Mediastinal hematoma as an unusual intrathoracic manifestation of Boerhaave Syndrome: A case report.

INTRODUCTION: Boerhaave Syndrome (BS) is rare but life-threatening condition caused by a sudden increase in the intraluminal pressure due to vomiting. We present a case of BS manifesting as a posterior mediastinal hematoma, indicative of a potentially fatal condition. PRESENTATION OF CASE: A 51-year-old man presented with acute chest pain after vomiting. Enhanced Computed Tomography revealed mediastinal fluid with a left pleural effusion, leading to a diagnosis of BS. Emergency surgery revealed a posterior mediastinal hematoma with active bleeding due to a torn proper esophageal artery. Hemostasis and a wall repair were performed, and the patient was discharged uneventfully. DISCUSSION: This case highlights two important aspects. Firstly, a spontaneous esophageal perforation can manifest as a mediastinal hematoma due to the subpleural arterial injury, delaying bacterial spillage. While preoperative thoracentesis may not always diagnose BS accurately, bloody thoracic drainage can serve as an alternative diagnostic sign. Secondly, the mediastinal hematoma itself poses a serious risk, as it can lead to a catastrophic outcome even before bacterial contamination occurs, emphasizing the necessity of a timely surgical intervention in BS cases. CONCLUSION: BS can manifest as a mediastinal hematoma, and the absence of gastrointestinal content in the thoracic drainage does not rule out the possibility of BS. Prompt surgical intervention remains essential, as a mediastinal hematoma alone can result in a catastrophic outcome. This case highlights the significance of a comprehensive diagnostic assessment for BS.

The outcome of closure of inguinal hernia with laparoscopic percutaneous extraperitoneal closure in young adults.

BACKGROUND: Hernioplasty is one of the most commonly performed surgeries. However, the optimal procedure for young adults has not been defined yet. Our study compared the outcomes of laparoscopic percutaneous extraperitoneal closure (LPEC) in young adults with outcomes in children. MATERIAL AND METHODS: We retrospectively reviewed patients aged 0-30 years who underwent LPEC. Data regarding age, sex, hernia type, surgical time, pre-intraoperative laterality, contralateral patent processus vaginalis (CPPV), and complications were analyzed. RESULTS: LPEC was performed on 2642 patients in our hospital. Of these, 51 patients were young adults (aged 15-30 years). Asymptomatic CPPV in unilateral patients was frequent in the <15-year age group (50.2%) compared to the 15-30-year age group (15.9%). The median surgical time was shorter in the <15-year age group (19 min, interquartile range [IQR]: 24-33) compared to that of the 15-30-year age group (33 min, IQR: 23.3-40.8). CONCLUSIONS: This is the first report on the outcomes in young adult patients who underwent LPEC. The median surgical time was longer in the 15-30-year age group than in the <15-year age group. The median follow-up was 4.7 years with no intra-postoperative complications, such as postoperative bleeding, infection, persistent pain, and recurrence. LPEC is an effective, cosmetic, and safe surgical treatment in young adults and children.

Neodymium magnets migrated into an internal supravesical hernia: a rare case of foreign body ingestion in children.

BACKGROUND: Foreign body (FB) ingestion is a common event in children. The management of the ingested FB depends on the location, type, number, size of the FBs, patient age, and symptoms. Although most FBs pass spontaneously through the gastrointestinal tract without causing serious injuries, the ingestion of multiple high-powered magnetic pieces, especially neodymium magnets (NMs) increases the risks of morbidity and mortality. Supravesical hernia (SH) is rarely occurs in children, and few studies have reported SH in pediatric patients. We report an extremely rare case of ingested NMs that migrated into an internal SH in a pediatric patient. CASE PRESENTATION: A 3-year-old boy who had accidentally swallowed two NMs 3 days ago presented with vomiting and lower abdominal pain. X-ray imaging and computed tomography (CT) suspected the presence of a 1.0-cm radiopaque FB located in the terminal ileum dorsal side of the bladder. Although his abdominal pain was gradually getting better after oral feeding, repeat abdominal X-ray imaging showed that the FB was in a stagnant in position. Therefore, surgical intervention was planned to remove the FB 1 week after his admission. Under general anesthesia, laparoscopic and fluoroscopic examinations were performed and the cecum was found adhered to the retroperitoneum between the right medial umbilical fold and the right wall of the urinary bladder. The FB was presumed to be located at the tip of the incarcerated cecum in the retroperitoneal space. Peritoneum incision was started near the medial inguinal fossa, and the Retzius space was opened in a manner similar to the transabdominal pre-peritoneal approach for inguinal hernia repair. Consequently, the patient was diagnosed with internal SH with FB migration. The incarcerated cecum was pulled out, which revealed intestinal wall perforation. The FB remained in the retroperitoneal space in the pelvic cavity. The FB was easily removed using intestinal forceps and identified as combined two NMs. The postoperative course was good, and the patient was discharged on postoperative day 5. CONCLUSIONS: We experienced an extremely rare case of a pediatric patient who swallowed multiple NMs that migrated into an internal SH, and the laparoscopic minimally invasive removal was successful.

