Meeting actual benchmarks for short- and long-term outcomes after cytoreductive surgery for peritoneal surface malignancy at a newly established academic treatment center.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is a curative treatment for selected patients with peritoneal surface malignancy. Reaching actual outcomes benchmarks is challenging given the complex nature of peritoneal surface malignancy surgery. The aim of this study was to assess how the benchmarks for morbidity and oncologic outcome can be reached at a newly established program for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. METHODS: Building on existing institutional experience in complex abdominal surgery and interdisciplinary ovarian cancer treatment, a peritoneal surface malignancy center for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy was established at the Medical University of Vienna using a structured mentoring process. This is a retrospective analysis of the first 100 consecutive patients. Morbidity and mortality were assessed using the Clavien-Dindo classification, and oncologic outcomes using overall survival. RESULTS: Major morbidity and mortality were 26% and 3%, and median overall survival was 49.0 months. In patients with colorectal peritoneal metastases, the median overall survival was 35.1 months (all colorectal peritoneal metastases patients) and 48.8 months in the subgroup with Peritoneal Surface Disease Severity Score ≤3. No median overall survival could be calculated in patients with low-grade appendiceal mucinous neoplasms, appendiceal adenocarcinoma, or peritoneal mesothelioma due to >50% of patients being alive at the end of follow-up. CONCLUSION: We show that the current morbidity and oncological outcomes benchmarks can be reached within the first 100 cases of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy at a newly established peritoneal surface malignancy center. Previous institutional experience in complex abdominal surgery and a structured mentoring process are key factors in achieving this goal.

Novel mutations of the calcium-sensing receptor impede differential diagnosis of primary hyperparathyroidism and familial hypocalciuric hypercalcemia.

BACKGROUND: Familial hypocalciuric hypercalcemia 1 (FHH1) is an autosomal dominant disorder caused by inactivating mutations in the calcium-sensing receptor (CaSR) gene, commonly leading-in contrast to primary hyperparathyroidism (PHPT)-to asymptomatic hypercalcemia. It is important to establish the correct diagnosis, as surgery may be curative in PHPT, but most likely ineffective in FHH. The study aims to evaluate patients with FHH1, initially misinterpreted as PHPT and some even undergone surgery. METHODS: CaSR-genotyping was conducted, various biochemical parameters including twenty-four-hour urinary Ca excretion (24hU CE) and the calculated relation of urinary Ca clearance to creatinine clearance (CCCR), type of surgery and 1-year follow-up data of fourteen patients with proven FHH1 were evaluated retrospectively. RESULTS: Genetic analysis revealed a total of nine novel heterozygous variants in the CaSR gene in our study population. Six of fourteen patients (42.9%) underwent surgery for initially suspected PHPT, showing normalized biochemical parameters immediately after surgery. In 1-year follow-up, however, five of six operated patients (83.3%) showed normal parathyroid hormone (PTH), but elevated serum calcium levels. In contrast, only one of the operated patients (16.7%) presented both PTH and serum calcium in the normal range. Histology showed adenoma in three (50%), hyperplasia in two (33.3%), and normal parathyroid tissue in one (16.7%) of the patients. CONCLUSIONS: We discovered novel heterozygous variants in the CaSR gene, which considerably impede differential diagnosis of PHPT and FHH1. Furthermore, our results indicate that parathyroid surgery fails to provide long-term benefits for patients with FHH1 and suspected PHPT, even though this coincidence seems to exist.

Papillary thyroid cancer: the value of bilateral diagnostic lymphadenectomy.

