Trop-2 is a ubiquitous and promising target in pancreatic adenocarcinoma.

BACKGROUND: Trop-2 is overexpressed in tumor cells of various cancers, including pancreatic ductal adenocarcinoma (PDAC), and has emerged as a potent therapeutic target. We evaluated Trop-2 expression both at the transcriptomic and protein levels, and its correlation with tumor features and patients' outcomes in a large cohort of PDAC. METHODS: We included patients undergoing pancreatic resection for PDAC in 5 academic hospitals in France and Belgium. Transcriptomic profiles were obtained from FFPE tissue samples, with paired primary -25and metastatic lesions when available. Protein expression was evaluated by immunohistochemistry (IHC) using tissue micro-arrays. RESULTS: 495 patients (male 54%, median age 63 years) were included between 1996 and 2012. Trop-2 mRNA expression was significantly associated to tumor cellularity, but no association with survival nor with any clinical or pathological features was observed, with tumor cells showing an overall high expression among every subgroup. Trop-2 mRNA expression was maintained between primary and metastatic lesion in all 26 paired samples evaluated. In 50 tumors assessed by IHC, 30%, 68% and 2% harbored a high, medium, or low Trop-2 expression score, respectively. Trop-2 staining was significantly associated to mRNA expression, but not to survival or any pathological features. CONCLUSIONS: Our results suggest Trop-2 overexpression as a ubiquitous marker of PDAC tumor cells and thus a promising therapeutic target to evaluate in these patients.

Tumor budding is an independent prognostic factor in stage III colon cancer patients: a post-hoc analysis of the IDEA-France phase III trial (PRODIGE-GERCOR).

BACKGROUND: Histological characteristics at the invasive front may reflect tumor aggressiveness; specifically, tumor budding (Bd) is an emerging prognostic biomarker in colon cancer (CC). We explored further the significance of Bd for risk stratification by evaluating survival of stage III CC patients included in the IDEA-France phase III trial. PATIENTS AND METHODS: This post-hoc study was conducted on tissue slides from 1048 stage III CC patients. Bd was scored by central review by the Bd criteria of the 2016 International Tumor Budding Consensus Conference (ITBCC 2016) and classified as Bd1 (0-4 buds/0.785 mm2), Bd2 (5-9 buds), and Bd3 (≥10 buds) categories. Disease-free survival (DFS) and overall survival (OS) were analyzed by the log-rank test. Clinicopathological features and Immunoscore® were correlated with Bd. RESULTS: Overall, Bd1, Bd2, and Bd3 were observed in 39%, 28%, and 33% of CC, respectively. Bd2 and Bd3 were associated with vascular (P = 0.002) and perineural invasions (P = 0.0009). The 3-year DFS and the 5-year OS rates for Bd (1 versus 2-3) were 79.4% versus 67.2% (P = 0.001) and 89.2% versus 80.8% (P = 0.001), respectively. This was confirmed after adjustment for relevant clinicopathological features for DFS [hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.12-1.77, P = 0.003] and OS (HR 1.65, 95% CI 1.22-2.22, P = 0.001). When combined with pTN stage and Immunoscore® subgroups, Bd significantly improved disease prognostication. CONCLUSIONS: Bd demonstrated its independent prognostic value for DFS and OS. Given these findings, Bd as per the ITBCC 2016 should be mandatory in every pathology report in stage III CC patients. Bd and Immunoscore® could play a complementary role in personalized health care in this setting.

Relevance of biopsy-derived pancreatic organoids in the development of efficient transcriptomic signatures to predict adjuvant chemosensitivity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients are frequently treated by chemotherapy. Even if personalized therapy based on molecular analysis can be performed for some tumors, PDAC regimens selection is still mainly based on patients' performance status and expected efficacy. Therefore, the establishment of molecular predictors of chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. We have recently developed an RNA-based signature that predicts the efficacy of adjuvant gemcitabine using 38 PDAC primary cell cultures. While demonstrated its efficiency, a significant association with the classical/basal-like PDAC spectrum was observed. We hypothesized that this flaw was due to the basal-like biased phenotype of cellular models used in our strategy. To overcome this limitation, we generated a prospective cohort of 27 consecutive biopsied derived pancreatic organoids (BDPO) and include them in the signature identification strategy. As BDPO's do not have the same biased phenotype as primary cell cultures we expect they can compensate one with each other and cover a broader range of molecular phenotypes. We then obtained an improved signature predicting gemcitabine sensibility that was validated in a cohort of 300 resected PDAC patients that have or have not received adjuvant gemcitabine. We demonstrated a significant association between the improved signature and the overall and disease-free survival in patients predicted as sensitive and treated with adjuvant gemcitabine. We propose then that including BDPO along primary cell cultures represent a powerful strategy that helps to overcome primary cell cultures limitations producing unbiased RNA-based signatures predictive of adjuvant treatments in PDAC.

