Atezolizumab plus modified docetaxel, cisplatin, and fluorouracil as first-line treatment for advanced anal cancer (SCARCE C17-02 PRODIGE 60): a randomised, non-comparative, phase 2 study.

BACKGROUND: The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2 study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus. METHODS: In this randomised, open-label, non-comparative, phase 2 study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m2 docetaxel and 40 mg per m2 cisplatin on day 1 and 1200 mg per m2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This trial is registered with ClinicalTrials.gov, NCT03519295, and is closed to new participants. FINDINGS: 97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8-28·4). The median age of participants was 64·1 years (IQR 56·2-71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35-55) in group A and 43% (29-58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47-100) in group A and 40% (19-85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3-4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths. INTERPRETATION: Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies. FUNDING: GERCOR, Roche.

Circulating levels of 3-hydroxymyristate, a direct quantification of endotoxaemia in noninfected cirrhotic patients.

BACKGROUND & AIMS: The quantification of lipopolysaccharide (LPS) in biological fluids is challenging. We aimed to measure plasma LPS concentration using a new method of direct quantification of 3-hydroxymyristate (3-HM), a lipid component of LPS, and to evaluate correlations between 3-HM and markers of liver function, endothelial activation, portal hypertension and enterocyte damage. METHODS: Plasma from 90 noninfected cirrhotic patients (30 Child-Pugh [CP]-A, 30 CP-B, 30 CP-C) was prospectively collected. The concentration of 3-HM was determined by high-performance liquid chromatography coupled with mass spectrometry. RESULTS: 3-HM levels were higher in CP-C patients (CP-A/CP-B/CP-C: 68/70/103 ng/mL, P = 0.005). Patients with severe acute alcoholic hepatitis (n = 16; 113 vs 74 ng/mL, P = 0.012), diabetic patients (n = 22; 99 vs 70 ng/mL, P = 0.028) and those not receiving beta blockers (n = 44; 98 vs 72 ng/mL, P = 0.034) had higher levels of 3-HM. We observed a trend towards higher baseline levels of 3-HM in patients with hepatic encephalopathy (n = 7; 144 vs 76 ng/mL, P = 0.45) or SIRS (n = 10; 106 vs 75 ng/mL, P = 0.114). In multivariate analysis, high levels of 3-HM were associated with CP (OR = 4.39; 95%CI = 1.79-10.76) or MELD (OR = 8.24; 95%CI = 3.19-21.32) scores. Patients dying from liver insufficiency (n = 6) during a 12-month follow-up had higher baseline levels of 3-HM (106 vs 75 ng/mL, P = 0.089). CONCLUSIONS: In noninfected cirrhotic patients, 3-HM arises more frequently with impairment of liver function, heavy alcohol consumption, diabetic status, nonuse of beta blockers and a trend towards poorer outcome is also observed. The direct mass measurement of LPS using 3-HM appears reliable to detect transient endotoxaemia and promising to manage the follow-up of cirrhotic patients.

Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study.

