A Phase I-II multicenter trial with Avelumab plus autologous dendritic cell vaccine in pre-treated mismatch repair-proficient (MSS) metastatic colorectal cancer patients; GEMCAD 1602 study.

BACKGROUND: Immune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects. METHODS: This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage. RESULTS: A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1-5.3 months] and overall survival was 12.2 months [3.2-23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways. CONCLUSIONS: The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities.

Impact of microscopic incomplete resection for colorectal liver metastases on surgical margin recurrence: R1-Contact vs R1 < 1 mm margin width.

BACKGROUND: Several studies highlighted an inferior outcome of R1 resection for colorectal cancer liver metastases (CRLM); it is still unclear whether directly involved margins (R1-contact) are associated with a poorer outcome compared to R1 < 1 mm. The aim of this study is to analyze the impact on surgical margin recurrence (SMR) of R1-contact vs R1 < 1 mm patients. METHODS: Patients who underwent surgery for CRLM between 2009-2018 with both R1 resections on final histology were included and compared in terms of recurrence and survival. Factors associated with SMR were assessed by univariate and multivariate analysis. RESULTS: Out of 477, 77 (17.2%) patients showed R1 resection (53 R1-Contact and 24 R1 < 1 mm). Overall recurrence rate was 79.2% (R1 < 1 mm = 70.8% vs R1-contact group = 83%, P = .222). Median disease-free survival (DFS) and disease-specific survival (DSS) were significantly higher in R1 < 1 mm vs R1-contact group (93 vs 55 months; P = .025 and 69 vs 46 months; P = .038, respectively). The SMR rate was higher in R1-contact compared to R1 < 1 mm group (30.2% vs 8.3%; P = .036). At univariate analysis, age, number of metastases, open surgical approach, RAS status, and R1-contact were associated with SMR. At multivariate analysis, R1-contact margin was the only factor independently associated with higher SMR (OR = 5.6; P = .046). CONCLUSIONS: R1-contact margin is independently associated with SMR after liver resection for CRLM. Patients with R1-contact margin will also experience poorer DFS and DSS.

PET/CT Integrated With CT Colonography in Preoperative Obstructive Colorectal Cancer by Incomplete Optical Colonoscopy: A Prospective Study.

AIM: The aim of this study was to evaluate if integrating whole-body PET/CT with CT colonography (PET/CTC) improves the preoperative diagnosis of obstructive colorectal cancer (CRC). METHODS: We prospectively included 47 consecutive patients (18 women and 29 men; mean age, 71 ± 14 years) suspected of having CRC by optical colonoscopy, which was not completed due to obstructive masses. To perform PET/CTC, a small caliber Foley catheter was inserted to distend the colon with CO2 insufflations. Polyps measuring 10 mm or larger were considered as high risk of malignancy. All findings were histologically confirmed. RESULTS: Colorectal cancer was localized in the sigmoid (n = 21), rectum (n = 7), rectosigmoid junction (n = 5), ascending (n = 7), descending (n = 5), and transverse (n = 2) colon. All tumors showed FDG uptake (mean ± SD SUVmax, 20.02 ± 9.9) including one synchronic tumor (SUVmax, 10.46). Forty-seven polyps were histologically confirmed as smaller than 10 mm (n = 35) and 10 mm or larger (n = 12). All 12 polyps 10 mm or larger showed FDG uptake (SUVmax range, 3.08-19.5), but only one smaller than 10 mm could be identified by PET. Pathological lymph nodes were diagnosed in 17/47 cases after surgical removal with a sensitivity and specificity for CTC and PET/CTC of 71% and 97% and 59% and 100%, respectively. Liver metastases were confirmed in 9 patients and in 4/9 along with lung metastases (n = 2) or implants (n = 2), showing a sensitivity and specificity for CTC of 89% and 100% and both 100% for PET/CTC. CONCLUSIONS: PET/CTC is a reliable technique for staging CRC and diagnosing synchronous tumors. In this series, PET/CTC was not able to identify small polyps but showed potential use for ruling out 10 mm or larger polyps at high risk of malignancy.