A transcriptomic signature to predict adjuvant gemcitabine sensitivity in pancreatic adenocarcinoma.

BACKGROUND: Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. PATIENTS AND METHODS: Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated. RESULTS: The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred- (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred-: 91.3 months [95% confidence interval (CI): 61.2-not reached] versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value. CONCLUSION: The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.

Diagnostic of hepatic fibrosis with the XL probe of the Fibroscan versus biopsies in patients candidates to bariatric surgery.

BACKGROUND AND AIMS: The risks of the histological evaluation for metabolic liver disease in severe obese subjects led to the development of the Fibroscan® device. The main objective of our study is to evaluate the diagnostic performance of XL probe for the measurement of hepatic fibrosis compared to histological examination, in obese subjects operated from bariatric surgery. METHODS: We included patients free from chronic liver diseases. Liver measurement and controlled attenuation parameter (CAP) were carried out using the Fibroscan®. Liver biopsies were performed during bariatric surgery and evaluated by two pathologists. Correlation between vibration-controlled transient elastography (VCTE) and fibrosis stage was assessed using the Kendall correlation coefficient. Diagnosis performance was assessed using receiver-operating-characteristic curve analysis together with its 95% confidence interval. Cut-off value maximizing the Youden index was computed together with specificity, sensitivity, positive and negative predictive values. RESULTS: The average age and body mass index were 41 years and 43 kg/m2, respectively (n = 108). Forty-one percent of patients presented fibrosis on the histological results. The Kendall correlation coefficient between fibrosis stage and liver stiffness measurement (LSM) was κ = 0.33, p<10-5. ROC analysis for the detection of fibrosis indicated the following values: 0.70 [0.60-0.79] for F≥1, 0.83 [0.72-0.92] for F≥2, 0.90 [0.83-0.97] for F≥3. Optimal cut-offs maximizing the Youden index were 7.0 kPa for F≥1, 8.1 kPa for F≥2 and 8.7 kPa for F≥3. CONCLUSION: Fibroscan® appears to be reliable for detection of significant and severe fibrosis in severe obese patients such as candidates for bariatric surgery. CLINICAL TRIAL NUMBER: NCT03548597.

[A tularemia mimicking lymphoma]. / Une tularémie mimant un lymphome.

INTRODUCTION: Adenopathies are a frequent cause of recourse in internal medicine. When histological analysis reveals the presence of granuloma, multiple infectious or non-infectious etiologies are considered. If diagnoses of lymphoma, sarcoidosis or tuberculosis are easily mentioned, tularemia should also be considered in the differential diagnosis. OBSERVATION: A 54-year-old patient had a fever at the evening with night sweats and a cough resistant to two lines of antibiotics. A thoraco-abdomino-pelvic CT scan revealed hilar and mediastinal adenopathies that appeared hypermetabolic with PET-TDM, as well as pulmonary nodules. A PCR performed on lymph node biopsy and serology allowed the diagnosis of tularemia. The evolution was favourable after antibiotic treatment. CONCLUSION: The association of fever, night sweats, altered general state and mediastinal adenopathies should be considered as a diagnosis of tularemia. Ganglionic biopsy, combined with molecular biology techniques and serology, can confirm the diagnosis.

Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France PRODIGE-GERCOR cohort study.

