Retrospective analysis of the immunogenic effects of intra-arterial locoregional therapies in hepatocellular carcinoma: a rationale for combining selective internal radiation therapy (SIRT) and immunotherapy.

BACKGROUND: Immunotherapy represents a promising option for treatment of hepatocellular carcinoma (HCC) in cirrhotic patients but its efficacy is currently inconsistent and unpredictable. Locoregional therapies inducing immunogenic cell death, such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT), have the potential to act synergistically with immunotherapy. For the development of new approaches combining locoregional treatments with immunotherapy, a better understanding of the respective effects of TACE and SIRT on recruitment and activation of immune cells in HCC is needed. To address this question, we compared intra-tumor immune infiltrates in resected HCC after preoperative treatment with TACE or SIRT. METHODS: Data fromr patients undergoing partial hepatectomy for HCC, without preoperative treatment (SURG, n = 32), after preoperative TACE (TACE, n = 16), or preoperative SIRT (n = 12) were analyzed. Clinicopathological factors, tumor-infiltrating lymphocytes (TILs), CD4+ and CD8+ T cells, and granzyme B (GZB) expression in resected HCC, and postoperative overall and progression-free survival were compared between the three groups. RESULTS: Clinicopathological and surgical characteristics were similar in the three groups. A significant increase in TILs, CD4+ and CD8+ T cells, and GZB expression was observed in resected HCC in SIRT as compared to TACE and SURG groups. No difference in immune infiltrates was observed between TACE and SURG patients. Within the SIRT group, the dose of irradiation affected the type of immune infiltrate. A significantly higher ratio of CD3+ cells was observed in the peri-tumoral area in patients receiving < 100 Gy, whereas a higher ratio of intra-tumoral CD4+ cells was observed in patients receiving > 100 Gy. Postoperative outcomes were similar in all groups. Irrespective of the preoperative treatment, the type and extent of immune infiltrates did not influence postoperative survival. CONCLUSIONS: SIRT significantly promotes recruitment/activation of intra-tumor effector-type immune cells compared to TACE or no preoperative treatment. These results suggest that SIRT is a better candidate than TACE to be combined with immunotherapy for treatment of HCC. Evaluation of the optimal doses for SIRT for producing an immunogenic effect and the type of immunotherapy to be used require further evaluation in prospective studies.

The burden of low anterior resection syndrome on quality of life in patients with mid or low rectal cancer.

BACKGROUND: Low anterior resection (LAR) with total mesorectal excision (TME) for mid and low rectal cancer is standard of care, reducing local recurrence and enhancing long-term survival. However, this surgery is associated with a constellation of major defecatory problems that are collectively referred to as low anterior resection syndrome (LARS). The aims of this study were to evaluate the frequency of LARS in patients who have undergone LAR and to assess the impact of LARS on long-term quality of life (QoL). METHODS: This was a single-center prospective survey study on patients who underwent LAR and TME for low or mid rectal cancer between 2007 and 2015. LARS score and QLQ-C30 questionnaires were used to evaluate patient's bowel functions and quality of life, respectively. Associations between LARS and QoL were evaluated. RESULTS: Fifty-seven patients out of 65 eligible agreed to participate in the study. Forty-three (66%) patients returned complete questionnaires. Five patients (11.6%) had no LARS, 7 had minor LARS (16.3%), and 31 had major LARS (72.1%). In univariate analysis, BMI > 30 kg/m2 was predictive of major LARS (p = 0.047). Major LARS did not impair global QoL (p = 0.75), function scores, or social scales, and was not associated with any of the symptom scores except for diarrhea (p = 0.02). CONCLUSION: LARS is a frequent occurrence after LAR and TME for rectal cancer (72.1%) and is more prevalent in morbidly obese patients. However, the occurrence of LARS does not appear to have a direct impact on QoL except for the occurrence of diarrhea.

Indocyanine green fluorescence imaging for sentinel lymph node detection in colorectal cancer: A systematic review.