Colon capsule endoscopy versus CT colonography in FIT-positive colorectal cancer screening subjects: a prospective randomised trial-the VICOCA study.

BACKGROUND: Colon capsule endoscopy (CCE) and CT colonography (CTC) are minimally invasive techniques for colorectal cancer (CRC) screening. Our objective is to compare CCE and CTC for the identification of patients with colorectal neoplasia among participants in a CRC screening programme with positive faecal immunochemical test (FIT). Primary outcome was to compare the performance of CCE and CTC in detecting patients with neoplastic lesions. METHODS: The VICOCA study is a prospective, single-centre, randomised trial conducted from March 2014 to May 2016; 662 individuals were invited and 349 were randomised to CCE or CTC before colonoscopy. Endoscopists were blinded to the results of CCE and CTC. RESULTS: Three hundred forty-nine individuals were included: 173 in the CCE group and 176 in the CTC group. Two hundred ninety individuals agreed to participate: 147 in the CCE group and 143 in the CTC group. In the intention-to-screen analysis, sensitivity, specificity and positive and negative predictive values for the identification of individuals with colorectal neoplasia were 98.1%, 76.6%, 93.7% and 92.0% in the CCE group and 64.9%, 95.7%, 96.8% and 57.7% in the CTC group. In terms of detecting significant neoplastic lesions, the sensitivity of CCE and CTC was 96.1% and 79.3%, respectively. Detection rate for advanced colorectal neoplasm was higher in the CCE group than in the CTC group (100% and 93.1%, respectively; RR = 1.07; p = 0.08). Both CCE and CTC identified all patients with cancer. CCE detected more patients with any lesion than CTC (98.6% and 81.0%, respectively; RR = 1.22; p = 0.002). CONCLUSION: Although both techniques seem to be similar in detecting patients with advanced colorectal neoplasms, CCE is more sensitive for the detection of any neoplastic lesion. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02081742 . Registered: September 16, 2013.

Assessment of Response to Neoadjuvant Chemoradiotherapy by 18F-FDG PET/CT in Patients With Locally Advanced Esophagogastric Junction Adenocarcinoma.

PURPOSE: The outcome of locally advanced adenocarcinoma of the esophagogastric junction (AEG) treated with preoperative chemoradiotherapy is heterogeneous, and favorable response to this treatment is a key factor in the patient's prognosis. The aim of this study was to evaluate F-FDG PET/CT in assessing metabolic response in patients with AEG. MATERIALS AND METHODS: This prospective study evaluated all consecutive patients with potentially operable locally advanced AEG who were candidates for neoadjuvant chemoradiotherapy. PET/CT and contrast-enhanced thoracoabdominal CT were performed at baseline and 2 weeks after completion of chemoradiotherapy for response evaluation. The response rate was assessed using Response Evaluation Criteria in Solid Tumors criteria for contrast-enhanced thoracoabdominal CT and Positron Emission Tomography Response Criteria in Solid Tumors criteria for PET/CT. The regression rate was assessed using a 5-grade histopathology scoring system of the surgically resected tumor. Metastatic lesions were confirmed by histopathology examination or imaging and clinical follow-up at 6 months. RESULTS: A total of 40 cases were finally included in the study. Distant metastases were found in the baseline PET/CT in 6 of 40 cases (retroperitoneal [2] or mediastinal/hiliar [1] lymph nodes and liver [2] or bone [1] metastases) and were therefore excluded from surgery. Pathologic response correlated with the ΛSUVmax threshold of ≤45% (P = 0.033). CT response correlated well with both the baseline SUVmax (P = 0.039) and the ΛSUVmax (P = 0.001). Five-year survival curves for AEG correlated with the ΛSUVmax using a threshold of ≤45% for both progression-free and overall survival. CONCLUSIONS: F-FDG PET/CT is useful for diagnosing nonsuspected metastasis before neoadjuvancy in potentially operable AEG. The ΛSUV correlates with pathologic response and is a long-term independent prognostic factor of survival.