BACKGROUND: The Immunoscore (IS), which prognostically classifies stage I-III colon cancer (CC) patients, was evaluated in the International Duration Evaluation of Adjuvant Therapy (IDEA) France cohort study investigating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy in stage III CC patients. PATIENTS AND METHODS: Densities of CD3+ and CD8+ T cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS. Mismatch repair status was determined by immunohistochemistry or by pentaplex PCR. Prediction of disease-free survival (DFS) by IS was analyzed by a multivariable Cox regression model in each study arm. Harrell's C-statistics were used to investigate the IS performance. RESULTS: Samples of 1322 patients were available. IS Low, Intermediate (Int), and High were observed in 43.6%, 47.0%, and 9.4% of patients, respectively. IS Low identified patients at higher risk of relapse or death compared with Int + High [hazard ratio (HR) = 1.54; 95% confidence interval (CI) 1.24-1.93, P = 0.0001]. The 3-year DFS was 66.80% (95% CI 62.23-70.94) for IS Low and 77.14% (95% CI 73.50-80.35) for IS Int + High. In multivariable analysis, IS remained significantly independently associated with DFS (P = 0.003) when adjusted for sex, histological grade, T/N stage, and microsatellite instability. For mFOLFOX6-treated patients (91.6% of the cohort), a statistical significant interaction was observed for the predictive value of IS for treatment duration (3 versus 6 months) in terms of DFS (P = 0.057). IS Int + High significantly predicted benefit of 6 months of treatment (HR = 0.53; 95% CI 0.37-0.75; P = 0.0004), including clinically low- and high-risk stage III CC (all P < 0.001). Conversely, patients with IS Low (46.4%) did not significantly benefit from the 6-month mFOLFOX6 versus the 3-month mFOLFOX6. CONCLUSIONS: The prognostic value of IS for DFS was confirmed in patients with stage III CC treated with oxaliplatin-based chemotherapy. Its predictive value for DFS benefit of longer duration of mFOLFOX6 adjuvant treatment was found in IS Int + High. These results will be validated in an external independent cohort. CLINICALTRIALS. GOV REGISTRATION: NCT03422601; EudraCT Number: 2009-010384-16.

[Use of targeting therapy in Erdheim-Chester disease: A case report with neurologic involvement]. / Utilisation de thérapie ciblée dans la maladie d'Erdheim-Chester : à propos d'un cas avec atteinte du système nerveux central.

INTRODUCTION: Erdheim-Chester disease (ECD) is a rare multisystemic disease characterised by an infiltration of various organs by CD68+ CD1a- histiocytes. The clinical and radiological presentation is very variable. CASE REPORT: We report the case of a 71-year-old woman with ECD which was revealed by neurological and cutaneous manifestations. The diagnosis was confirmed by skin biopsy and the BRAFV600E mutation was identified in skin tissue, leading to the use of combined therapy targeting the RAS-RAF-ERK-MEK pathway. This therapy allowed an improvement of cutaneous manifestations but neurological manifestations lead to death, underlying their notable severity. CONCLUSION: Our case report shows the persistent diagnostic difficulty of the ECD and the particular gravity of neurologic involvement.

Loss of SMARCB1 expression in colon carcinoma.

SMARCB1 is a tumor suppressor gene, which is part of SWI/SNF complex involved in transcriptional regulation. Recently, loss of SMARCB1 expression has been reported in gastrointestinal carcinomas. Our purpose was to evaluate the incidence and prognostic value of SMARCB1 loss in colon carcinoma (CC). Patients with stage III CC (n= 1695), and a second cohort of 23 patients with poorly differentiated CC were analyzed. Immunohistochemistry for SMARCB1 was performed on tissue microarrays, and cases with loss of expression were controlled on whole sections. Loss of SMARCB1 was compared with the clinico-pathological and molecular characteristics, and the prognostic value was evaluated. Loss of SMARCB1 was identified in 12 of 1695 (0.7%) patients with stage III CC. Whole section controls showed a complete loss in only one of these cases, corresponding to a medullary carcinoma. SMARCB1 loss was not associated with histological grade, tumor size nor survival. In the cohort of poorly differentiated CC, we detected 2/23 (8.7%) cases with loss of SMARCB1; one was rhabdoid while the other had medullary and mucinous histology. These 2 cases were deficient for MisMatched Repair (dMMR) and mutated for BRAF. SMARCB1 loss is rare in stage III CC, but appears more frequent in poorly differentiated CC.

