Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE.

BACKGROUND: Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC. PATIENTS AND METHODS: Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively. RESULTS: Patients (n = 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n = 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D. CONCLUSIONS: Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage 2. TRIAL REGISTRATION: NCT03812796 (registered 23rd January 2019).

Interobserver variation in the classification of tumor deposits in rectal cancer-is the use of histopathological characteristics the way to go?

The focus on lymph node metastases (LNM) as the most important prognostic marker in colorectal cancer (CRC) has been challenged by the finding that other types of locoregional spread, including tumor deposits (TDs), extramural venous invasion (EMVI), and perineural invasion (PNI), also have significant impact. However, there are concerns about interobserver variation when differentiating between these features. Therefore, this study analyzed interobserver agreement between pathologists when assessing routine tumor nodules based on TNM 8. Electronic slides of 50 tumor nodules that were not treated with neoadjuvant therapy were reviewed by 8 gastrointestinal pathologists. They were asked to classify each nodule as TD, LNM, EMVI, or PNI, and to list which histological discriminatory features were present. There was overall agreement of 73.5% (κ 0.38, 95%-CI 0.33-0.43) if a nodal versus non-nodal classification was used, and 52.2% (κ 0.27, 95%-CI 0.23-0.31) if EMVI and PNI were classified separately. The interobserver agreement varied significantly between discriminatory features from κ 0.64 (95%-CI 0.58-0.70) for roundness to κ 0.26 (95%-CI 0.12-0.41) for a lone arteriole sign, and the presence of discriminatory features did not always correlate with the final classification. Since extranodal pathways of spread are prognostically relevant, classification of tumor nodules is important. There is currently no evidence for the prognostic relevance of the origin of TD, and although some histopathological characteristics showed good interobserver agreement, these are often non-specific. To optimize interobserver agreement, we recommend a binary classification of nodal versus extranodal tumor nodules which is based on prognostic evidence and yields good overall agreement.

Radical resection of large metastatic non-functioning pancreatic neuroendocrine carcinoma complicated by splenic vein thrombosis and sinistral portal hypertension.

INTRODUCTION AND IMPORTANCE: There are limited reports in the literature of radical surgical resection for pancreatic neuroendocrine carcinoma (PNEC). In patients with non-functioning PNEC (NF-PNEC) within the tail of the pancreas tumours can cause splenic vein thrombosis (SVT) and subsequent sinitral portal hypertension (SPH). Radical surgical resection in such patients with concomitant liver metastasis has not previously been reported. CASE PRESENTATION: We present a 67-year old female patient who presented with a large NF-PNEC within the tail of the pancreas with liver metastasis. We performed a distal pancreatectomy, splenectomy, partial gastrectomy and liver resection to achieve radical resecton. DISCUSSION: All patients with NF-PNEC within the tail of the pancreatic should be considered for radical surgical resection. In the presence of multi-visceral involvement and complications such as SVT and/or SPH multi-speciality surgical expertise is likely to be required. CONCLUSION: Radical multi-visceral resection for large NF-PNEC can be safely performed in the presence of SVT and SPH.

Ex vivo specimen MRI and pathology confirm a rectosigmoid mesenteric waist at the junction of the mesorectum and mesocolon.

AIM: Continuity of the mesentery has recently been established and may provide an anatomical basis for optimal colorectal resectional surgery. Preliminary data from operative specimen measurements suggest there is a tapering in the mesentery of the distal sigmoid. A mesenteric waist in this area may be a risk factor for local recurrence of colorectal cancer. This study aimed to investigate the anatomical characteristics of the mesentery at the colorectal junction. METHOD: In this cross-sectional study, 20 patients were recruited. After planned colorectal resection, the surgical specimens were scanned in a MRI system and subsequently dissected and photographed as per national pathology guidelines. Mesenteric surface area and linear measurements were compared between MRI and pathology to establish the presence and location of a mesenteric waist. RESULTS: Specimen analysis confirmed that a narrowing in the mesenteric surface area was consistently apparent at the rectosigmoid junction. Above the anterior peritoneal reflection, the surface area and posterior distance of the mesentery of the upper rectum initially decreased before increasing as the mesentery of the sigmoid colon. These anatomical properties created the appearance of a mesenteric 'waist' at the rectosigmoid junction. Using the anterior reflection as a reference landmark, the rectosigmoid waist occurred at a mean height of 23.6 and 21.7 mm on MRI and pathology, respectively. CONCLUSION: A rectosigmoid waist occurs at the junction of the mesorectum and mesocolon, and is a mesenteric landmark for the rectum that is present on both radiology and pathology.

