vitro with cancer patients' sera or cancer patients' sera-derived exosomes. Treated cells were injected into NOD-SCID mice. Immunohistochemical analyses were performed to determine the differentiation state of the xenotransplants. Mass spectrometry analyses of proteins from cancer exosomes and the BRCA1-KO fibroblasts' membrane were performed to investigate possible de novo expression of molecules involved in vesicles uptake. Blocking of the identified molecules in vitro was performed and in vivo experiments were conducted to confirm the role of these molecules in the malignant transformation carried out by cancer-derived exosomes. RESULTS: Cells treated with exosomes isolated from cancer patients' sera underwent malignant transformation and formed tumors when transplanted into immunodeficient mice. Histological analyses showed that the tumors were carcinomas that differentiated into the same lineage of the primary tumors of blood donors. Oncosuppressor mutation promoted the de novo expression, on the plasma membrane of target cells, of receptors, responsible for the increased uptake of cancer-derived exosomes. The selective blocking of these receptors inhibited the horizontal transfer of malignant traits. CONCLUSION: These findings strengthen the hypothesis that oncogenic factors transferred via circulating cancer exosomes, induce malignant transformation of target cells even at distance. Oncosuppressor genes might protect the integrity of the cell genome by inhibiting the uptake of cancer-derived exosomes.

Transfer of malignant traits as opposed to migration of cells: A novel concept to explain metastatic disease.

Metastatic disease is believed to develop following dissemination of cells to target organs. Inability of this theory to effectively explain certain phenomena such as patterns of metastatic spread, late metastasis formation, different gene patterns between primary cancer and metastasis have brought forward the need for alternative models. Recent discoveries have strengthened the validity of theories supporting a humoral transfer of malignant traits as opposed to migration of malignant cells to explain metastatic disease in cancer patients. In light of this new evidence, we would like to highlight a model that offers a new perspective to explain cancer metastasis. In the system that we theorize, genetic material released by cancer cells would travel, either free or packed in exosomes, through the blood. Target cells located in organs deriving from the same embryological layer might uptake this genetic material due to expression of specific receptors. Interplay with the immune system would determine the fate of these oncofactors and would regulate their ability to circulate in the blood, integrate in the genome and be transcribed. We also hypothesize that the expression of cell membrane receptors such as integrins, to which cancer exosomes ligate might be mediated by inherited or acquired oncosuppressor mutations.

Reprogramming Malignant Cancer Cells toward a Benign Phenotype following Exposure to Human Embryonic Stem Cell Microenvironment.

The embryonic microenvironment is well known to be non-permissive for tumor development because early developmental signals naturally suppress the expression of proto-oncogenes. In an analogous manner, mimicking an early embryonic environment during embryonic stem cell culture has been shown to suppress oncogenic phenotypes of cancer cells. Exosomes derived from human embryonic stem cells harbor substances that mirror the content of the cells of origin and have been reported to reprogram hematopoietic stem/progenitor cells via horizontal transfer of mRNA and proteins. However, the possibility that these embryonic stem cells-derived exosomes might be the main effectors of the anti-tumor effect mediated by the embryonic stem cells has not been explored yet. The present study aims to investigate whether exosomes derived from human embryonic stem cells can reprogram malignant cancer cells to a benign stage and reduce their tumorigenicity. We show that the embryonic stem cell-conditioned medium contains factors that inhibit cancer cell growth and tumorigenicity in vitro and in vivo. Moreover, we demonstrate that exosomes derived from human embryonic stem cells display anti-proliferation and pro-apoptotic effects, and decrease tumor size in a xenograft model. These exosomes are also able to transfer their cargo into target cancer cells, inducing a dose-dependent increase in SOX2, OCT4 and Nanog proteins, leading to a dose-dependent decrease of cancer cell growth and tumorigenicity. This study shows for the first time that human embryonic stem cell-derived exosomes play an important role in the tumor suppressive activity displayed by human embryonic stem cells.

Adult colo-colonic intussusception caused by congenital bands: A case report and literature review.