Laparoscopic splenectomy for a wandering spleen complicating gastric varices: report of a case.

Wandering spleen is a rare clinical entity, and its chronic torsion of the vascular pedicle result in splenic vein occlusion leading to gastric varices. Here, we present a case of wandering spleen complicating gastric varices in a 40-year-old female. Three-dimensional CT (3D-CT) clearly showed the disruption of the splenic vein at the origin of the vascular pedicle and collateral development of the gastric varices. The patient was electively treated with laparoscopic splenectomy. Difficulty of prediction of the splenic vein recanalization to improve the varices was the reason for the use of splenectomy versus splenopexy. The varices were successfully diminished 3 months after the surgery. After review of cases of complicating gastric varices in the literatures, splenectomy is still a secure way to treat an adult patient with wandering spleen with complicating gastric varices.

Asynchronous abdomino-parasacral resection of a giant pelvic lipoma protruding to the left buttock.

INTRODUCTION: Few reports detail adequate surgical management of giant pelvic tumors that traverse the sciatic foramen. PRESENTATION OF CASE: We present a case of a giant retroperitoneal pelvic lipoma that presented with a dumbbell shape on imaging, occupying the entire lesser pelvis and protruding to the gluteus through the sciatic foramen. Surgery was performed for en bloc resection of the tumor. DISCUSSION: A parasacral approach with the patient in the prone position was necessary to dissect the tumor in the buttock, manipulate around the sciatic foramen and preserve collateral blood flow for the gluteal muscle. An abdominal approach was also essential to ligate the internal iliac vessels involved in the tumor. Accordingly changings the position of the patient during the operation were required. Division of the sacrotuberous and sacrospinous ligaments and packing of the soft tumor into a plastic bag were useful to pass the buttock portion through the foramen without the tumor breaking off. CONCLUSION: The asynchronous abdomino-parasacral approach with several turnings of the patient's body and plastic bag packing of the tumor were advantageous to manage en bloc resection of the giant pelvic lipoma presented in this case study.

DNA methylation alterations of AXIN2 in serrated adenomas and colon carcinomas with microsatellite instability.

