Identifying Recurrence Risk Factors in CT-Confirmed Acute Appendicitis in Adults Managed Non-operatively During the COVID-19 Pandemic.

BACKGROUND/OBJECTIVE:  Acute appendicitis (AA) is predominantly managed with appendectomy, but can be treated non-operatively, leading to a high risk of recurrence. Non-operative management has been more common since the COVID-19 pandemic affected the feasibility of performing surgery. This case-control study analyzed non-operatively managed patients in order to identify clinical and radiological factors associated with recurrence risk.  Methods: Over 12 months, 48 adults with CT-proven AA managed non-operatively were identified, and followed up for at least six further months to assess them for recurrence (readmission to hospital more than 14 days after discharge and after symptom resolution, requiring treatment for appendicitis). Clinical and CT data were collected and a Cox regression survival analysis was performed to produce hazards ratios (HRs). RESULTS:  Of the 48 patients, 12 (25%) experienced a recurrence up until the end of the follow-up period, eight of whom were then treated operatively, and four treated non-operatively. On the univariate analysis, greater recurrence risk was observed in patients with diabetes mellitus, higher heart rate (on admission and maximum value during admission), lower white cell count and neutrophils and appendiceal wall thinning on CT. On the multivariate analysis, diabetes mellitus (HR=7.72, p=0.021) and higher heart rate (HR=1.08, p=0.018) were associated with statistically significant greater recurrence risk. CONCLUSIONS:  Diabetes mellitus and higher heart rate on admission are associated with greater recurrence risk of AA managed non-operatively. No CT findings were associated with statistically significant greater risk. Clinicians should, therefore, consider DM and heart rate when making decisions on appendicitis management, especially during the COVID-19 pandemic but also beyond it.

A rare case of heterotopic pancreatitis and intestinal malrotation in a COVID-19 positive patient. COVID-19, causative or coincidence?

INTRODUCTION AND IMPORTANCE: Heterotopic pancreas (HP) is defined as the presence of pancreatic tissue without anatomical and vascular continuity with the main body of the pancreas. HP typically remains asymptomatic, however complications such as acute pancreatitis can arise. Gastrointestinal involvement with coronavirus disease 2019 (COVID-19) is not uncommon and there are reported cases of associated pancreatitis. CASE PRESENTATION: A 31-year-old male presented to the Emergency department (ED) with a 3-day history of right iliac fossa pain. The patient was found to have COVID-19 and a planned laparoscopic appendectomy was later converted to a midline laparotomy when a mass close to the duodeno-jejunal (DJ) flexure was identified. Following a hand-sewn anastomosis the patient made a good post-operative recovery. Histology illustrated the presence of heterotopic pancreatic tissue within the small bowel with underlying fat necrosis typical of acute pancreatitis. Follow-up radiology supported the intraoperative finding of intestinal malrotation. CLINICAL DISCUSSION: Rarely the combined presence of intestinal malrotation and HP in patients has been noted. Heterotopic pancreatitis can present in a multitude of ways and it is a difficult diagnosis to make pre-operatively. Emerging literature documents the potential presentation of COVID-19 with acute pancreatitis. The expression of angiotensin-converting enzyme 2 (ACE2) receptors on the pancreas is believed to play a role. CONCLUSION: This is the first documented case of heterotopic pancreatitis with intestinal malrotation in a COVID-19 positive patient. We hypothesise that the COVID-19 infection contributed to the heterotopic pancreatitis.

Trans-thoracic versus retropleural approach for symptomatic thoracic disc herniations: comparative analysis of 94 consecutive cases.