BACKGROUND: The incidence of anal squamous cell carcinoma has been increasing markedly in the past few decades. Currently, there is no validated treatment for advanced-stage anal squamous cell carcinoma. Therefore, we aimed to validate the clinical activity and safety of docetaxel, cisplatin, and fluorouracil (DCF) chemotherapy in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma. METHODS: We did a multicentre, single-arm, phase 2 study. We recruited patients from 25 academic hospitals, cancer research centres, and community hospitals in France who were aged 18 years or older with histologically confirmed anal squamous cell carcinoma, with metastatic disease or with unresectable local recurrence; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and with at least one evaluable lesion according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Chemotherapy-naive patients received either six cycles of standard DCF (75 mg/m2 docetaxel and 75 mg/m2 cisplatin on day 1 and 750 mg/m2 per day of fluorouracil for 5 days, every 3 weeks) or eight cycles of modified DCF (40 mg/m2 docetaxel and 40 mg/m2 cisplatin on day 1 and 1200 mg/m2 per day of fluorouracil for 2 days, every 2 weeks), which were administered intravenously. The choice between the standard versus modified regimens was recommended based on, but not limited to, age (≤75 years vs >75 years) and ECOG performance status (0 vs 1). The primary endpoint was investigator-assessed progression-free survival at 12 months from the first DCF cycle; for the primary endpoint to be met, at least 11 (17%) of 66 enrolled patients had to be alive without disease progression at 12 months. Efficacy and safety analyses were done in a modified intention-to-treat population, defined as all patients who were evaluable for progression at 12 months who received at least one cycle of DCF. This trial is registered at ClinicalTrials.gov, number NCT02402842, and the final results are presented here. FINDINGS: Between Sept 17, 2014, and Dec 7, 2016, we enrolled 69 patients. Of these patients, three did not receive DCF. Of the 66 patients who received treatment, 36 received the standard DCF regimen and 30 received modified DCF. The primary endpoint was met: 31 (47%) of 66 patients were alive and progression free at 12 months. 22 (61%) of 36 patients who received the standard DCF regimen and 18 (60%) of 30 patients who received the modified DCF regimen had disease progression at data cutoff. 46 (70%) of 66 patients had at least one grade 3-4 adverse event (30 [83%] of 36 in the standard DCF regimen and 16 [53%] of 30 in the modified DCF regimen). The most common grade 3-4 adverse events were neutropenia (15 [23%]; eight [22%] for standard DCF vs seven [23%] for modified DCF), diarrhoea (12 [18%]; nine [25%] vs three [10%]), asthenia (ten [15%]; eight [22%] vs two [7%]), anaemia (ten [15%]; six [17%] vs four [13%]), lymphopenia (eight [12%]; three [8%] vs five [17%]), mucositis (seven [11%]; seven [19%] vs none), and vomiting (seven [11%]; five [14%] vs two [7%]). No grade 4 non-haematological adverse events and febrile neutropenia were observed with modified DCF, whereas three (8%) grade 4 non-haematological adverse events and five (14%) cases of febrile neutropenia were reported with standard DCF. 97 serious adverse events were reported (69 in patients who received the standard DCF regimen [61 drug-related] and 28 in those given the modified DCF regimen [14 drug-related]). No treatment-related deaths were recorded. INTERPRETATION: Compared with standard DCF, modified DCF provided long-lasting response with good tolerability in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma with ECOG performance status of 0-1 in the first-line setting, and therefore could be considered as a new standard of care for these patients. Regarding the elevated risk of high-grade and serious adverse events and febrile neutropenia, standard DCF cannot be recommended in this situation. FUNDING: Besançon University Hospital and Ligue contre le cancer Grand-Est.

Increased levels of circulating platelet-derived microparticles are associated with metastatic cutaneous melanoma.

We investigated the plasma levels of PMPs in patients with 45 stage III and 45 stage IV melanoma. PMPs were characterised by flow cytometry and their thrombogenic activity. We also investigated the link between PMPs circulating levels and tumor burden. The circulating levels of PMPs were significantly higher in stage IV (8500 µL-1 ) than in patients with stage III (2041 µL-1 ) melanoma (P=.0001). We calculated a highly specific (93.3%) and predictive (91.7%) cut-off value (5311 µL-1 ) allowing the distinction between high-risk stage III and metastatic stage IV melanoma. The thrombogenic activity of PMPs was significantly higher in patients with stage IV melanoma (clotting time: 40.7 second vs 65 second, P=.0001). There was no significant association between the radiological tumoral syndrome and the plasma level of PMPs. Our data suggest the role of PMPs in metastatic progression of melanoma.

Preoperative diagnosis of gangrenous acute cholecystitis: usefulness of CEUS.

PURPOSE: To evaluate CEUS for the preoperative diagnosis of gangrenous acute cholecystitis. SUBJECTS AND METHODS: This prospective study was approved by our institution's ethical committee. Fifty-six patients who underwent both US and CEUS and were confirmed as presenting with acute cholecystitis at pathology were included. Clinical data, mean time until surgery, macroscopic appearance of the GB, and the presence of gangrene at pathology were noted. Baseline US images and CEUS cine clips were analyzed by two experienced radiologists. Statistical analyses were performed. RESULTS: Gangrenous acute cholecystitis was diagnosed in 23 (41%) patients and uncomplicated acute cholecystitis in 33 (59%). Patients with gangrenous acute cholecystitis were found to be older (p = 0.048). Mean time from CEUS to surgery was found to be shorter in patients presenting with gangrenous acute cholecystitis (p = 0.052). At US, GB short axis ≥4 cm (p = 0.039) and GB wall interruption (p = 0.037) showed a statistically significant association with the diagnosis of gangrenous acute cholecystitis. On CEUS, discontinuous or irregular GB wall enhancement was reported in 19/23 (83%) patients with gangrenous acute cholecystitis and showed association with the presence of gangrene at pathology (p = 0.001). The interobserver agreement for the presence of discontinuous or irregular GB wall enhancement on CEUS images was good. CONCLUSION: Performing CEUS on patients presenting with US findings of acute cholecystitis is relevant, since the presence of a discontinuous or irregular enhancement of the GB wall appears to be correlated with the diagnosis of gangrenous acute cholecystitis.

Spigelian hernia: CT findings and clinical relevance.