Should 18F-FDG PET/CT Be Routinely Performed in the Clinical Staging of Locally Advanced Gastric Adenocarcinoma?

PURPOSE: The aim of this study was to evaluate F-FDG PET/CT compared with conventional imaging techniques in the clinical management of patients with locally advanced gastric cancer (LAGC). METHODS: A prospective study between January 2010 and December 2011 in patients with suspected LAGC was conducted in our hospital. F-FDG PET/CT, contrast-enhanced CT (CECT), endoscopic ultrasound, and laparoscopy were performed in all cases. Standard whole-body F-FDG PET/CT images were obtained centered on the stomach at 1 and 2 hours after injection of 4.0 MBq/kg of F-FDG. Findings were confirmed by histopathology or by imaging follow-up in nonoperable patients. RESULTS: Fifty consecutive patients with confirmed LAGC (20 women, 30 men) with a mean ± SD age of 65.7 ± 12.1 years were included. Using Lauren classification, 24 patients were intestinal subtype, and 26 were diffuse subtype. Thirty-five patients with locoregional lymph node involvement and 22 with distant metastases were confirmed as peritoneal metastases (n = 15), retroperitoneal (n = 2) or mediastinal lymph nodes (n = 1), and liver (n = 3) or bone metastases (n = 1). Patients with signet ring carcinoma showed significantly less F-FDG uptake (P = 0.001). SUVmax correlated with tumor grading (P < 0.05). Standard and delayed F-FDG PET/CT and CECT images identified LAGC in 24, 27, and 28 of 30 patients, respectively. The sensitivity and specificity for F-FDG PET/CT and CECT to detect metastases were 68% and 100% and 64% and 93%, respectively. Contrast-enhanced CT and F-FDG PET/CT diagnosed only 6 of the 15 patients with confirmed peritoneal metastases. The impact in therapeutic management of F-FDG PET/CT and CECT was 24% and 22%, respectively. Kaplan-Meier survival curves for the LGAC showed a significant correlation between SUVmax and overall survival using an SUVmax threshold of less than 3.96 (P = 0.04). CONCLUSIONS: F-FDG PET/CT should be recommended for staging of LAGC; however, F-FDG PET/CT and CECT cannot replace laparoscopy to rule out peritoneal metastases. Delayed F-FDG PET/CT images show an increase of F-FDG uptake in most cases, improving LAGC detection. The grade of F-FDG uptake represents a significant prognostic tool in this series.

Neumatosis intestinal secundaria a quimioterapia con 5-fluorouracilo / Pneumatosis intestinalis due to 5-fluorouracil chemotherapy

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Phase II randomised trial of autologous tumour lysate dendritic cell plus best supportive care compared with best supportive care in pre-treated advanced colorectal cancer patients.