PURPOSE: The authors illustrate their results in the surgical treatment of symptomatic thoracic disc herniations (TDHs) by comparing the traditional open to the less invasive retropleural lateral approaches. METHODS: Retrospective review of 94 consecutive cases treated at a single Institution between 1988 and 2014. Fifty-two patients were males, 42 females, mean age was 53.9 years. Mean follow-up was 46.9 months (12-79 months). 33 patients were diagnosed with a giant thoracic disc herniation (GTDH). Upon admission, the most common symptoms were: motor impairment (91.4%, n = 86), neuropathic radicular pain with VAS > 4 (50%), bladder and bowel dysfunction (57.4% and 41.4% respectively) and sensory disturbances (29.7%). The surgical approach was based upon level, laterality and presence or absence of calcified lesions. RESULTS: Decompression was performed in 7 cases via a thoraco-laparo-phrenotomy and in 87 cases via an antero-lateral thoracotomy. Out of the latter cases, 49 (56%) were trans-thoracic trans-pleural approaches (TTA) and 38 (44%) were less invasive retropleural approaches (MIRA). At follow-up, there were 59.5% neurologically intact patients according to the McCormick Scale, while 64.8% and 67% had no bladder or bowel dysfunction respectively. Complications occurred in 24 patients (25.5%). Pulmonary complications were the commonest (12.7%) with pleural effusion being significantly more common in patients treated with TTA compared to MIRA (20% vs 5.2%: X2 4.13 P:0.042). Severe post-operative neuralgia (VAS 7-10) was also significantly more frequent in the TTA group (22.4% vs 2.6% X2 7.07 p 0.0078). CONCLUSIONS: MIRA is a safe and effective technique to obtain adequate TDH decompression and is associated with lower morbidity compared to TTA.

Methionine adenosyltransferase α2 sumoylation positively regulate Bcl-2 expression in human colon and liver cancer cells.

Ubiquitin-conjugating enzyme 9 (Ubc9) is required for sumoylation and inhibits apoptosis via Bcl-2 by unknown mechanism. Methionine adenosyltransferase 2A (MAT2A) encodes for MATα2, the catalytic subunit of the MATII isoenzyme that synthesizes S-adenosylmethionine (SAMe). Ubc9, Bcl-2 and MAT2A expression are up-regulated in several malignancies. Exogenous SAMe decreases Ubc9 and MAT2A expression and is pro-apoptotic in liver and colon cancer cells. Here we investigated whether there is interplay between Ubc9, MAT2A and Bcl-2. We used human colon and liver cancer cell lines RKO and HepG2, respectively, and confirmed key finding in colon cancer specimens. We found MATα2 can regulate Bcl-2 expression at multiple levels. MATα2 binds to Bcl-2 promoter to activate its transcription. This effect is independent of SAMe as MATα2 catalytic mutant was also effective. MATα2 also directly interacts with Bcl-2 to enhance its protein stability. MATα2's effect on Bcl-2 requires Ubc9 as MATα2's stability is influenced by sumoylation at K340, K372 and K394. Overexpressing wild type (but not less stable MATα2 sumoylation mutants) protected from 5-fluorouracil-induced apoptosis in both colon and liver cancer cells. Colon cancer have higher levels of sumoylated MATα2, total MATα2, Ubc9 and Bcl-2 and higher MATα2 binding to the Bcl-2 P2 promoter. Taken together, Ubc9's protective effect on apoptosis may be mediated at least in part by sumoylating and stabilizing MATα2 protein, which in turn positively maintains Bcl-2 expression. These interactions feed forward to further enhance growth and survival of the cancer cell.

Polyamine and methionine adenosyltransferase 2A crosstalk in human colon and liver cancer.