INTRODUCTION: Intussusception refers to the telescoping of a segment of bowel into the lumen of an adjacent segment. While pediatric intussusception is common and generally idiopathic, adult intussusception is exceedingly rare and is usually attributable to a pathologic lead point. PRESENTATION OF CASE: 37-year-old man who presented with abdominal pain, and was preoperatively diagnosed with a colo-colonic intussusception. Intraoperatively, the lead point was found to be congenital bands, and there was no evidence of underlying malignancy. He underwent a laparoscopic-assisted extended right hemicolectomy with side-to-side ileo-colic anastomosis. DISCUSSION: Colo-colonic intussusception is a rare cause of intestinal obstruction in adults. Patients generally present with subacute abdominal pain and obstructive symptoms, rendering the clinical diagnosis challenging. Computed tomography has been shown to be the most accurate diagnostic imaging modality. Due to the high incidence of underlying malignancy in adult colo-colonic intussusception, en-bloc resection of the involved bowel segment remains the standard of care. CONCLUSION: Congenital bands can serve as a lead point in colo-colonic intussusception, particularly in younger adults. Prompt surgical intervention remains paramount to limit morbidity.

Transfer of malignant trait to BRCA1 deficient human fibroblasts following exposure to serum of cancer patients.

BACKGROUND: It was reported that metastases might occur via transfer of biologically active blood circulating molecules from the primary tumor to distant organs rather than only migration of cancer cells. We showed in an earlier study that exposure of immortalized human embryonic kidney cells (HEK 293) to cancer patient sera, induce their transformation into undifferentiated cancers due to a horizontal transfer of malignant traits. In the present work, we tested the hypothesis that even other human cells as long as they are deficient for a single oncosuppressor gene might undergo malignant transformation when exposed to human cancer serum. METHODS: We used the CRISPR/Cas9 system to establish a stable BRCA1 knockout (KO) in human fibroblasts. The BRCA1-KO fibroblasts were exposed to cancer patients' sera or healthy patients' sera for 2 weeks. Treated cells were analyzed for cell proliferation and transformation to study their susceptibility to the oncogenic potential of cancer patients' sera and to determine the possible mechanisms underlying their hypothesized transformation. RESULTS: BRCA1-KO fibroblasts treated with cancer patients' sera displayed higher proliferation and underwent malignant transformation as opposed to wild type control fibroblasts, which were not affected by exposure to cancer patients' sera. The malignant transformation was not seen when BRCA1-KO fibroblasts were treated with healthy human sera. Histological analysis of tumors generated by BRCA1-KO fibroblasts showed that they were carcinomas with phenotypical characteristics related to the cancers of the blood donor patients. Interestingly, BRCA1-KO fibroblasts were significantly more prone to internalize serum-derived exosomes, when compared to wild type fibroblasts. This suggests that oncosuppressor genes might protect the integrity of the cell genome also by blocking integration of cancer-derived exosomes. CONCLUSION: These data support the hypothesis that any human cells carrying a single oncosuppressor mutation is capable of integrating cancer factors carried in the blood and undergo complete malignant transformation. Oncosuppressor genes might protect the cell genome by impeding the integration inside the cells of these mutating factors.

Prevention of perineal hernia after laparoscopic and robotic abdominoperineal resection: review with illustrative case series of internal hernia through pelvic mesh.

ABSTRACT: This review is intended to raise awareness of placing a pelvic mesh to prevent perineal hernias in cases of minimally invasive (MIS) abdominoperineal resections (APR) and, in doing so, causing internal hernias through the mesh. In this article, we review the published literature and present an illustrative series of 4 consecutive cases of early internal hernia through a pelvic mesh defect. These meshes were placed to prevent perineal hernias after laparoscopic or robotic APRs. The discussion centres on 3 key questions: Should one be placing a pelvic mesh following an APR? What are some of the technical details pertaining to the initial mesh placement? What are the management options related to internal hernias through such a mesh?