PURPOSE: Papillary thyroid carcinoma (PTC) spreads early to lymph nodes (LN). However, prophylactic central (CND) and lateral neck dissection (LND) is controversially discussed in patients with clinically negative nodes (cN0). The preoperative prediction of LN metastasis is desirable as re-operation is associated with higher morbidity and poor prognosis. The study aims to analyse possible benefits of a systemic bilateral diagnostic lateral lymphadenectomy (DLL) for intraoperative LN staging. METHODS: Preoperative prediction of LN metastasis by conventional ultrasound (US) was correlated with the results of DLL and intra-/postoperative complications in 118 consecutive patients with PTC (cN0) undergoing initial thyroidectomy and bilateral CND and DLL. RESULTS: Lateral LNs (pN1b) were positive in 43/118 (36.4%) patients, including skip lesions (n = 6; 14.0%). Preoperative US and intraoperative DLL suspected lateral LN metastasis in 19/236 (TP: 8.1%) and 54/236 (TP: 22.9%) sides at risk, which were confirmed by histology. Sixty-seven out of 236 (FN: 28.4%) and 32/236 (FN: 13.6%) sides at risk with negative preoperative US and intraoperative DLL lateral LN metastasis were documented. DLL was significantly superior compared to US regarding sensitivity (62.8% vs 22.1%; p < 0.002), positive predictive value (100% vs 76.0%), negative predictive value (82.4% vs 68.2%), and accuracy (86.4% vs 69.1%), but not specificity (100% vs 96.0%; p = 0.039). DLL-related complications (haematoma) occurred in 6/236 [2.5%] sides at risk, including chylous fistula in 2/118 [1.7%] patients. CONCLUSION: DLL can be recommended for LN staging during initial surgery in patients with PTC to detect occult lateral LN metastasis not suspected by US in order to plan lateral LN dissection.

Cerebral microbleeds following thoracic endovascular aortic repair.

BACKGROUND: Stroke and neurological injury are a complication of thoracic endovascular aortic repair (TEVAR). Cerebral microbleeds (CMBs) are common in patients with white matter damage to the brain secondary to chronic vasculopathy. The aim of this study was to examine the occurrence of CMBs after TEVAR, and to evaluate their association with patient and procedural factors. METHODS: Patients who underwent TEVAR between September 2018 and January 2020 in two specialist European aortic centres were analysed. All patients underwent postoperative susceptibility-weighted MRI. The location and number of CMBs were identified, and analysed with regard to procedural aspects, clinical outcome, and Fazekas score as an indicator of pre-existing vascular leucoencephalopathy. RESULTS: Some 91 patients were included in the study. A total of 1531 CMBs were detected in 58 of 91 patients (64 per cent). In the majority of affected patients, CMBs were found bilaterally (79 per cent). Unilateral CMBs in the right or left hemisphere occurred in 16 and 5 per cent of patients respectively (P < 0.001). More CMBs were found in the middle cerebral than in the vertebrobasilar/posterior and anterior cerebral artery territories (mean(s.d.) 3.35(5.56) versus 2.26(4.05) versus 0.97(2.87); P = 0.045). Multivariable analysis showed an increased probability of CMBs after placement of TEVAR stent-grafts with a proximal diameter of at least 40 mm (odds ratio (OR) 6.85, 95 per cent c.i. 1.65 to 41.59; P = 0.007) and in patients with a higher Fazekas score on postoperative T2-weighted MRI (OR 2.62, 1.06 to 7.92; P = 0.037). CONCLUSION: CMBs on postoperative MRI are common after endovascular repair in the aortic arch. Their occurrence appears to be associated with key aspects of the procedure and pre-existing vascular leucoencephalopathy.

Multiplexed DNA Methylation Analysis in Colorectal Cancer Using Liquid Biopsy and Its Diagnostic and Predictive Value.