PARAGON II - A single arm multicentre phase II study of neoadjuvant therapy using irinotecan bead in patients with resectable liver metastases from colorectal cancer.

PURPOSE: Perioperative chemotherapy confers a 3-year progression free survival advantage following resection of colorectal liver metastases (CRLM), but is associated with significant toxicity. Chemoembolisation using drug eluting PVA microspheres loaded with irinotecan (DEBIRI) allows sustained delivery of drug directly to tumour, maximising response whilst minimising systemic exposure. This phase II single arm study examined the safety and feasibility of DEBIRI before resection of CRLM. METHODS: Patients with resectable CRLM received lobar DEBIRI 1 month prior to surgery, with a radiological endpoint of near stasis. The trial had a primary end-point of tumour resectability (R0 resection). Secondary end-points included safety, pathologic tumour response and overall survival. RESULTS: 40 patients received DEBIRI, with a median dose of 103 mg irinotecan (range 64-175 mg). Morbidity was low (2.5%, CTCAE grade 2) with no evidence of systemic chemotoxicity. All patients proceeded to surgery, with 38 undergoing resection (95%, R0 resection rate 74%). 30-day post-operative mortality was 5% (n = 2), with neither death TACE related. 66 lesions were resected, with histologic major or complete pathologic response seen in 77.3% of targeted lesions. At median follow up of 40.6 months, 12 patients (34.3%) had died of recurrent disease with a median overall survival of 50.9 months. Nominal 1, 3 and 5-year OS was 93, 78 & 49% respectively. CONCLUSIONS: Resection after neoadjuvant DEBIRI for CRLM is feasible and safe. Single treatment with DEBIRI resulted in tumour pathologic response and median overall survival comparable to that seen after systemic neoadjuvant chemotherapy. Registered at clinicaltrials.gov (NCT00844233).

Tumour size and differentiation predict survival after liver resection for hepatocellular carcinoma arising from non-cirrhotic and non-fibrotic liver: a case-controlled study.

AIMS: The aims of this study were to assess the outcomes of patients who underwent potentially curative hepatic resection for hepatocellular carcinoma (HCC) in a background of non-cirrhotic/non-fibrotic livers, and to determine prognostic factors that influenced survival. METHODS: Over a 15-year period, all patients undergoing hepatectomy for HCC were identified. Collated data included demographics, laboratory analysis, operative findings and histo-pathological data. Survival differences between these factors following liver resection were determined. RESULTS: 57 patients were included with a median age of 70 years. The majority of patients underwent a hemi-hepatectomy or more radical resection (n = 37). Overall R0 resection rate was 90.4% (n = 51). The overall morbidity and mortality rates were 26.3% and 3.5%, respectively. The median follow-up period was 28 months. The 1-, 3- and 5- year disease-free survival was 65.4%, 41.8% and 39.1%, and the overall survival was 73.5%, 49.6% and 39.5%, respectively. AFP (p = 0.039) was the only predictor of poorer disease-free survival on univariate analysis. On multi-variable analysis, poorly differentiated tumour and large tumour size were independent predictors of overall survival. CONCLUSIONS: Liver resection is a feasible treatment option for HCC in non-cirrhotic/non-fibrotic livers with good survival outcome. Tumour size and differentiation are adverse predictors of outcome in these patients.

Renal cell carcinoma metastases to gallbladder.

A 74-year old man underwent a radical cholecystectomy for presumed gallbladder cancer. The histology of the resected specimen in fact revealed the lesion to be metastatic renal cell carcinoma from his resected right nephrectomy performed 14 years previously.

Radiological assessment of response to neoadjuvant transcatheter hepatic therapy with irinotecan-eluting beads (DEBIRI(®)) for colorectal liver metastases does not predict tumour destruction or long-term outcome.

INTRODUCTION: Transcatheter hepatic therapy with irinotecan-eluting beads (DEBIRI(®)) allows targeted delivery of irinotecan direct to liver tissue and colorectal liver metastases (CRLM). Accurate assessment of tumour response to therapy is vital to guide optimal treatment. Preliminary work has suggested existing criteria for radiological response may not reflect pathological response after neoadjuvant DEBIRI. This study assessed the relationship between existing and novel radiological response criteria and pathological tumour response as well as long-term outcome. METHODS: Patients with easily resectable CRLM were treated with DEBIRI 4 weeks prior to resection and pathological tumour response graded using a validated system. Radiological response was assessed using RECIST and novel morphological response criteria. RESULTS: Twenty-two patients with 37 lesions were treated with DEBIRI. Median residual tumour was 20% (range 0-80), median necrosis 45% (10-100) and median fibrosis 10% (10-70). Twenty patients (91%) demonstrated stable disease by RECIST, with 11 (50%) demonstrating partial morphological response. Neither radiological response criteria correlated with pathological response. Overall median disease free survival (DFS) was 13.6 months (95% CI 4.7-22.5). Radiological response was not associated with DFS. CONCLUSION: Existing criteria reporting short-term radiological response to DEBIRI do not accurately predict pathological tumour response or long-term outcome. Further work is necessary to define the optimum timing and method of assessing response to DEBIRI.