Indocyanine green fluorescence-imaging (ICG-FI) has emerged as a potential tool for increasing the accuracy of staging of patients with primary colorectal cancer (CRC) through the detection of sentinel lymph nodes (SLNs). Here, we report the results of a systematic review of the available literature in the clinical setting of ex vivo and in vivo ICG-FI for the detection of SLNs in primary colorectal cancer. PubMed, Scopus, and Cochrane literature databases were searched for original articles on the use of ICG in the setting of clinical studies of CRC. Eighty studies were identified and screened, 23 were assessed for eligibility and 10 were included for review. Both ex vivo and in vivo ICG-FI are reported to be feasible for the detection of SLNs in CRC. The reported sensitivity of both techniques remains low, varying from 0% to 100% for the in vivo technique and 57% for the ex vivo technique. ICG-FI has not yet been shown to perform better than the standard blue dye technique. In addition, large variability among reported studies in terms of techniques used (ICG dose, type of injection), type of pathologic analyses performed (HE, IHC, serial section), and definition of positive LN status for sensitivity calculations made them difficult to compare directly. ICG-FI is a promising technique for the detection of SLNs in the setting of CRC but more work needs to be done to clearly define protocols and indications for its use and to test its efficacy in larger patient populations.

Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features.

BACKGROUND & AIMS: Genomic studies have revealed subtypes of pancreatic ductal adenocarcinoma (PDA) based on their molecular features, but different studies have reported different classification systems. It is a challenge to obtain high-quality, freshly frozen tissue for clinical analysis and determination of PDA subtypes. We aimed to redefine subtypes of PDA using a large number of formalin-fixed and paraffin-embedded PDA samples, which are more amenable to routine clinical evaluation. METHODS: We collected PDA samples from 309 consecutive patients who underwent surgery from September 1996 through December 2010 at 4 academic hospitals in Europe; nontumor tissue samples were not included. Samples were formalin fixed and paraffin embedded. DNA and RNA were isolated; gene expression, targeted DNA sequencing, and immunohistochemical analyses were performed. We used independent component analysis to deconvolute normal, tumor, and microenvironment transcriptome patterns in samples. We devised classification systems from an unsupervised analysis using a consensus clustering approach of our data set after removing normal contamination components. We associated subtypes with overall survival and disease-free survival of patients using Cox proportional hazards regression with estimation of hazard ratios and 95% confidence interval. We used The Cancer Genome Consortium and International Cancer Genome Consortium PDA data sets as validation cohorts. RESULTS: We validated the previously reported basal-like and classical tumor-specific subtypes of PDAs. We identified features of the PDA, including microenvironment gene expression patterns, that allowed tumors to be categorized into 5 subtypes, called pure basal like, stroma activated, desmoplastic, pure classical, and immune classical. These PDA subtypes have features of cancer cells and immune cells that could be targeted by pharmacologic agents. Tumor subtypes were associated with patient outcomes, based on analysis of our data set and the International Cancer Genome Consortium and The Cancer Genome Consortium PDA data sets. We also observed an exocrine signal associated with acinar cell contamination (from pancreatic tissue). CONCLUSIONS: We identified a classification system based on gene expression analysis of formalin-fixed PDA samples. We identified 5 PDA subtypes, based on features of cancer cells and the tumor microenvironment. This system might be used to select therapies and predict patient outcomes. We found evidence that the previously reported exocrine-like (called ADEX) tumor subtype resulted from contamination with pancreatic acinar cells. ArrayExpress accession number: E-MTAB-6134.

The potential benefit of adjuvant chemotherapy in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy is not predicted by tumor regression grade.

INTRODUCTION: Recommended treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (NACRT) followed by surgery and total mesorectal excision (TME). The role of adjuvant chemotherapy (ACT) in this regimen is still debated. Assessment of Dworak's tumor regression grade (TRG) after NACRT could potentially select patients who might benefit from ACT. MATERIALS AND METHODS: Data for patients who underwent NACRT and TME for LARC between 2007 and 2014 were retrieved from the Bordet Institute database. Overall survival (OS) and disease-free survival (DFS) were calculated for the whole population, according to whether or not they received ACT, and according to TRG. RESULTS: We included 74 patients (38 males) with a median age of 62.7 years (33-84 years). AJCC stage cIIIb disease was the most frequent (73%). Pathologic complete response (pCR) was achieved in 13 patients (17.6%). ACT was administered to 42 patients (56.8%). Five-year OS and DFS of patients who received ACT or not were 92 and 84.5% (p = ns), and 79.9 and 84.8% (p = ns), respectively. OS was related to TRG (cut-off value of 3) (p = 0.001). ACT administration was not correlated with improved outcomes in any TRG groups. CONCLUSION: TRG is a prognostic factor for both OS and DFS but does not appear to have a significant benefit for the selection of patients with LARC treated with NACRT who might benefit from the administration of ACT. Prospective randomized trials with larger populations are needed to identify factors that predict which patients may benefit from the administration of ACT.