OBJECTIVE: The purpose of our study was to evaluate the clinical relevance of preoperative CT in distinguishing between the two subtypes of spigelian hernia (SH). MATERIALS AND METHODS: We reviewed retrospectively the CT images of 35 patients. The patients were divided into two groups on the basis of the SH subtype: interstitial SH group (n = 15) and subcutaneous SH group (n = 20). Clinical characteristics of patients and CT findings were analyzed. Bowel ischemia on surgery was also noted. RESULTS: Sixteen right hernias and 19 left hernias were observed. Fifteen interstitial SH (43%) and 20 subcutaneous SH (57%) were found. No type of content showed a statistically significant association with one or other subtype of SH. Nine of the 26 patients presenting with SH with SB content showed signs of SBO on CT. Closed-loop SBO on CT was present in 5 of the 26 patients with SB content. An interstitial SH was observed in all of these 5 patients (p = 0.039). Surgery was performed on 10 patients. Bowel ischemia was found on surgery in 4 patients and showed no statistically significant association with a particular subtype of SH (p = 0.6). CONCLUSION: Our study shows the importance of performing CT in SH. CT provides the diagnosis of SH, shows SH content, and demonstrates the presence of SBO or closed-loop SBO. Moreover, the distinction between the two subtypes of SH on CT appears to be of clinical relevance since closed-loop SBO is statistically associated with interstitial SH and the optimal surgical approach may differ.

[Radiologic response assessment in metastatic colorectal cancers]. / Mesure de la réponse radiologique scannographique des cancers colorectaux métastatiques : état des lieux et perspectives.

The increasing indications of cytostatic biotherapies and the improvement in metastatic surgery have profoundly changed the management of metastatic colorectal cancer (mCRC) patients. Then the development of prognostic and predictive scores would be useful to stratify the treatments. Tumor radiological measurement is crucial to estimate treatment efficacy, and to predict pathological response and survival, and this parameter is included when a prognostic score is developed. But the standard size-based radiologic criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), was designed ten years ago to assess tumor volume reduction after cytotoxic chemotherapy only. Nowadays, this method may be insufficient for mCRC patients. The aim of this review is to describe the different radiological assessments evaluated in mCRC, and to underline their correlations with patient's survival and pathologic response. A better knowledge of these radiological measurements would help to better integrate them in prospective trials, and in the prognostic and predictive scores. The choice of radiological measurement could be discussed regarding patient's situation, combining different approaches, and assessing tumoral mass quantification.

Does IV contrast extravasation on CT in anticoagulant-related rectus sheath and iliopsoas hematoma predict hematoma expansion and patient outcomes?

OBJECTIVE: The purpose of the study was to evaluate if IV contrast extravasation on CT in anticoagulant-related rectus sheath and iliopsoas hematoma predict hematoma expansion and patient outcomes. MATERIALS AND METHODS: All patients presented with anticoagulation-related spontaneous IP hematoma or RS hematoma and who underwent contrast-enhanced CT exploration, with injection of a contrast material, from January 2012 to January 2015 in our institution were included in this study. Considering the retrospective nature of our study, our institutional review board judged our study to be exempted from ethical approval and no patient consent was required. Computed tomography (CT) images were retrospectively analyzed blindly of the evolution and treatment of hematomas. The type of muscle involved; the presence of contrast extravasation after contrast injection; the volume of the hematoma, as well as, clinical and biological results (hemoglobin value g/dL); and for each patient, the type of anticoagulation used, patient's treatment and outcomes were noted. The analyses were conducted using R 3.1.0. All statistical tests were 2-sided, and probability values <0.05 were regarded as significant. RESULTS: Sixty-eight patients were reviewed. Among 68 patients, 44 (65%) patients presented spontaneous IP hematoma and 24/68 (35%) a RS hematoma. There were 37 men (54%) and 31 (46%) women, ranging from 39 to 93 years with a median age of 75 years. Hemodynamic instability was statistically associated with IP hematomas and large volume of hematoma (p < 0.001). Only 15 patients had follow-up CT, 10 without and with IV contrast, 2 with IV contrast only, and 3 without contrast. Follow-up CT was performed from J0 to J8. Detection of contrast extravasation did not appear related to hemodynamically instability (p = 0.35), to a neurological deficit (p = 1), or to the increase in the volume of the hematoma on follow-up CT (p = 0.81). The different types of anticoagulant were not related to muscular type more than the other (p = 0.9). Among anticoagulant therapy, only vitamin K antagonist therapy was statistically associated with surgery (p = 0.04). CONCLUSION: CT extravasation of contrast material in IP and RS hematoma does not appear to be related with clinical criteria of severity, and therefore should not be solely considered as a radiological decision criteria.

Retro-ureteral internal hernia after transperitoneal ureter reimplantation: an unusual cause of small bowel obstruction.

Report of a case of surgically confirmed closed-loop small bowel obstruction due to internal hernia following transperitoneal ureter reimplantation. Multidetector computed tomography (CT) demonstrated the presence and the cause of this unusual postsurgical internal hernia. The CT findings are presented herein.