BACKGROUND: Recent work led to recognize sessile serrated adenomas (SSA) as precursor to many of the sporadic colorectal cancers with microsatellite instability (MSI). However, comprehensive analyses of DNA methylation in SSA and MSI cancer have not been conducted. METHODS: With an array-based methylation sensitive amplified fragment length polymorphism (MS-AFLP) method we analyzed 8 tubular (TA) and 19 serrated (SSA) adenomas, and 14 carcinomas with (MSI) and 12 without (MSS) microsatellite instability. MS-AFLP array can survey relative differences in methylation between normal and tumor tissues of 9,654 DNA fragments containing all NotI sequences in the human genome. RESULTS: Unsupervised clustering analysis of the genome-wide hypermethylation alterations revealed no major differences between or within these groups of benign and malignant tumors regardless of their location in intergenic, intragenic, promoter, or 3' end regions. Hypomethylation was less frequent in SSAs compared with MSI or MSS carcinomas. Analysis of variance of DNA methylation between these four subgroups identified 56 probes differentially altered. The hierarchical tree of this subset of probes revealed two distinct clusters: Group 1, mostly composed by TAs and MSS cancers with KRAS mutations; and Group 2 with BRAF mutations, which consisted of cancers with MSI and MLH1 methylation (Group 2A), and SSAs without MLH1 methylation (Group 2B). AXIN2, which cooperates with APC and ß-catenin in Wnt signaling, had more methylation alterations in Group 2, and its expression levels negatively correlated with methylation determined by bisulfite sequencing. Within group 2B, low and high AXIN2 expression levels correlated significantly with differences in size (P = 0.01) location (P = 0.05) and crypt architecture (P = 0.01). CONCLUSIONS: Somatic methylation alterations of AXIN2, associated with changes in its expression, stratify SSAs according to some clinico-pathological differences. We conclude that hypermethylation of MLH1, when occurs in an adenoma cell with BRAF oncogenic mutational activation, drives the pathway for MSI cancer by providing the cells with a mutator phenotype. AXIN2 inactivation may contribute to this tumorigenic pathway either by mutator phenotype driven frameshift mutations or by epigenetic deregulation contemporary with the unfolding of the mutator phenotype.

Increased polyamine intake inhibits age-associated alteration in global DNA methylation and 1,2-dimethylhydrazine-induced tumorigenesis.

Polyamines (spermine and spermidine) play many important roles in cellular function and are supplied from the intestinal lumen. We have shown that continuous high polyamine intake inhibits age-associated pathologies in mice. The mechanism by which polyamines elicit these effects was examined. Twenty-four week old Jc1:ICR male mice were fed one of three experimental chows containing different polyamine concentrations. Lifetime intake of high polyamine chow, which had a polyamine content approximately three times higher than regular chow, elevated polyamine concentrations in whole blood, suppressed age-associated increases in pro-inflammatory status, decreased age-associated pathological changes, inhibited age-associated global alteration in DNA methylation status and reduced the mortality in aged mice. Exogenous spermine augmented DNA methyltransferase activity in Jurkat and HT-29 cells and inhibited polyamine deficiency-induced global alteration in DNA methylation status in vitro. In addition, increased polyamine intake was associated with a decreased incidence of colon tumors in BALB/c mice after 1,2-demethylhydrazine administration; 12 mice (60%) in the low polyamine group developed tumors, compared with only 5 mice (25%) in the high polyamine group (Fisher's exact probability = 0.027, p = 0.025). However, increased polyamine intake accelerated the growth of established tumors; maximal tumor diameter in the Low and High groups was 3.85±0.90 mm and 5.50±1.93 mm, respectively (Mann-Whitney test, p = 0.039). Spermine seems to play important roles in inhibiting age-associated and polyamine-deficient induced abnormal gene methylation as well as pathological changes including tumorigenesis.

The accumulation of DNA demethylation in Sat α in normal gastric tissues with Helicobacter pylori infection renders susceptibility to gastric cancer in some individuals.

Helicobacter pylori (HP) infection is widely recognized as a risk factor for gastric cancer, but only a minority of infected individuals develop gastric cancer. The aim of this study was to determine whether DNA demethylation in non-cancerous gastric mucosa (NGM) significantly enhances susceptibility to gastric cancer. A total of 165 healthy volunteers, including 83 HP-positive and 82-negative individuals, as well as 83 patients with single and 18 with synchronous double gastric cancer (GC) were enrolled in this study. The relative demethylation levels (RDLs) of repetitive sequences, including Alu, LINE-1 and Sat α, were quantified by real-time methylation-specific polymerase chain reaction. The Alu RDL did not exhibit any differences within each respective group, whereas LINE-1 RDL was significantly elevated in cancer tissues compared with the NGM in the other groups (P<0.001). Our results indicated that a gradual increase in Sat α RDL correlated with HP infection and cancer development. Sat α RDL was significantly elevated in the NGM in HP-positive compared with HP-negative (P<0.001), and significantly elevated in cancer tissues (P<0.001). Although the Sat α RDL of the NGM in the total population increased in an age-dependent manner, it was significantly increased in a fraction of younger GC patients (<45 years) compared with all of the others (45 years or older, P=0.0391). In addition, double GC exhibited a significantly higher Sat α RDL in the NGM compared with single GC (P=0.0014). In these two fractions, Sat α RDL in the NGM exhibited an inverse correlation with age. In conclusion, the present study demonstrated that the accumulation of DNA demethylation in Sat α RDL in the NGM with HP infection potentially renders susceptibility to gastric cancer in a fraction of GC patients younger than 45 years or in patients with multiple cancers.