Schwannoma of the colon and rectum: a systematic literature review.

BACKGROUND: Schwannomas of the colon and rectum are rare among gastrointestinal schwannomas. They are usually discovered incidentally as a submucosal mass on routine colonoscopy and diagnosed on pathologic examination of the operative specimen. Little information exists on the diagnosis and management of this rare entity. The aim of this study is to report a case of cecal schwannoma and the results of a systematic review of colorectal schwannoma in the literature. MAIN BODY: PubMed, Scopus, and Cochrane database searches were performed for case reports and case series of colonic and rectal schwannoma. Ninety-five patients with colonic or rectal schwannoma from 70 articles were included. Median age was 61.5 years (59% female). Presentation was asymptomatic (28%), rectorrhagia (23.2%), or abdominal pain (15.8%). Schwannoma occurred in the left and sigmoid colon in 36.8%, in the cecum and right colon in 30.5%, and in the rectum in 21.1%. Median tumor size was 3 cm and 56.2% of patients who underwent preoperative colonoscopy had a typical smooth submucosal mass. At pathology, 97.9, 13.7, and 5.3% of schwannomas stained positive for S100, vimentin, and GFAP, respectively. The median mitotic index was 1/50. CONCLUSIONS: Colorectal schwannoma is a very rare subtype of gastrointestinal schwannoma which occurs in the elderly, almost equally in men and women. Schwannoma should be included in the differential diagnosis of a submucosal lesion along with gastrointestinal stromal tumor, neuro-endocrine tumors, and leiomyoma-leiomyosarcoma. Definitive diagnosis is based on immunohistochemistry of the operative specimen. Rarely malignant, surgery is the mainstay of treatment.

Circulating tumor DNA in early response assessment and monitoring of advanced colorectal cancer treated with a multi-kinase inhibitor.

Predictive biomarkers are eagerly awaited in advanced colorectal cancer (aCRC). Targeted sequencing performed on tumor and baseline plasma samples in 20 patients with aCRC treated with regorafenib identified 89 tumor-specific mutations of which ≥50% are also present in baseline plasma. Droplet digital PCR (ddPCR) assays were optimized to monitor circulating tumor DNA (ctDNA) levels in plasmatic samples collected throughout the treatment course and showed the importance of using the absolute value for ctDNA rather than the mutant/wild type ratio in monitoring the therapy outcome. High baseline cell free DNA (cfDNA) levels are associated with shorter overall survival (OS) (HR 7.38, P=0.001). An early increase (D14) in mutated copies/mL is associated with a significantly worse PFS (HR 6.12, P=0.008) and OS (HR 8.02, P=0.004). These data suggest a high prognostic value for early ctDNA level changes and support the use of blood-born genomic markers as a tool for treatment.

Selective internal radiation therapy (SIRT) before partial hepatectomy or radiofrequency destruction for treatment of hepatocellular carcinoma in cirrhotic patients: a feasibility and safety pilot study.

BACKGROUND/PURPOSE: Preoperative selective internal radiation therapy (SIRT) may improve the results of partial hepatectomy (PH) or radiofrequency destruction (RF) for hepatocellular carcinoma (HCC) in patients with cirrhosis. The aim of this study was to evaluate the feasibility and safety of this combined approach. METHODS: Patients with cirrhosis and HCC selected for PH or RF were prospectively included and systematically proposed for preoperative SIRT. Feasibility and safety of SIRT and post-SIRT PH or RF were assessed. RESULTS: Thirty patients were included. SIRT was contraindicated in seven, due to lack of access to tumour artery or to hepato-pulmonary shunts. SIRT was performed in 23 patients without significant complications. Post-SIRT, surgery was refuted in seven patients, due to tumour progression or the patient's deteriorating condition. After surgery, major complications were observed in 2/16 patients (12.5%) and one patient died 52 days post-surgery. A major tumour pathological response was seen in most patients who underwent surgery after SIRT. CONCLUSIONS: On intention-to-treat basis, the overall feasibility of combining preoperative SIRT and surgery was limited. Preoperative SIRT did not increase expected operative morbidity, but post-SIRT, a third of patients were refuted for surgery. Accurate selection criteria and potential long-term oncological benefit of this approach remains to be determined. ClinicalTrials.gov NCT01686880.

