Update on Histological Reporting Changes in Neuroendocrine Neoplasms.

PURPOSE OF REVIEW Classification and nomenclature of neuroendocrine neoplasms (NEN) have frequently changed over the last years. These changes reflect both increasing knowledge and international standardisation. RECENT FINDINGS The most recent changes in the Gastro-Entero-Pancreatic system induced the concept of well-differentiated NET with high proliferation rate (NET G3), explaining partially the heterogeneity of G3 NEN. Even if the nomenclature in pulmonary NEN is still different, the terms 'carcinoid' and 'atypical carcinoid' are widely overlapping with NET G1 and NET G2. Molecular data shows an additional heterogeneity both in well-differentiated NET and poorly differentiated NEC. However, no studies are available demonstrating clinical usefulness yet. The heterogeneity of NEN regarding the organ of origin, differentiation and molecular subtypes make development of personalised therapy a challenge needing more international and interdisciplinary collaborations and clinical trials allowing stratification according to biological subgroups

How to Counter the Problem of R1 Resection in Duodenopancreatectomy for Pancreatic Cancer?

Objective: Although duodenopancreatectomy has been standardized for many years, the pathological examination of the specimen was re-described in the last years. In methodical pathological studies up to 85% had an R1 margin.1,2 These mainly involved the posterior und medial resection margin.3 As a consequence we need to optimize and standardize the pathological workup of the specimen and to extend the surgical resection, where possible without risk for the patient. Method and Result: In an instructive video we show the technique of duodenopancreatectomy with emphasis on the dorsal and medial resection margin. Furthermore we show the standardized pathological workup of the specimen, involving the reporting of all the resection margins. Conclusion: To accurately determine R1 status at the posterior and medial resection margin, a close collaboration between pathologist and surgeon is crucial. Pathologists do a standardized workup of the resected specimen with staining of the surfaces and systematic analysis of all the resection margins. Surgeons need to extend the resection of the pancreatic head to the superior mesenteric artery by dorsal dissectio

Stereotactic Image-Guidance for Ablation of Malignant Liver Tumors

Stereotactic percutaneous ablation is a rapidly advancing modality for treatment of tumors in soft solid organs such as the liver. Each year, there are about 850,000 cases of primary liver cancer worldwide. Although surgical resection still is the gold standard for most cases, only 20–30% of patients are candidates for it, due to the advanced stage of the disease. Surgery can also be a huge burden to the patient and his/her quality of life might be temporarily severely reduced due to long hospital stays, complications, and slow recovery. To overcome these disadvantages, thermo-ablation of tumors of up to 3 cm has become a more viable alternative especially in the last decade, offering a potentially equally effective but minimally invasive and tissue sparing treatment alternative. In conjunction with improved CT imaging, stereotactic image-guidance techniques and image fusion technology were introduced to increase safety, efficacy, and accuracy of this treatment. Stereotactic image-guidance leads to a simple, fast, and accurate placement of the ablation probe into the liver tumor, which is a prerequisite for a complete destruction of the tumor by ablation. More and more physicians, including surgeons, consider ablation a viable alternative to resection whenever feasible. Patients undergoing such a minimally invasive treatment benefit from a shorter hospital stays, reduced complication rates, and faster recovery

Heat shock protein 90 (HSP90) inhibitors in gastrointestinal cancer: where do we currently stand?-A systematic review.

PURPOSE Dysregulated expression of heat shock proteins (HSP) plays a fundamental role in tumor development and progression. Consequently, HSP90 may be an effective tumor target in oncology, including the treatment of gastrointestinal cancers. METHODS We carried out a systematic review of data extracted from clinicaltrials.gov and pubmed.gov, which included all studies available until January 1st, 2022. The published data was evaluated using primary and secondary endpoints, particularly with focus on overall survival, progression-free survival, and rate of stable disease. RESULTS Twenty trials used HSP90 inhibitors in GI cancers, ranging from phase I to III clinical trials. Most studies assessed HSP90 inhibitors as a second line treatment. Seventeen of the 20 studies were performed prior to 2015 and only few studies have results pending. Several studies were terminated prematurely, due to insufficient efficacy or toxicity. Thus far, the data suggests that HSP90 inhibitor NVP-AUY922 might improve outcome for colorectal cancer and gastrointestinal stromal tumors. CONCLUSION It currently remains unclear which subgroup of patients might benefit from HSP90 inhibitors and at what time point these inhibitors may be beneficial. There are only few new or ongoing studies initiated during the last decade

Pancreatic Neuroendocrine Tumors: How Much Surgery is Safe?