Hepatic activation of irinotecan predicts tumour response in patients with colorectal liver metastases treated with DEBIRI: exploratory findings from a phase II study.

PURPOSE: The response of colorectal liver metastases to the cytotoxic agent irinotecan varies widely. Attempts to correlate tumour metabolism with response have been mixed. This study investigated the hepatic metabolism of irinotecan as a potential predictor of tumour response to irinotecan-eluting beads (DEBIRI). METHODS: Ten patients with colorectal liver metastases were treated with 200 mg irinotecan (as DEBIRI) as part of the PARAGON II study. Hepatic expression of key metabolising enzymes was measured using mass spectrometry-based proteomics. Serum drug concentrations and hepatic irinotecan metabolism were characterised and correlated with tumour response. RESULTS: Serum concentrations of irinotecan metabolites did not correlate with hepatic metabolism or pathological response. There was a strong correlation between hepatic CES-2 expression and activation of irinotecan (r (2) = 0.96, p < 0.001). Patients with a UGT1A1*28 6/7 SNP showed no difference in drug metabolism or pathological response. Hepatic CES-2 mediated activation of irinotecan clearly correlated with tumour replacement by fibrosis (r (2) = 0.54, p = 0.01). CONCLUSION: This study provides the first evidence that hepatic activation of irinotecan predicts tumour response. Delivery of liver-targeted irinotecan to normal liver tissue rather than tumour may be a more rational approach to maximise response.

Hepatic steatosis, body mass index and long term outcome in patients undergoing hepatectomy for colorectal liver metastases.

BACKGROUND: Hepatic steatosis (HS) is as an independent risk factor for morbidity and mortality post-hepatectomy. Recent studies report significant correlation between chemotherapy (now frequently employed pre-hepatectomy for colorectal liver metastases (CRLM)), HS and steatohepatitis. Furthermore, raised body mass index (BMI) predisposes to HS. However, no previous study has analysed the effect of HS on long-term survival. METHOD: A retrospective analysis of a prospective consecutive cohort of 102 patients undergoing hepatectomy with 60 months follow-up data was performed. Resection specimens were examined histologically and the degree of steatosis graded accordingly. The data was compared to BMIs and other clinical characteristics. Statistical analyses included log-rank, contingency, logistic regression and Fisher's exact tests. RESULTS: No detectable fatty change in 27 patients; 1 patient had cirrhosis; 57 had HS: 26 graded mild; 10 moderate, 21 severe and 17 not graded. 1 patient (BMI 29.5 kg/m(2)) had steatohepatitis but survived surgery. No significant difference in median survival between patients with and without HS (28.6 vs. 32.3 months, log-rank p>0.05). Results were similar between patients with BMI<25 and BMI>or=25 (32.3 vs. 36.8 months, log-rank p>0.05). Analyses of BMI against steatosis grade showed that patients with a higher BMI were at an increased risk of having a more severe HS (logistic regression, p<0.01; Fisher's exact, p<0.01). Contingency analyses on the influence of diabetes, chemotherapy and increasing number of risk factors on the likelihood of obtaining HS were insignificant (Fisher's exact, all p>0.05). CONCLUSION: While patients with higher body mass index values are at increased risk of having more severe hepatic steatosis, neither BMI nor hepatic steatosis significantly influences long-term survival. We conclude therefore that neither obesity nor hepatic steatosis has significant prognostic relevance on long-term survival of CRLM patients undergoing hepatectomy.

[Rhabdoid tumor of the kidney arising in a newborn infant: description of a case with ultrastructural observations]. / Tumore rabdoide del rene ad insorgenza neonatale: descrizione di un caso con osservazioni ultrastrutturali.

INTRODUCTION: Rhabdoid tumour of the kidney is a new independent entity. Before it was considered a variant of Wilms tumor of the kidney. Now we have enough parametres to define the rhabdoid tumor: immunohistochemistry positive by the vimentin, special histological features and behaviour. CASE: We report a very aggressive case of rhabdoid tumor found in a two week old infant. RESULTS: We studied aspects of histology and histochemistry. We found a positivity for vimentin and many cells in apoptosis. DISCUSSION: The mild positivity for vimentin and the high number of cells in apoptosis suggest a relationship between apoptosis and behaviour.