Fatal Septic Shock Associated with Herpes Simplex Virus Hepatitis: A Case Report.

Herpes simplex viruses are endemic worldwide, with an estimated seroprevalence of approximately 70% in developed countries. However, it is less well known that they are one of the viral causes of fulminant hepatitis (<2%) and constitute <1% of all causes of acute liver failure. We describe the case of an 89-year-old man who developed sepsis caused by a urinary tract infection due to drug-sensitive Escherichia coli. After empirical treatment with piperacillin-tazobactam was initiated, the patient's condition worsened with shock, acute liver and renal failure, encephalopathy and persistent fever, that led to admission to the intensive care unit. The emergence of an acute abdomen prompted exploratory laparotomy but the patient died soon after surgery from abdominal haemorrhage. Immunohistochemical analysis of a liver biopsy specimen identified herpes simplex virus (HSV) hepatitis. The authors emphasize the need for better understanding of this rare condition in order to more precisely identify patients at risk who need more aggressive evaluation and empirical treatment, especially patients presenting with marked hepatic cytolysis with a rapidly worsening clinical evolution. LEARNING POINTS: Herpes simplex virus hepatitis should be considered in patients with acute liver failure.This condition can occur even in immunocompetent individuals.Empirical treatment with aciclovir should be initiated in case of clinical suspicion.

Sequential tumor-directed and lobar radioembolization before major hepatectomy for hepatocellular carcinoma.

Preoperative radioembolization may improve the resectability of liver tumor by inducing tumor shrinkage, atrophy of the embolized liver and compensatory hypertrophy of non-embolized liver. We describe the case of a cirrhotic Child-Pugh A patient with a segment IV hepatocellular carcinoma requiring a left hepatectomy. Preoperative angiography demonstrated 2 separated left hepatic arteries, for segment IV and segments II-III. This anatomic variant allowed sequential radioembolizations, delivering high-dose 90Yttrium (160 Gy) to the tumor, followed 28 d later by lower dose (120 Gy) to segments II-III. After 3 mo, significant tumor response and atrophy of the future resected liver were obtained, allowing uneventful left hepatectomy. This case illustrates that, when anatomic disposition permits it, sequential radioembolizations, delivering different 90Yttrium doses to the tumor and the future resected liver, could represent a new strategy to prepare major hepatectomy in cirrhotic patients, allowing optimal tumoricidal effect while reducing the toxicity of the global procedure.

Sentinel Lymph Node Detection by Blue Dye Versus Indocyanine Green Fluorescence Imaging in Colon Cancer.

BACKGROUND/AIM: Nodal staging is used in colorectal cancer (CRC) to determine which patients should receive adjuvant chemotherapy. The aim of this study was to evaluate the role of indocyanine green fluorescence imaging (ICG-FI) in sentinel lymph node (SLN) detection compared to the standard technique. MATERIALS AND METHODS: Twenty patients with CRC admitted for elective colectomy were included (NCT01995591). Ex vivo SLN detection was performed using patent blue (PB) and free ICG injected around the tumor. RESULTS: Identification rates were 95% (19/20) for both techniques. Sensitivity was 43% for PB and 57% for ICG. Correlation between the techniques was 83%. FI was more sensitive in patients with body mass index (BMI) >25 kg/m(2) Serial section analysis did not allow for up-staging of patients. CONCLUSION: The use of ICG-FI is superior to the blue dye technique in patients with a BMI >25 kg/m(2) However, the sensitivity of ICG-FI in SLN detection remains low, with a high rate of false-negative results.

Leiomyomatosis peritonealis disseminata: case report and review of the literature.

Leiomyomatosis peritonealis disseminata (LPD) is typically a benign and rare disorder found in female patients, prior to menopause. It can be found in the subperitoneal or peritoneal spaces and is represented by multiple different sized myomatous nodules (smooth muscle tumors). Additionally, it has also been found in women after menopause as well as in men. Despite the fact that high levels of estrogen and progesterone play a significant role in this disorder, the mechanism behind LPD development and a definitive therapeutic concept has yet to be conceived. This disorder is mostly found incidentally during imaging or surgery as it is often an asymptomatic condition. The present case reports an incident of LPD, clinically similar to peritoneal metastases, in a patient with a past history of dermatofibrosarcoma of Darier and Ferrand.