Progress towards molecular-based management of childhood Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing abundant CD1a+ CD207+ histiocytes that lead to the destruction of affected tissues. This disease has a remarkable pleiotropic clinical presentation and most commonly affects young children. Although the current mortality rate is very low for childhood LCH patients (<2%), reactivation frequently occurs after a long period of disease control and the rates of permanent complications and sequelae remain high. Advances in genomic sequencing technologies in this past decade have highlighted somatic molecular alterations responsible for the disease in around 80% of childhood LCH cases. More than half of these cases harbored the BRAFV600E mutation, and most other mutations also concerned proteins involved in the MAPKinase pathway. In addition to improving what is known about the LCH pathology, this molecular knowledge provides opportunities to optimize patient management. The BRAFV600E mutation is associated with more severe presentations of the disease, a high reactivation rate, and a high permanent complication rate; this mutation therefore paves the way for future stratified management approaches. These therapies may be based on the patient's molecular status as well as other clinical characteristics of the disease that are independently associated with undesired events. Moreover, as observed in patients with solid tumors, the BRAFV600E allele can be detected in the circulating cell-free DNA of patients with severe BRAFV600E-mutated LCH. Quantification of the plasmatic BRAFV600E load for this group of patients can precisely monitor response to therapy. Finally, targeted therapies, such as BRAF inhibitors, are new therapeutic options especially designed for refractory multisystemic LCH involving risk organs. However, the long-term efficacy, long-term tolerance, optimal protocol scheme, and appropriate modalities of administration for these innovative therapies for children still need to be defined, a huge challenge.

Influence of Molecular Status on Recurrence Site in Patients Treated for a Stage III Colon Cancer: a Post Hoc Analysis of the PETACC-8 Trial.

BACKGROUND: Recurrence patterns in stage III colon cancer (CC) patients according to molecular markers remain unclear. The objective of the study was to assess recurrence patterns according to microsatellite instability (MSI), RAS and BRAFV600E status in stage III CC patients. METHODS: All stage III CC patients from the PETACC-8 randomized trial tested for MSI, RAS and BRAFV600E status were included. The site and characteristics of recurrence were analyzed according to molecular status. Survival after recurrence (SAR) was analyzed. RESULTS: A total of 1650 patients were included. Recurrence occurred in 434 patients (26.3%). Microsatellite stable (MSS) patients had a significantly higher recurrence rate (27.2% vs. 18.7%, P = 0.02) with a trend to more pulmonary recurrence (28.8% vs. 12.9%, P = 0.06) when compared to MSI patients. MSI patients experienced more regional lymph nodes compared to MSS (12.9% vs. 4%, P = 0.046). In the MSS population, the recurrence rate was significantly higher in RAS (32.2%) or BRAF (32.3%) patients when compared to double wild-type patients (19.9%) (p < 0.001); no preferential site of recurrence was observed according to RAS and BRAFV600E mutations. Finally, decreased SAR was observed in the case of peritoneal recurrence or more than two recurrence sites. CONCLUSIONS: Microsatellite, RAS and BRAFV600E status influences recurrence rates in stage III CC patients. However, only microsatellite status seems to be associated with specific recurrence patterns. More than two recurrence sites and recurrence in the peritoneum were associated with poorer SAR.

A case of Erdheim-Chester disease with spinal cord compression and sphenoid sinus involvement.

Erdheim-Chester disease is a rare form of non-Langerhans cell histiocytosis. It is an inflammatory disorder associated with BRAF V600E mutation in 50% of cases. This multisystem disease is rarely associated with spinal involvement. Neurological involvement is an independent predictive factor of poor prognosis. The diagnosis is histopathological based on CD68-positive and CD1A-negative histiocytes. Treatment with interferon-alpha is an independent predictor of survival in Erdheim-Chester disease and vemurafenib has also been shown to be effective for BRAF V600E mutation. We report a clinical case of a 51-year-old patient with multiple and rare locations of Erdheim-Chester disease, particularly at the sphenoid sinus.

[Rosai-Dorfman disease: Diagnosis and therapeutic challenges]. / La maladie de Destombes-Rosai-Dorfman : évolution du concept, classification et prise en charge.

Rosai-Dorfman disease (RDD) was first described by the French pathologist Paul Destombes in 1965. It frequently affects children or young adults and is characterized by the presence of large histiocytes with emperipolesis. More than 50 years after this first description, the pathogenesis of this rare disease is still poorly understood. The revised classification of histiocytoses published in 2016 identified various forms of RDD, from familial RDD to IgG4-associated RDD. Almost 90% of the patients with RDD have cervical lymph nodes involvement although all the organs may virtually be involved. Outcomes are typically favorable. Treatments may be necessary in case of compression or obstruction, and are not well codified. The main therapeutic strategies rely on surgery, radiotherapy, steroids, immunosuppressive drugs or interferon-alpha and cladribine.