Background: Neuroendocrine tumors of the pancreas (pNET) are rare. Often the patients are asymptomatic for a long time and present late with metastasized disease. Although there are guidelines for the treatment of these tumors, there is no clear consensus whether the resection of liver metastases may be combined with the primary tumor. Method: We retrospectively analyzed the patients operated at our institution between 1/2003 and 12/2012. The patients were analyzed for demographic and clinical data, surgical treatment, tumor size and stage, histology, complications, survival and tumor recurrence over time. Results: We analyzed 53 patients, 23 females, 30 males. Patients with a one-step surgical approach to pancreas and liver had similar morbidity and mortality compared to patients with disease confined to the pancreas. The primary tumors were smaller in tumors confined to the pancreas. Angioinvasion as well as positive lymph nodes were strongly correlated with synchronous or metachronous liver metastases. Progression free survival was shorter in patients with primary metastasized disease. Conclusion: The treatment of pNET is challenging. The surgical approach should be tailored to the patient’s general condition. Patients benefit from extended and combined resections even in metastasized or locally advanced situations. Combined pancreatic and hepatic surgery may be performed safely

Parenchymal-sparing hepatectomy for colorectal liver metastases reduces postoperative morbidity while maintaining equivalent oncologic outcomes compared to non-parenchymal-sparing resection.

BACKGROUND Modern chemotherapy and repeat hepatectomy allow to tailor the surgical strategies for the treatment of colorectal liver metastases (CRLM). This study addresses the hypothesis that parenchymal-sparing hepatectomy reduces postoperative complications while ensuring similar oncologic outcomes compared to the standardized non-parenchymal-sparing procedures. METHODS Clinicopathological data of patients who underwent liver resection for CRLM between 2012 and 2019 at a hepatobiliary center in Switzerland were assessed. Patients were stratified according to the tumor burden score [TBS2 = (maximum tumor diameter in cm)2 + (number of lesions)2)] and were dichotomized in a lower and a higher tumor burden cohort according to the median TBS. Postoperative outcomes, overall survival (OS) and recurrence-free survival (RFS) of patients following parenchymal-sparing resection (PSR) for CRLM were compared with those of patients undergoing non-PSR. RESULTS During the study period, 153 patients underwent liver resection for CRLM with curative intent. PSR was performed in 79 patients with TBS <4.5, and in 42 patients with TBS ≥4.5. Perioperative chemotherapy was administered in equal rates in both groups (PSR vs. non-PSR) both in TBS ≥4.5 and TBS <4.5. In patients with lower tumor burden (TBS <4.5), PSR was associated with lower overall complication rate (15.2% vs. 46.2%, p = 0.009), a trend for lower major complication rate (8.9% vs. 23.1%, p = 0.123), and shorter length of hospital stay (5 vs. 9 days, p = 0.006) in comparison to non-PSR. For TBS <4.5, PSR resulted in equivalent 5-year OS (48% vs. 39%, p = 0.479) and equivalent 5-year RFS rates (44% vs. 29%, p = 0.184) compared to non-PSR. For TBS ≥4.5, PSR resulted in lower postoperative complication rate (33.3% vs. 63.2%, p = 0.031), a trend for lower major complication rate (23.8% vs. 42.2%, p = 0.150), lower length of hospital stay (6 vs. 9 days, p = 0.005), equivalent 5-year OS (29% vs. 22%, p = 0.314), and equivalent 5-year RFS rates (29% vs. 18%, p = 0.156) compared to non-PSR. Among all patients treated with PSR, patients undergoing minimal-invasive hepatectomy had equivalent 5-year OS (42% vs. 37%, p = 0.261) and equivalent 5-year RFS (34% vs. 34%, p = 0.613) rates compared to patients undergoing open hepatectomy. CONCLUSIONS PSR for CRLM is associated with lower postoperative morbidity, shorter length of hospital stay, and equivalent oncologic outcomes compared to non-PSR, independently of tumor burden. Our findings suggest that minimal-invasive PSR should be considered as the preferred method for the treatment of curatively resectable CRLM, if allowed by tumor size and location

The Role of Conventional and Stereotactic Microwave Ablation for Intrahepatic Cholangiocarcinoma.