Aberrant methylation of the Pleckstrin and Sec7 domain-containing gene is implicated in ulcerative colitis-associated carcinogenesis through its inhibitory effect on apoptosis.

The Pleckstrin and Sec7 domain-containing (PSD) gene, which regulates skeletal rearrangements, has been found to be more frequently methylated both in ulcerative colitis (UC)-associated colorectal cancer tissues (5 of 7; 71.4%) and matched normal epithelia (4 of 7; 57.1%) compared to non-neoplastic UC epithelia (6 of 22; 27.3%) and sporadic colorectal cancer tissues (6 of 32; 18.8%). The levels of PSD mRNA were positively correlated with the methylation status of PSD, as shown by both MSP and bisulfite sequencing. To determine the potential role of PSD silencing in the mechanisms underlying UC-associated carcinogenesis, the levels of senescence, proliferation and apoptosis were evaluated in a normal human fibroblast cell line (NHDF) in which 93% of PSD expression was knocked down by a small-interfering RNA (si-RNA). Although there were no significant differences in the levels of senescence and proliferation caused by PSD knockdown, the level of apoptosis was significantly decreased by PSD knockdown (5.3% in siControl-treated cells vs. 0.67% in siPSD-treated cells, p=0.0001). In addition, reactive oxygen species inducers accelerated apoptosis in NHDF and a neutrophil-like cell line, which was significantly reduced by PSD knockdown. To verify the effect of PSD methylation in tissue sections including 21 samples from UC patients with or without tumors, we elucidated PSD promoting accumulation of filamentous-actin (F-actin) and apoptosis by immunohistochemistry and TUNEL assay, respectively. Both levels of accumulation of F-actin and apoptosis were significantly decreased in specimens from UC patients with PSD methylation compared to those without PSD methylation (F-actin: 0.69±0.86 with vs. 1.57±0.51 without, p=0.0031, apoptotic index: 0.31±0.63 with vs. 1.0±0.88 without, p=0.0277). In conclusion, our results indicate that PSD methylation plays a significant role in the mechanisms underlying UC-associated carcinogenesis through its inhibitory effect on apoptosis in the interaction between colorectal mucosa and neutrophils.

Aberrant methylation of PSD disturbs Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis in ulcerative colitis-associated carcinogenesis.

We previously reported that the Pleckstrin and Sec7 domain-containing (PSD) gene is preferentially methylated in patients with ulcerative colitis (UC) who developed colorectal cancer (CRC), and is implicated in UC-associated carcinogenesis through its inhibition of apoptosis. This study aimed to determine the potential effect of PSD methylation on its downstream molecule, Ras-related C3 botulinum toxin substrate 1 (Rac1), which governs neutrophil chemotaxis and apoptosis signaling. PSD was knocked down in a normal human fibroblast cell line (HNDF) and a neutrophil-like cell line (HL-60). Both NHDF and HL-60 cells exhibited numerous filamentous-actin (F-actin) rich membrane extensions, resulting in the activation of Rac1; this activation was hampered by PSD silencing. Lipopolysaccharide, a reactive oxygen species (ROS) inducer, stimulated NHDF cells to release ROS and activated caspase­3/7 in the presence of neutrophils, which was inhibited by PSD knockdown. Migration assays demonstrated that chemotaxis of HL-60 cells was affected by PSD silencing in NHDF cells. Tissue sections from 6 UC patients with CRC and 15 UC patients without CRC were examined. To verify Rac1-mediated chemotaxis in tissue sections, we evaluated the grade of neutrophil infiltration by histological assessment and assessed F-actin and PSD expression by immunohistochemistry. Neutrophil infiltration, F-actin and PSD expression were significantly decreased in specimens from UC patients with PSD methylation compared with those without. Decreased levels of F-actin expression were observed in colorectal mucosa, as well as in infiltrating cells with PSD methylation. PSD expression was preferentially inhibited in colorectal mucosa by PSD methylation, whereas PSD expression was rarely observed in infiltrating cells, regardless of PSD methylation status. These data indicate that aberrant methylation of PSD occurs in UC-associated colorectal mucosa, enabling circumvention of Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis, and thus plays a pivotal role in the mechanisms underlying UC-associated carcinogenesis.