Methionine adenosyltransferase (MAT) is an essential enzyme that is responsible for the biosynthesis of S-adenosylmethionine (SAMe), the principal methyl donor and precursor of polyamines. MAT1A is expressed in normal liver and MAT2A is expressed in all extrahepatic tissues. MAT2A expression is increased in human colon cancer and in colon cancer cells treated with mitogens, whereas silencing MAT2A resulted in apoptosis. The aim of the current work was to examine the mechanism responsible for MAT2A-dependent growth and apoptosis. We found that in RKO (human adenocarcinoma cell line) cells, MAT2A siRNA treatment lowered cellular SAMe and putrescine levels by 70-75%, increased apoptosis and inhibited growth. Putrescine supplementation blunted significantly MAT2A siRNA-induced apoptosis and growth suppression. Putrescine treatment (100pmol/L) raised MAT2A mRNA level to 4.3-fold of control, increased the expression of c-Jun and c-Fos and binding to an AP-1 site in the human MAT2A promoter and the promoter activity. In human colon cancer specimens, the expression levels of MAT2A, ornithine decarboxylase (ODC), c-Jun and c-Fos are all elevated as compared to adjacent non-tumorous tissues. Overexpression of ODC in RKO cells also raised MAT2A mRNA level and MAT2A promoter activity. ODC and MAT2A are also overexpressed in liver cancer and consistently, similar MAT2A-ODC-putrescine interactions and effects on growth and apoptosis were observed in HepG2 cells. In conclusion, there is a crosstalk between polyamines and MAT2A. Increased MAT2A expression provides more SAMe for polyamines biosynthesis; increased polyamine (putrescine in this case) can activate MAT2A at the transcriptional level. This along with increased ODC expression in cancer all feed forward to further enhance the proliferative capacity of the cancer cell.

MAT2B-GIT1 interplay activates MEK1/ERK 1 and 2 to induce growth in human liver and colon cancer.

UNLABELLED: Methionine adenosyltransferase 2B (MAT2B) encodes for two variant proteins (V1 and V2) that promote cell growth. Using in-solution proteomics, GIT1 (G Protein Coupled Receptor Kinase Interacting ArfGAP 1) was identified as a potential interacting partner of MAT2B. Here, we examined the functional significance of this interplay. Coimmunoprecipitation experiments examined protein interactions. Tissue expression levels of proteins were examined using immunohistochemistry and western blotting. Expression levels of proteins were varied using transient knockdown or overexpression to observe the effect of alterations in each protein on the entire complex. Direct interaction among individual proteins was further verified using in vitro translated and recombinant proteins. We found both MAT2B variants interact with GIT1. Overexpression of V1, V2, or GIT1 activated mitogen-activated protein kinase kinase 1 (MEK1) and extracellular signal-regulated kinase (ERK), raised cyclin D1 protein level, and increased growth, whereas the opposite occurred when V1, V2, or GIT1 was knocked down. MAT2B and GIT1 require each other to activate MEK1/ERK and increase growth. MAT2B directly interacts with MEK1, GIT1, and ERK2. Expression level of V1, V2, or GIT1 directly influenced recruitment of GIT1 or MAT2B and ERK2 to MEK1, respectively. In pull-down assays, MAT2B directly promoted binding of GIT1 and ERK2 to MEK1. MAT2B and GIT1 interact and are overexpressed in most human liver and colon cancer specimens. Increased expression of V1, V2, or GIT1 promoted growth in an orthotopic liver cancer model, whereas increased expression of either V1 or V2 with GIT1 further enhanced growth and lung metastasis. CONCLUSION: MAT2B and GIT1 form a scaffold, which recruits and activates MEK and ERK to promote growth and tumorigenesis. This novel MAT2B/GIT1 complex may provide a potential therapeutic gateway in human liver and colon cancer. (HEPATOLOGY 2012).

S-adenosyl methionine regulates ubiquitin-conjugating enzyme 9 protein expression and sumoylation in murine liver and human cancers.