RESUME: L'objectif du présent examen est de sensibiliser les praticiens au risque associé à la pose d'un treillis pelvien visant à prévenir les hernies périnéales après une résection abdominopérinéale à effraction minimale, pratique qui peut entraîner une hernie interne. Nous nous penchons ici sur les articles publiés à ce sujet et présentons une série éloquente de 4 cas consécutifs de hernies internes précoces attribuables à un défaut du treillis. Les dispositifs avaient été mis en place pour prévenir une hernie périnéale après des résections laparoscopiques ou robotiques. La discussion porte sur 3 questions centrales : Devrait-on poser un treillis pelvien à la suite d'une résection abdominopérinéale? Quels sont les éléments techniques à surveiller lors de la pose initiale? Quelles sont les options de prise en charge des hernies internes causées par les treillis?

Novel blood test to predict neoplastic activity in healthy patients and metastatic recurrence after primary tumor resection.

We reported that single oncosuppressor-mutated (SOM) cells turn malignant when exposed to cancer patients' sera. We tested the possibility to incorporate this discovery into a biological platform able to detect cancer in healthy individuals and to predict metastases after tumor resection. Blood was drawn prior to tumor resection and within a year after surgery. Blood samples from healthy individuals or metastatic patients were used as negative and positive controls, respectively. Patients at risk for cancer were included in the screening cohort. Once treated, cells were injected into nonobese diabetic/severe combined immunodeficiency mice to monitor tumor growth. All samples of sera coming from metastatic patients transformed SOM cells into malignant cells. Four samples from screened patients transformed SOM cells. Further clinical tests done on these patients showed the presence of early cancerous lesions despite normal tumor markers. Based on the xenotransplants size, we were able to predict metastasis in three patients before diagnostic tests confirmed the presence of the metastatic lesions. These data show that this serum-based platform has potentials to be used for cancer screening and for identification of patients at risks to develop metastases regardless of the Tumor Node Metastasis (TNM) stage or tumor markers level.

Transfer of malignant trait to immortalized human cells following exposure to human cancer serum.

BACKGROUND: Human cancer cells can transfer signaling molecules to neighboring and distant cells predisposing them to malignant transformation. This process might contribute to tumor progression and invasion through delivery of oncogenes or inhibitors of tumor suppressor genes, derived from the primary tumor cells, to susceptible target cells. The oncogenic potential of human cancer serum has been described in immortalized mouse fibroblasts but has not been shown yet in human cells. The objective of this study was to determine whether metastatic cancer patient sera have the ability to induce neoplastic transformation in immortalized human embryonic kidney (HEK293) cells, human embryonic stem cells (hESCs), human mesenchymal stem cells (hMSCs) and human adult liver fibroblasts (hALFs). METHODS: Early passage HEK293 cells, hESCs, hMSCs and hALFs were exposed to cancer patient serum, or cancer cells-derived condition medium for 3 weeks. Treated cells were analyzed for cell proliferation and transformation both in vitro and in vivo. RESULTS: HEK293 cells exposed to cancer serum increased their proliferative capability and displayed characteristics of transformed cells, as evaluated by in vitro anchorage-independent growth assay and in vivo tumorigenesis in immunodeficient mice. The same phenotypes were acquired when these cells were cultured in cancer cell line conditioned medium suggesting that the putative oncogenic factors present in the serum might derive directly from the primary tumor. Histopathological analyses revealed that the tumors arising from cancer patient serum and conditioned medium-treated HEK293 cells were poorly differentiated and displayed a high proliferative index. In contrast, neither of these phenomena was observed in treated hMSCs and hALFs. Intriguingly enough, hESC-treated cells maintained their self-renewal and differentiation potentials, as shown by in vitro sphere formation assay and in vivo development of teratomas in immunodeficient mice. CONCLUSION: Our results indicate that cancer patients serum is able to induce oncogenic transformation of HEK293 cells and maintain the self-renewal of hESCs. To our knowledge, this is the first study that demonstrates the oncogenic transformation potential of cancer patient serum on human cells. In depth characterization of this process and the molecular pathways involved are needed to confirm its validity and determine its potential use in cancer therapy.

Total sacrectomy for recurrent rectal cancer - A case report featuring technical details and potential pitfalls.