Identification of a potent epigenetic biomarker for resistance to camptothecin and poor outcome to irinotecan-based chemotherapy in colon cancer.

Drug resistance remains a major obstacle to successful cancer treatment. Genome-wide comprehensive analysis identified a novel gene, glucocorticoid-induced protein-coding gene (DEXI), which was frequently methylated in colorectal (CRC; 36 of 73 patients; 49%) and gastric (28 of 89 patients; 31%) cancer patients. Here, we show that DEXI methylation is implicated in mechanisms facilitating resistance to camptothecin (CPT) via inhibition of apoptosis. Silencing of DEXI by siRNA significantly reduced CPT-induced apoptosis in a fibroblast cell line (1/6-fold; p<0.01) originally expressing endogenous DEXI. Restored expression of DEXI by 5-aza-2'-deoxycytidine (DAC) significantly enhanced susceptibility to CPT (3-fold; p<0.01) in a colon cancer cell line originally suppressing endogenous DEXI due to almost complete methylation. Exogenous induction of DEXI confirmed that DEXI per se contributed to enhanced susceptibility to CPT. 5-Fluorouracil (5-FU) did not exhibit these synergistic effects by DEXI restoration. Further, to estimate the clinical usefulness of DEXI methylation status as biomarker for drug resistance to irinotecan (CPT-11), 16 CRC patients who underwent FOLFIRI (5-FU + CPT-11) therapy because they were refractory to FOLFOX (5-FU + oxaliplatin) were analyzed. Significantly poor response and outcome were observed in 8 CRC patients harboring DEXI methylation. In 8 CRC patients harboring DEXI methylation disease control rate, progression-free survival and overall survival were 25.0%, 2 and 11.8 months, respectively, whereas in 8 CRC patients without DEXI methylation they were 62.5%, 5.3 and 15 months, respectively (p<0.01). These significant differences were not observed in patients undergoing treatment with FOLFOX. In conclusion, silencing of DEXI leads to resistance, but restored expression enhances susceptibility to CPT in vitro and DEXI methylation results in poor response and outcome to CPT-11-based chemotherapy, suggesting that DEXI is a potent therapeutic target and an epigenetic biomarker for the selection of patients more likely to benefit from CPT-11-based chemotherapy.

Array-based identification of common DNA methylation alterations in ulcerative colitis.

Patients with long-standing ulcerative colitis (UC) have higher risk of developing colorectal cancer. Albeit the causes remain to be understood, epigenetic alterations have been suggested to play a role in the long-term cancer risk of these patients. In this work, we developed a novel microarray platform based on methylation-sensitive amplified fragment length polymorphism (MS-AFLP) DNA fingerprinting. The over 10,000 NotI sites of the human genome were used to generate synthetic primers covering these loci that are equally distributed into CpG rich regions (promoters and CpG islands) and outside the CpG islands, providing a panoramic view of the methylation alterations in the genome. The arrays were first tested using the colon cancer cell line CW-2 showing the reproducibility and sensitivity of the approach. We next investigated DNA methylation alterations in the colonic mucosa of 14 UC patients. We identified epigenetic alterations affecting genes putatively involved in UC disease, and in susceptibility to develop colorectal cancer. There was a strong concordance of methylation alterations (both hypermethylation and hypomethylation) shared by the cancer cells of the CW-2 cell line and the non-cancer UC samples. To the best of our knowledge, this work defines the first high-throughput aberrant DNA methylation profiles of the colonic mucosa of UC patients. These epigenetic profiles provide novel and relevant knowledge on the molecular alterations associated to the UC pathology. Some of the detected alterations could be exploited as cancer risk predictors underlying a field defect for cancerization in UC-associated carcinogenesis.