BACKGROUND: Autologous tumour lysate dendritic cell vaccine (ADC) has T-cell stimulatory capacity and, therefore, potential antitumour activity. We designed a phase II randomised trial of ADC + best supportive care (BSC) (experimental arm [EA]) compared with BSC (control arm [CA]), in pre-treated metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: Patients with progressive mCRC, at least to two chemotherapy regimens and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, were randomised to EA versus CA. Stratification criteria: ECOG PS (0-1 versus 2) and lactate dehydrogenase (ULN). EA was administered subcutaneously till progressive disease. Primary end-point was progression-free survival (PFS) at 4 months. RESULTS: Fifty-two patients were included (28 EA/24 CA). An interim analysis recommended early termination for futility. No objective radiological response was observed in EA. Median PFS in EA was 2.7 months (95% confidence interval [CI], 2.3-3.2 months) versus 2.3 months (95% CI, 2.1-2.5 months) in CA (p = 0.628). Median overall survival (OS) was 6.2 months (95% CI, 4.4-7.9 months) in EA versus 4.7 months (95% CI, 2.3-7 months) in CA (p = 0.41). No ADC-related adverse events were reported. Immunization induces tumour-specific T-cell response in 21 of 25 (84%) patients. Responder patients have an OS of 7.3 months (95% CI, 5.2-9.4 months) versus 3.8 months (95% CI, 0.6-6.9 months) in non-responders; p = 0.026). CONCLUSION: Our randomised clinical trial comparing ADC + BSC versus BSC in mCRC demonstrates that ADC generates a tumour-specific immune response but not benefit on PFS and OS. Our results do not support the use of ADC alone, in a phase III trial.

Endoluminal brachytherapy in the treatment of oesophageal cancer. Technique description, case report and review of the literature.

Endoesophageal brachytherapy is a useful technique for the palliative treatment of dysphagia in advanced oesophageal cancer. This technique offers good results on dysphagia control and quality of life.We report the case of a patient treated with this technique presenting complete response to the dysphagia. We describe endoesophageal brachyterapy technique and we comment on the literature.

Braquiterapia endoluminal esofágica en el tratamiento del cáncer de esófago: descripción de la técnica, a propósito de un caso y revisión de la literatura / Endolminal brachytherapy in the treatment of oesophageal cancer. Technique description, case report and review of the literature

La braquiterapia endoesofágica es una técnica útil en el tratamiento paliativo de la disfagia secundaria al cáncer de esófago avanzado. Ofrece buenos resultados en cuanto a control de la disfagia y calidad de vida. Presentamos el caso de una paciente con cáncer de esófago avanzado con resolución completa de su disfagia después de dicho tratamiento. Describimos la técnica y resultados de la literatura

Endoesophageal brachytherapy is a useful technique for the palliative treatment of dysphagia in advanced oesophageal cancer. This technique offers good results on dysphagia control and quality of life. We report the case of a patient treated with this technique presenting complete response to the dysphagia. We describe endoesophageal brachyterapy technique and we comment on the literature

Leiomyosarcoma of the inferior vena cava: feasibility of surgical resection. A report of two cases

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Is there a role for PET/CT with esophagogastric junction adenocarcinoma?

The value of 18F-FDG PET/CT in the initial diagnosis and in the locoregional staging of esophagogastric junction adenocarcinoma is not fully established. However, 18F-FDG PET/CT is widely accepted as the best modality for identification of suspected metastases in staging of the disease. Results published in the literature suggest that 18F-FDG PET/CT may provide useful information for response assessment to neoadjuvancy and to differentiate responding and nonresponding tumors. We review the potential role of 18F-FDG PET/CT imaging in staging, restaging, and prognostic value after chemoradiation therapy in esophagogastric junction adenocarcinoma.

Adjuvant therapy sparing in rectal cancer achieving complete response after chemoradiation.

AIM: To evaluate the long-term results of conventional chemoradiotherapy and laparoscopic mesorectal excision in rectal adenocarcinoma patients without adjuvant therapy. METHODS: Patients with biopsy-proven adenocarcinoma of the rectum staged cT3-T4 by endoscopic ultrasound or magnetic resonance imaging received neoadjuvant continuous infusion of 5-fluorouracil for five weeks and concomitant radiotherapy. Laparoscopic surgery was planned after 5-8 wk. Patients diagnosed with ypT0N0 stage cancer were not treated with adjuvant therapy according to the protocol. Patients with ypT1-2N0 or ypT3-4 or N+ were offered 5-fluorouracil-based adjuvant treatment on an individual basis. An external cohort was used as a reference for the findings. RESULTS: One hundred and seventy six patients were treated with induction chemoradiotherapy and 170 underwent total mesorectal excision. Cancer staging of ypT0N0 was achieved in 26/170 (15.3%) patients. After a median follow-up of 58.3 mo, patients with ypT0N0 had five-year disease-free and overall survival rates of 96% (95%CI: 77-99) and 100%, respectively. We provide evidence about the natural history of patients with localized rectal cancer achieving a complete response after preoperative chemoradiation. The inherent good prognosis of these patients will have implications for clinical trial design and care of patients. CONCLUSION: Withholding adjuvant chemotherapy after complete response following standard neoadjuvant chemoradiotherapy and laparoscopic mesorectal excision might be safe within an experienced multidisciplinary team.