UNLABELLED: Ubiquitin-conjugating enzyme 9 (Ubc9) is required for sumoylation and is overexpressed in several malignancies, but its expression in hepatocellular carcinoma (HCC) is unknown. Hepatic S-adenosyl methionine (SAMe) levels decrease in methionine adenosyltransferase 1A (Mat1a) knockout (KO) mice, which develop HCC, and in ethanol-fed mice. We examined the regulation of Ubc9 by SAMe in murine liver and human HCC, breast, and colon carcinoma cell lines and specimens. Real-time polymerase chain reaction and western blotting measured gene and protein expression, respectively. Immunoprecipitation followed by western blotting examined protein-protein interactions. Ubc9 expression increased in HCC and when hepatic SAMe levels decreased. SAMe treatment in Mat1a KO mice reduced Ubc9 protein, but not messenger RNA (mRNA) levels, and lowered sumoylation. Similarly, treatment of liver cancer cell lines HepG2 and Huh7, colon cancer cell line RKO, and breast cancer cell line MCF-7 with SAMe or its metabolite 5'-methylthioadenosine (MTA) reduced only Ubc9 protein level. Ubc9 posttranslational regulation is unknown. Ubc9 sequence predicted a possible phosphorylation site by cell division cycle 2 (Cdc2), which directly phosphorylated recombinant Ubc9. Mat1a KO mice had higher phosphorylated (phospho)-Ubc9 levels, which normalized after SAMe treatment. SAMe and MTA treatment lowered Cdc2 mRNA and protein levels, as well as phospho-Ubc9 and protein sumoylation in liver, colon, and breast cancer cells. Serine 71 of Ubc9 was required for phosphorylation, interaction with Cdc2, and protein stability. Cdc2, Ubc9, and phospho-Ubc9 levels increased in human liver, breast, and colon cancers. CONCLUSION: Cdc2 expression is increased and Ubc9 is hyperphosphorylated in several cancers, and this represents a novel mechanism to maintain high Ubc9 protein expression that can be inhibited by SAMe and MTA.

Surgical treatment of gastric cancer with coexistent abdominal aortic aneurysm. Personal experience and literature review.

BACKGROUND/AIMS: There are great controversies regarding the surgical management of abdominal aortic aneurysm (AAA) with coexistent gastrointestinal cancers. The aim of this study was to report our experience of AAA with concomitant gastric cancer and to compare our results with the literature. METHODOLOGY: From January 1988 to December 2002, six patients with simultaneous diagnosis of AAA and gastric cancer were operated on at the First Department of General Surgery, University of Verona, Italy. The study was completed with the review of the literature data collected by Medline search. RESULTS: The surgical treatment of the cases observed at our Institution, 2 treated by a staged procedure, 2 by synchronous surgery and 2 in which the AAA remained untreated due to the evidence of metastatic disease at laparotomy, were described. Furthermore 47 cases, previously described in literature, 21 who underwent staged surgery, 23 with a synchronous procedure and 3 in which the treatment was limited to the tumor were analyzed. CONCLUSIONS: 1) Synchronous treatment of AAA and gastric cancer is feasible, 2) it can be done with an adequate extent of gastric resection and nodal dissection in the majority of cases, 3) it has a complications rate comparable to the staged procedure.

Using the angio-seal to achieve hemostasis in prosthetic endovascular surgery: report of three cases.

At least 10% of patients who undergo bilateral aortofemoral bypass are at risk of needing a reoperation for late prosthetic thrombosis because of reduced outflow as the disease progresses. To prevent occlusion of the prostheses, we performed endovascular surgery with transprosthetic access for distal stenosis. We report our experience of using the Angio-Seal with transprosthetic access after angioplasty in three patients who had undergone bilateral aortofemoral bypass. Hemostasis was achieved in all three patients. There were no complications, such as hemorrhage, hematoma, or prosthetic infection, and all three patients were discharged within 24 h. At the 12-, 15-, and 24-month follow-up, none of the patients had any sign of recurrent claudication. Using the Angio-Seal in bilateral aortofemoral bypass provided the means of treating distal stenosis by endovascular surgery with transprosthetic access. This method is both rapid and safe, and may broaden the indications for the endovascular treatment of distal arteriopathies in patients with vascular prostheses.