Early diagnosis of colorectal cancer (CRC) is of high importance as prognosis depends on tumour stage at the time of diagnosis. Detection of tumour-specific DNA methylation marks in cfDNA has several advantages over other approaches and has great potential for solving diagnostic needs. We report here the identification of DNA methylation biomarkers for CRC and give insights in our methylation-sensitive restriction enzyme coupled qPCR (MSRE-qPCR) system. Targeted microarrays were used to investigate the DNA methylation status of 360 cancer-associated genes. Validation was done by qPCR-based approaches. A focus was on investigating marker performance in cfDNA from 88 patients (44 CRC, 44 controls). Finally, the workflow was scaled-up to perform 180plex analysis on 110 cfDNA samples, to identify a DNA methylation signature for advanced colonic adenomas (AA). A DNA methylation signature (n = 44) was deduced from microarray experiments and confirmed by quantitative methylation-specific PCR (qMSP) and by MSRE-qPCR, providing for six genes' single areas under the curve (AUC) values of >0.85 (WT1, PENK, SPARC, GDNF, TMEFF2, DCC). A subset of the signatures can be used for patient stratification and therapy monitoring for progressed CRC with liver metastasis using cfDNA. Furthermore, we identified a 35-plex classifier for the identification of AAs with an AUC of 0.80.

The role of intraoperative parathyroid hormone (IOPTH) determination for identification and surgical strategy of sporadic multiglandular disease in primary hyperparathyroidism (pHPT).

Intraoperative PTH monitoring (IOPTH) made minimally invasive parathyroidectomy in patients with primary HPT possible. However, with the increasing accuracy of preoperative localization studies there is a growing discussion if IOPTH is necessary in patients with localized single gland disease (concordant preoperative localization studies). Different interpretation criteria have been developed - each with their particular advantages and disadvantages, but the "perfect" criterion is still missing. Despite several pitfalls, which can be recognized intraoperatively and do not necessarily lead to a more extensive surgery, IOPTH seems to be a useful adjunct in surgery for PHPT. However, according to current guidelines, selected patients may be operated without IOPTH but need to be informed about the possibly increased risk of recurrent disease.

Efficacy of calcium excretion and calcium/creatinine clearance ratio in the differential diagnosis of familial hypocalciuric hypercalcemia and primary hyperparathyroidism.

BACKGROUND: Twenty-four-hour renal calcium-excretion (CE) and calcium/creatinine-clearance-ratio (CCCR), respectively, are widely used to rule out familial hypocalciuric hypercalcemia (FHH) in patients with suspected primary hyperparathyroidism before surgery. The aim was to evaluate the practicability of CE compared to CCCR. PATIENTS AND METHODS: We analyzed biochemical parameters, surgical treatment, gene mutation results, and long-term follow-up data of 198 patients (including 14 patients with FHH) and the discriminative power of CE and CCCR. RESULTS: Twenty four patients (12.1%) had a low CE and 35 patients (20.2%) had a CCCR indicating FHH. However, eight patients with FHH (57.1%) had a normal or increased CE. Correspondingly, only eight cases of FHH (57.1%) were correctly predicted by CCCR. Sensitivity/specificity were 42.9%/89.9% for CE and 64.3%/79.9% for CCCR, showing no statistical differences (P = 0.482) between both methods. CONCLUSION: Neither CE nor CCCR was able to distinguish between PHPT and FHH but may help to narrow down potential FHH patients.

Circulating Free Methylated Tumor DNA Markers for Sensitive Assessment of Tumor Burden and Early Response Monitoring in Patients Receiving Systemic Chemotherapy for Colorectal Cancer Liver Metastasis.