Second-generation dual-energy computed tomography of the abdomen: radiation dose comparison with 64- and 128-row single-energy acquisition.

PURPOSE: This study was designed to compare the radiation dose in abdominal dual-energy (DE) and single-energy (SE) acquisitions obtained in clinical practice with a second-generation DE computed tomography (DECT) and to analyze the dose variation in comparison with an SE acquisition performed with a 64-row SECT (SECT). METHODS: A total of 130 patients divided into 2 groups underwent precontrast and portal abdominal 128-row CT examination. In group A, DE portal acquisition was performed using a detector configuration of 2 × 40 × 0.6 mm, tube A at 80 kVp and a reference value of 559 mAs, tube B at 140 kVp and a reference value of 216 mAs, pitch 0.6, and online dose modulation; group B underwent SE portal acquisition using a detector configuration of 64 × 0.6 mm, 120 kVp and a reference value of 180 mAs, pitch 0.75, and online dose modulation. Group C consisted of 32 subjects from group A previously studied with 64-row SECT using the following parameters: detector configuration 64 × 0.6 mm, 120 kVp and a reference value of 180 mAs, pitch 0.75, and online dose modulation. In each group, the portal phase dose-length product and radiation dose (mSv) were calculated and normalized for a typical abdominal acquisition of 40 cm. RESULTS: After normalization to standard 40-cm acquisition, a dose-length product of 599.0 ± 133.5 mGy · cm (range, 367.5 ± 1231.2 mGy · cm) in group A, 525.9 ± 139.2 mGy · cm (range, 215.7-882.8 mGy · cm) in group B, and 515.9 ± 111.3 mGy · cm (range, 305.5-687.2 mGy · cm) in group C was calculated for portal phase acquisition.A significant radiation dose increase (P < 0.05) was observed in group A (10.2 ± 2.3 mSv) compared with group B (8.9 ± 2.4) and group C (8.8 ± 1.9 mSv). No significant difference (P > 0.05) was reported between SE 64- and 128-row acquisitions. A significant positive correlation between radiation dose and body mass index was observed in each group (group A, r = 0.59, P < 0.0001; group B, r = 0.35, P < 0.0001; group C, r = 0.20, P = 0.0098). CONCLUSIONS: In clinical practice, abdominal DECT acquisition shows a significant but minimal radiation dose increase, on the order of 1 mSv, compared with 64- and 128-row SE acquisition. The slightly increased radiation dose can be justified if the additional information obtained using a spectral imaging approach directly impacts on patient management or reduce the overall radiation dose with the generation of virtual unenhanced images, which can replace the precontrast acquisition.

Imaging bile duct tumors: staging.

Cholangiocarcinoma (CC) is the most frequent neoplasm of the biliary system. According to its anatomic origin in the biliary tree it is usually classified as intrahepatic, perihilar, or extrahepatic distal CC. Tumors originated in these areas differ in biological behavior and management. The stratification of the patients aligned to therapeutic options and prognosis is a key point in the management of CC. Thus, specific staging systems have been designed for each anatomical location. They are precise for surgical planning, to establish prognosis after surgery, or to compare the benefits of different therapeutic approaches, but they are less accurate to stratify patients into a therapeutic decision algorithm. Imaging tools, mainly multidetector computed tomography and magnetic resonance imaging (MRI), allow full assessment of the diagnosis and extension of the tumor. They are especially useful in establishing the correct diagnosis and determining resectability, which reaches a high negative predictive value, identifying those patients in whom surgery will not be effective. We will discuss the different staging systems for CC, the radiologic characteristics with classical and recently described signs that allow a confident diagnosis of the disease and the criteria for resectability of biliary tract malignancies.