INTRODUCTION: Total sacrectomy for recurrent rectal cancer is controversial. However, recent publications suggest encouraging outcomes with high sacral resections. We present the first case report describing technical aspects, potential pitfalls and treatment of complications associated with total sacrectomy performed as a treatment of recurrent rectal cancer. PRESENTATION OF CASE: A fifty-three year old man was previously treated at another institution with a low anterior resection (LAR) followed by chemo-radiation and left liver tri-segmentectomy for metastatic rectal cancer. Three years following the LAR, the patient developed a recurrence at the site of colorectal anastomosis, manifesting clinically as a contained perforation, forming a recto-cutaneous fistula through the sacrum. Abdomino-perineal resection (APR) and complete sacrectomy were performed using an anterior-posterior approach with posterior spinal instrumented fusion and pelvic fixation using iliac crest bone graft. Left sided vertical rectus abdominis muscle flap and right sided gracilis muscle flap were used for hardware coverage and to fill the pelvic defect. One year after the resection, the patient remains disease free and has regained the ability to move his lower limbs against gravity. DISCUSSION: The case described in this report features some formidable challenges due to the previous surgeries for metastatic disease, and the presence of a recto-sacral cutaneous fistula. An approach with careful surgical planning including considerationof peri-operative embolization is vital for a successful outcome of the operation. A high degree of suspicion for pseudo-aneurysms formation due infection or dislodgement of metallic coils is necessary in the postoperative phase. CONCLUSION: Total sacrectomy for the treatment of recurrent rectal cancer with acceptable short-term outcomes is possible.A detailed explanation to the patient of the possible complications and expectations including the concept of a very high chancefor recurrence is paramount prior to proceeding with such a surgery.

Outcomes and cost analysis of laparoscopic versus open appendectomy for treatment of acute appendicitis: 4-years experience in a district hospital.

BACKGROUND: Laparoscopic appendectomy is not yet unanimously considered the "gold standard" in the treatment of acute appendicitis because of its higher operative time, intra-abdominal abscess risk, and costs compared to open appendectomy. This study aimed to compare outcomes and cost of laparoscopic and open appendectomy in a district hospital. METHODS: A retrospective analysis of 230 patients who underwent appendectomy at the Division of General Surgery of the Civil Hospital of Ragusa, Italy, from May 2008 to May 2012 was performed. The variables analyzed included patients data (age, gender, previous abdominal surgery, preoperative WBC count, duration of symptoms, ASA risk score), rate of uncomplicated or complicated appendicitis, operative time, postoperative complications, length of hospital stay, and total costs. The patients were divided in two groups according to the surgical approach and compared for each variable. The results were analyzed using the t Student test for quantitative variables, and the Chi-square test with Yates correction and Fisher exact test for categorical. RESULTS: Laparoscopic appendectomy was performed in 139 patients, open appendectomy in 91. Two cases (1.4%) were converted to open procedure and included in the laparoscopic group data. Patient data and rate of complicated appendicitis were similar in the two study groups. There was no statistical difference (p = 0.476) in the mean operative time between the laparoscopic (52.2 min; range, 20-155) and open appendectomy (49.3 min; range, 20-110) groups. The overall incidence of minor and major complications was significantly lower (p = 0.006) after laparoscopic appendectomy (2.9%, 4 cases) than after open appendectomy (13.2%, 12 cases); rate of intra-abdominal abscess were similar. The length of hospital stay was significantly shorter (p = 0.001) in laparoscopic group (2.75 days; range, 1-8) than in open group (3.87 days; range, 1-19). The mean total cost was 2282 Euro in laparoscopic group and 2337 Euro in open group, with a no significant difference of 55 Euro (p = 0.812). CONCLUSION: Laparoscopic appendectomy is associated with fewer complications, shorter hospital stay, and similar operative time, intra-abdominal abscess rate, and total costs, compared with open appendectomy. Therefore, laparoscopic appendectomy can be recommended as preferred approach in acute appendicitis.

Surgical resection of ruptured fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLH) is a rare primary tumor of the liver, which typically arises from noncirrhotic livers and affects patients below the age of 35. We report on a 29-year-old male patient who presented with a ruptured FLH and was treated with surgical resection. Options for treatment and review of the management are described.