FDG-PET-driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study.

Dose-dense induction and up-front consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating patients with high-risk diffuse large B-cell lymphoma. GELA designed a randomized phase 2 trial evaluating the efficacy of either rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP) or rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP14) induction and a positron emission tomography (PET)-driven ASCT or standard immunochemotherapy (SIC) consolidation in age-adjusted international prognosis index 2 (aaIPI2)-aaIPI3 patients. PET was performed at baseline, after 2 (PET2) and 4 (PET4) induction cycles, and centrally assessed using international harmonization project (IHP) criteria. PET2-/PET4- patients were assigned SIC, PET2+/PET4- patients were assigned ASCT, and PET4+ patients were treated with the investigator's choice. The primary end-point was the 2007 international working group complete response (CR) rate after induction. Change in maximum standard uptake value (ΔSUVmax) after PET assessment was explored. Two hundred eleven patients were randomly assigned to R-ACVBP (n = 109) or R-CHOP14 (n = 102). PET4-/CR rates were 53%/47% with R-ACVBP and 41%/39% with R-CHOP14 (CR 95% confidence interval [CI], 38%-67% and 28%-54%, respectively; P = .076). Consolidation in the R-ACVBP and R-CHOP14 groups was SIC in 26% and 23% of patients and ASCT in 28% and 18% of patients, respectively. PET4 positivity was higher with R-CHOP14 vs R-ACVBP (54% vs 41%; P = .08), leading to more salvage therapy (37% vs 26%; P = .07) and lower event-free survival (EFS; 4-year EFS, 31% vs 43%; P < .01), but progression-free survival (PFS) and overall survival (OS) were similar in both groups. PET2-/PET4- and PET2+/PET4- patients had similar outcomes. Using ΔSUVmax, 79% of the patients were PET2-/PET4- ΔSUVmaxPET0-4 >70% was associated with better outcome (4-year PFS, 84% vs 35%; 4-year OS, 91% vs 57%; P < .0001), whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established, as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing an alternative to SIC, including ASCT.

Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies.

BACKGROUND: Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy. PATIENTS AND METHODS: We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed. RESULTS: We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P=0.003), but not to FOLFOX (P=0.911) and FOLFIRI + Bevacizumab (P=0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months). CONCLUSIONS: Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial.

French updated recommendations in Stage I to III melanoma treatment and management.

As knowledge continues to develop, regular updates are necessary concerning recommendations for practice. The recommendations for the management of melanoma stages I to III were drawn up in 2005. At the request of the Société Française de Dermatologie, they have now been updated using the methodology for recommendations proposed by the Haute Autorité de Santé in France. In practice, the principal recommendations are as follows: for staging, it is recommended that the 7th edition of AJCC be used. The maximum excision margins have been reduced to 2 cm. Regarding adjuvant therapy, the place of interferon has been reduced and no validated emerging medication has yet been identified. Radiotherapy may be considered for patients in Stage III at high risk of relapse. The sentinel lymph node technique remains an option. Initial examination includes routine ultrasound as of Stage II, with other examinations being optional in stages IIC and III. A shorter strict follow-up period (3 years) is recommended for patients, but with greater emphasis on imaging.

[Langerhans cell histiocytosis and Erdheim-Chester disease, a continuity?] / Histiocytose langerhansienne et maladie d'Erdheim-Chester, une continuité ?

INTRODUCTION: Erdheim-Chester disease and langerhans cell histiocytosis are two rare diseases separate on clinical, radiological and histological aspects. However, several cases involving both entities have been described. OBSERVATION: A 70-year-old man had a central diabetes insipidus, xanthelasmas, retroperitoneal fibrosis and osteosclerosis of the legs suggestive of Erdheim-Chester disease. Bone biopsy showed langerhans cell histiocytosis CD1a positive with the presence of BRAF V600E mutation. The patient was treated with vemurafenib with a good clinical course. CONCLUSION: The literature review finds forty observations linking the two diseases that may suggest a pathophysiological link, especially with the hematopoietic myeloid stem cell CD34+. The term inflammatory myeloid neoplasm was advanced.