Virtual unenhanced images of the abdomen with second-generation dual-source dual-energy computed tomography: image quality and liver lesion detection.

PURPOSES: We aimed to analyze the image quality, CT number, artifacts, radiation dose reduction, and coverage in abdominal virtual unenhanced (VU) and conventional unenhanced (CU) data sets obtained with a second-generation dual-energy computed tomography and to compare the sensitivity of VU and CU data sets for liver lesion detection. MATERIALS AND METHODS: One hundred eleven patients underwent triphasic abdominal CT examination that included single-energy CU and dual-energy arterial and portal phases. Virtual unenhanced images were generated from arterial (AVU) and portal (PVU) phases. Two abdominal radiologists independently (a) analyzed the image quality using a 5-point scale, CT number, and noise of the abdominal organs and (b) identified and characterized liver lesions in CU, AVU, and PVU. The triphasic abdominal examination was considered the reference standard for liver lesion detection and characterization. RESULTS: The quality of VU images was mostly excellent but not as good as CU images (P < 0.05). The mean (SD) image quality classified by readers 1 and 2 was 4.9 (0.2; range, 4.7-5.0) and 4.8 (0.5; range, 4.4-4.9) for CU, 4.7 (0.4; range, 4.3-4.9) and 4.6 (0.4; range, 4.2-4.8) for AVU, and 4.7 (0.6; range, 4.1-4.8) and 4.6 (0.4; range, 4.2-4.8) for PVU, respectively. The CT number of the liver, the spleen, the pancreas, the renal cortex and medulla, the aorta, and the retroperitoneal fat was higher in AVU and PVU than in CU images. A total of 270 liver lesions were found in 76 patients. Portal virtual unenhanced data set was more sensitive than AVU and CU were for hypodense lesions smaller than 1 cm. Reader 1 correctly detected 72/144 (50.0%), 61/144 (42.4%), and 55/144 (38.2%) hypodense lesions with PVU, AVU, and CU, respectively; and reader 2 correctly diagnosed 70/144 (48.7%), 62/144 (43.0%), and 53/144 (36.8%) lesions with PVU, AVU, and CU, respectively. Conventional unenhanced data set was more sensitive than AVU or PVU was for small calcified lesions. Reader 1 detected 24/40 (60.0%), 24/40 (60.0%), and 40/40 (100%) with PVU, AVU, and CU, respectively; and reader 2 detected 27/40 (67.5%), (25/40) 62.5%, and 40/40 (100%) with PVU, AVU, and CU, respectively. The dose reduction achieved by omitting the unenhanced acquisition was a mean (SD) of 21.1% (1.2%; P < 0.01). CONCLUSIONS: Second-generation abdominal VU data sets, despite a mostly excellent image quality, still cannot replace CU images in clinical practice because of limitations in material subtraction. ADVANCES IN KNOWLEDGE: 1. Second-generation abdominal VU data sets yield excellent image quality but are still slightly lower than that of CU. 2. More small hypodense liver lesions were detected in VU images than in CU images; however, a significant number of small calcified lesions were not identified in VU images. 3. Second-generation abdominal VU images are still not ready to replace CU images in clinical practice. Implications for Patient Care: 1. Using VU images in abdominal studies makes it possible to reduce the total radiation dose delivered to patients who need multiphasic acquisition by avoiding precontrast scan. 2. Erroneous material subtraction and incomplete abdominal coverage represent a limit in VU data set application in clinical routine.