BACKGROUND The incidence and mortality of intrahepatic cholangiocarcinoma (ICCA) is increasing worldwide and curative treatment options are limited due to the aggressive tumor biology and often late diagnosis. Resection of the primary tumor remains the only curative therapy available, as the benefit of palliative chemotherapy and radiotherapy is relatively small. In contrast to hepatocellular carcinoma, minimal-invasive thermal tumor ablation, and in particular stereotactic tumor ablation for small primary cancers or metastases, is not established and data are scarce. METHODS We conducted a literature review in the field of ICCA ablation and retrospective analysis of 10 patients treated by stereotactic microwave ablation (SMWA) for either primary ICCA or liver metastases of ICCA. RESULTS While current guidelines have no consensus for ablation of primary ICCA, some state that it might be an option in inoperable patients or those with recurrent disease. The literature review revealed 11 studies on microwave ablation for ICCA reporting that MWA for ICCA ≤ 5 cm might be safe and could be a treatment option for patients who are not candidates for surgery. No data has been published on stereotactic microwave ablation (SMWA) for ICCA. The analyses of our own data of 10 patients treated by SMWA for primary ICCA (n = 5) or recurrent ICCA (n = 5) show that the treatment is safe and efficient with short hospital stays and low complication rates. CONCLUSION Although thermal ablation, and in particular SMWA, might be a minimally invasive and tissue-sparing curative treatment alternative for small ICCA in the diseased liver and ICCA metastases, the oncologic benefit still needs to be shown in larger studies with longer follow-up

Beta-adrenergic regulation of pancreatic cancer progression

Cancer is one of the leading causes of death, with 8.2 million deaths worldwide and 14.1 million new cases in 2012. Pancreatic cancer (PaCa) is the fourth leading causes of cancer death worldwide, with around 280,000 new cases per year. The overall five-year survival rate is less than 5%, and effective therapies and tools to improve an early diagnosis are critically needed. Cure from PaCa depends on successful surgical resection of the primary tumour and improved 5-year survival rates over 20-30% have been reported in specialised centres following surgical resection. However, the majority of patients are diagnosed with advanced stage PaCa which prohibits surgical treatments. Even with tumour-free resection margins (R0 resection) recurrence rates are high and most patients eventually die of local tumour recurrence and metastatic disease. Current standard chemotherapeutic treatment in locally advanced and metastatic PaCa patients involves gemcitabine, but the overall prolongation of survival is disappointingly small (5-6 weeks). New and improved therapeutic strategies to treat PaCa and to prevent recurrence and metastasis require a more detailed understanding of the physiological regulators of PaCa progression and their mechanistic molecular and cellular mediators. There is accumulating evidence from human clinical studies and animal models that sympathetic nervous system (SNS) signalling through beta-adrenergic pathways promotes cancer progression. Adrenergic activation via hypertension or chronic stress induces systemic and local release of catecholamines. Catecholamines bind on β-adrenergic receptors (βAR) on tumour and stromal cells and induce a down stream signalling by activation of G-proteins resulting in the activation of adenyl cyclase and cyclic AMP accumulation, followed by the activation of protein kinase A (PKA). PKA activates transcription factors which may regulate cell proliferation. The impact of adrenergic signalling pathways on PaCa growth or metastasis in vivo (orthotopic model) has not been investigated. Nerve fibres from the SNS innervate the pancreas. From clinical results we know, that this perineural invasion by pancreatic cancer cells is one of the important routes of pancreatic cancer cell dissemination and therefore very important for the prognosis of patients with pancreatic cancer. Because of this relationship between pancreatic tumour cells and nerve fibres we think that pancreatic cancer cells may be sensitive to SNS regulation. We studied the effect of chronic stress on pancreatic cancer progression in an orthotopic mouse model. To track tumour progression and metastasis over time we used bioluminescence imaging. We found an increased tumour burden in chronic stressed animals. To confirm the importance of β-adrenergic signalling on cancer progression we performed pharmacological studies in vitro and in vivo. The effect of chronic stress on tumour progression could be blocked in vivo by a treatment with beta blockers. In vitro studies confirmed these results with an increased invasion and proliferation of cells treated with isoprenaline. These results supported our in vivo findings that beta blockers may reduce cancer progression