Ex vivo detection of tumoral lymph nodes of colorectal origin with fluorescence imaging after intraoperative intravenous injection of indocyanine green.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the potential role of indocyanine green (ICG) fluorescence imaging after intraoperative intravenous (IV) injection for the "ex vivo" detection of metastatic lymph nodes (mLNs) of colorectal cancer origin. METHODS: Fresh-fixed LNs in cassettes and/or paraffin-embedded LNs of patients included in a study that evaluated the role of ICG in the detection of peritoneal metastases of colorectal origin (Protocol NCT-01995591) were further explored with a dedicated near-infrared camera system for their fluorescence. An IV injection of ICG was delivered intraoperatively at 0.25 mg/kg. Signal to background ratios (SBRs) were calculated. RESULTS: LNs on operative specimens were evaluated for 12 patients (5 males, 7 females). A total of 182 LNs were analyzed. The mean LN number per patient was 15.2 (median: 15.5; range 3-22). SBRs of mLNs were significantly more fluorescent than benign LNs, 1.41 versus 1.04 arbitrary units (P < 0.0002). On univariate analysis, fluorescence was statistically correlated with LN surface area (>20 mm(2) ) (P < 0.0004). CONCLUSION: Ex vivo ICG fluorescence imaging after intraoperative IV injection represents a potential method for detecting invaded LN's of colorectal cancer origin on operative specimens. Further clinical studies are needed to better define optimal techniques. J. Surg. Oncol. 2016;114:348-353. © 2016 Wiley Periodicals, Inc.

Correlation between the response to cetuximab alone or in combination with irinotecan and the activated/phosphorylated epidermal growth factor receptor in metastatic colorectal cancer.

Despite staining positive for the epidermal growth factor receptor (EGFR), a significant number of EGFR-expressing colorectal cancers are resistant to cetuximab, a chimeric monoclonal antibody directed against EGFR. Activation of EGFR through the autophosphorylation of its tyrosine residues stimulates different signaling downstream pathways and may reflect the level of receptor utilization by the tumor. This study investigated activated/phosphorylated EGFR (pEGFR) in 23 patients with EGFR-positive metastatic colorectal cancer refractory to irinotecan and treated with cetuximab, alone or in combination with irinotecan. Seven patients received cetuximab, and 16 patients received cetuximab plus irinotecan. Among the 23 patients, six (26%) had a partial response, 10 (44%) had stable disease, and seven (30%) had progressive disease. Median duration of disease control (partial response + stable disease) was 6 months. Nineteen out of 20 EGFR-positive tumors (95%) stained positive for pEGFR and had a median pEGFR immunohistochemical score of 5. Disease control rates differed between patients with a pEGFR immunohistochemical score >or= 7 (7/7, 100%) and less than 7 (7/13, 53.8%), showing a trend toward higher disease control in patients with high levels of pEGFR (>or= 7) who were treated with cetuximab with or without irinotecan (P = .05).

Cellular angiofibroma of the vulva: a clinicopathological study of two cases with documentation of some unusual features and review of the literature.

BACKGROUND: Cellular angiofibroma (CA) of the vulva is a recently described condition, whose clinical and pathological features are poorly known. METHODS: We have encountered two cases of this very unusual tumor. Their clinical and pathological features were analyzed and compared to those reported in the literature. RESULTS: Both patients were middle-aged women. In each case, the lesion had the clinical appearance of a vulvar cyst, located in the lateral aspect of the clitoris and the right labium majus, respectively. Microscopically, the lesions were well circumscribed but not truly encapsulated. Both were composed of small spindle cells arranged in short fascicles and mixed up with relatively abundant small- or medium-sized rounded vessels. While mitotic activity was perceptible in both cases, no cellular atypia could be demonstrated. A striking feature seen in one case was the presence of pseudoangiomatous changes in the stroma, similar to those occasionally found in spindle cell lipoma. Phenotypically, the tumor cells consistently expressed vimentin, CD99, and both estrogen and progesterone receptors. A discrete CD34 or smooth muscle actin immunoreactivity was also found in one case. No expression of S-100 protein, Bcl-2 protein, CD117 (c-kit gene product), epithelial membrane antigen, desmin, or h-caldesmon could be demonstrated. CONCLUSION: This study further illustrates that CA of the vulva has distinct clinical and pathologic features that set it apart from the other soft tissue conditions involving this area. However, like many soft tissue neoplasms, this tumor also exhibits some variation in its histological or immunohistochemical features.