BACKGROUND: Neoadjuvant chemotherapy (neoCTx) followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CLM). Treatment response is generally assessed using radiologic imaging after several cycles of chemotherapy. However, earlier assessment of response would be desirable since nonresponders could be switched early to an alternative chemotherapy regimen. Recent evidence suggests that circulating free methylated tumor DNA is a highly sensitive biomarker and may more accurately reflect tumor burden and treatment response than conventional markers for CRC. PATIENTS AND METHODS: Thirty-four patients with CLM who received neoCTx prior to intended hepatic resection were included in this prospective nonrandomized study. Peripheral blood plasma was collected at baseline and before each cycle of neoCTx and was then analyzed for aberrant methylation of 48 CRC-associated genes. Methylation marker levels were correlated with baseline tumor volume and treatment response and compared with the standard tumor markers CEA and CA 19-9. RESULTS: The methylation markers SEPT9, DCC, BOLL, and SFRP2 were present in all patients at baseline and displayed a stronger correlation with tumor volume than CEA and CA 19-9. Serial measurement of these methylation markers allowed for discrimination between operated and nonoperated patients already after 1 cycle of neoCTx with high sensitivity and specificity. The early dynamic changes of SEPT9 and DCC also seemed to correlate with pathohistological response. CONCLUSION: Our data suggest that serial measurements of CRC-associated methylation markers could be a particularly valuable tool for early response assessment in patients receiving neoCTx for CLM.

Circulating cell-free DNA in plasma of colorectal cancer patients - A potential biomarker for tumor burden.

BACKGROUND: Measurement of cell-free DNA (cfDNA) in plasma - the so called liquid biopsy - is a novel method for early detection of cancer. Necrotic cancer cells release various DNA fragments that can be detected in plasma or serum. The aim of our study was to investigate the concentration of circulating ALU115, LINE79 and LINE297 fragments in plasma from venous and arterial blood of colorectal cancer (CRC) patients before, during and 5 days after surgical intervention. PATIENTS AND METHODS: Thirty patients (16 female, 14 male, median age 56 years), undergoing surgery for colorectal and appendix cancer, and 17 healthy volunteers were included in this study. Plasma samples were collected from patients and healthy individuals. Qualitative polymerase chain reaction (PCR) and quantitative real-time PCR analyses were conducted using specific primers for ALU115, LINE79 and LINE297. RESULTS: The concentration of ALU115 was significantly increased in plasma of CRC patients compared to the control group (p = 0.002). Interestingly, the concentration of LINE297 was significantly higher in healthy individuals than patients (p = 0.031). We did not find any difference regarding LINE79 between the two groups (p = 0.893). The total cfDNA concentration was slightly increased in plasma after the surgery (p < 0.056), however, the difference was not significant. Interestingly, no correlation was detected between the peritoneal carcinosis index (PCI) and conventional tumor markers. CONCLUSION: According to our results, the concentration of ALU115 in cfDNA could be a potential biomarker for diagnosis of CRC. LINE79 or the conventional tumor markers CEA or CA19-9 do not seem useful for the detection of malignant tumors. Whether the amount of LINE297 in cfDNA represents a reliable biomarker for early diagnosis has yet to be confirmed.

Trocar-site evisceration of the vermiform appendix following laparoscopic sigmoid colectomy: A case report.

INTRODUCTION: There is an ongoing debate whether prophylactic drainage or incidental appendectomy should be performed in patients undergoing colorectal surgery. On the other hand, it has been shown that the placement of drains through former trocar sites as well as the use of large (≥10mm) trocars, incomplete fascial closure or closed laparoscopy technique all predispose for the occurrence of trocar site hernias. PRESENTATION OF CASE: We report the case of a 59-year-old male patient who underwent laparoscopic sigmoid colectomy with primary anastomosis for recurrent sigmoid diverticulitis. Preoperative diagnostics revealed no abnormalities other than multiple diverticula in the sigmoid colon. The subsequent surgery was conducted without any complications. Due to inconspicuous intraoperative appearance of the vermiform appendix, no incidental appendectomy was performed. On the 4th postoperative day, the Easy Flow drain - which had been placed prophylactically through the 12mm trocar site in the right lower abdomen - was removed. Four hours after drain removal, trocar-site evisceration of the vermiform appendix occurred, requiring emergency surgery. DISCUSSION AND CONCLUSION: The present case is yet another argument for restricting the use of prophylactic drains in colorectal surgery as well as closing port sites of ≥10mm diameter. Furthermore, incidental appendectomy may be considered since it is able to prevent this type of complication and can be performed with minimal cost and morbidity.