Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy to Treat Pseudomyxoma Peritonei of Ovarian Origin: A Retrospective French RENAPE Group Study.

BACKGROUND: Ovarian pseudomyxoma peritonei (OPMP) are rare, without well-defined therapeutic guidelines. We aimed to evaluate cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) to treat OPMP. METHODS: Patients from the French National Network for Rare Peritoneal Tumors (RENAPE) database with proven OPMP treated by CRS/HIPEC and with histologically normal appendix and digestive endoscopy were retrospectively included. Clinical and follow-up data were collected. Histopathological and immunohistochemical features were reviewed. RESULTS: Fifteen patients with a median age of 56 years were included. The median Peritoneal Cancer Index was 16. Following CRS, the completeness of cytoreduction (CC) score was CC-0 for 9/15 (60%) patients, CC-1 for 5/15 (33.3%) patients, and CC-2 for 1/15 (6.7%) patients. The median tumor size was 22.5 cm. After pathological review and immunohistochemical studies, tumors were classified as Group 1 (mucinous ovarian epithelial neoplasms) in 3/15 (20%) patients; Group 2 (mucinous neoplasm in ovarian teratoma) in 4/15 (26.7%) patients; Group 3 (mucinous neoplasm probably arising in ovarian teratoma) in 5/15 (33.3%) patients; and Group 4 (non-specific group) in 3/15 (20%) patients. Peritoneal lesions were OPMP pM1a/acellular, pM1b/grade 1 (hypocellular) and pM1b/grade 3 (signet-ring cells) in 13/15 (86.7%), 1/15 (6.7%) and 1/15 (6.7%) patients, respectively. Disease-free survival analysis showed a difference (p = 0.0463) between OPMP with teratoma/likely-teratoma origin (groups 2 and 3; 100% at 1, 5, and 10 years), and other groups (groups 1 and 4; 100%, 66.6%, and 50% at 1, 5, and 10 years, respectively). CONCLUSION: These results suggested that a primary therapeutic strategy using complete CRS/HIPEC for patients with OPMP led to favorable long-term outcomes.

5-hmC loss is another useful tool in addition to BAP1 and MTAP immunostains to distinguish diffuse malignant peritoneal mesothelioma from reactive mesothelial hyperplasia in peritoneal cytology cell-blocks and biopsies.

The differentiation between reactive mesothelial hyperplasia (RMH) and diffuse malignant peritoneal mesothelioma (DMPM) is challenging especially when applied on peritoneal small samples. The use of BRCA-associated protein 1 (BAP1) and methylthioadenosine phosphorylase (MTAP) immunostains is familiar to identify malignant mesothelial proliferation. Recently, nuclear 5-hydroxymethylcytosine (5-hmC) was reported to be a new recognition tool of pleural mesothelial malignancy on surgical specimens. However, application of 5-hmC immunostaining has not yet studied in peritoneal specimens from small biopsies or cytology cell-blocks. The aim was to assess the diagnostic accuracy of this new marker combination to distinguish DMPM from RMH in biopsies and cell-blocks. Seventy-five cases were analyzed; among which, 38 were of cytological specimens including 6 RMH and 32 DMPM, and 37 tissue biopsies with 7 RMH and 30 DMPM. BAP1, MTAP, and 5-hmC immunostains were performed on all cases. RMH cases exhibited a retained staining with all immunostains. Among DMPM, BAP1 was lost in 71.8% of cytology cell-blocks and 66.7% of biopsies. MTAP was lost in 40.6% of cytology cell-blocks and 33.3% of biopsies. 5-hmC was lost in 40.6% of cytology cell-blocks and 30% of biopsies. The combination of BAP1, MTAP, and 5-hmC showed the best accuracy in differential diagnosis between RMH and DMPM (sensitivity = 0.84, specificity = 1 in cytology cell-blocks; sensitivity = 0.90, specificity = 1 in biopsy). The best diagnostic combination in peritoneal cytology effusion fluids and biopsies samples provided by BAP1, MTAP, and 5-hmC should be applied on a diagnostic step-wise algorithm by pathologists involved into the management of DMPM, because of their therapeutic implications.

Combined grade and nuclear grade are prognosis predictors of epithelioid malignant peritoneal mesothelioma: a multi-institutional retrospective study.

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant peritoneal mesothelioma. A recently described nuclear-grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The present study was undertaken to validate this grading system in epithelioid malignant peritoneal mesothelioma (EMPM) and to compare to combined grade, including nuclear atypia, mitotic count, and tumor necrosis. Cases of EMPM, from 1995 to 2018, were analyzed from 7 French institutions from RENAPE network. Solid growth, tumor necrosis, nuclear atypia, and mitotic count were evaluated by at least 3 pathologists from the RENAPATH group. The predictions in terms of OS and PFS of nuclear grade and combined grade were analyzed. Nuclear grade was computed combining nuclear atypia score and mitotic count into a grade of I-III. Another system combining nuclear atypia score, mitotic score, and tumor necrosis was evaluated and defined as a combined grade I-III. A total of 138 cases were identified. The median follow-up was 38.9 months (range: 1.1-196.6). Nuclear and combined grades III were independently associated with a shorter OS (p < 0.05), and a shorter PFS (p < 0.05). Patients with combined grade I tumors had the best overall and progression-free survivals, in comparison to nuclear grade I. In this large multicentric study, combined grade and nuclear grade were the best independent predictors of OS and PFS in EMPM. These systems should be easily described by pathologists involved into the management of malignant peritoneal mesothelioma, because of their potential therapeutic implications.

Tertiary lymphoid structures in epithelioid malignant peritoneal mesothelioma are associated with neoadjuvant chemotherapy, but not with prognosis.

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant peritoneal mesothelioma. The relationship between a strong adaptive immune response and a better prognosis in malignant solid tumors is widely known. Due to the low incidence of epithelioid malignant peritoneal mesothelioma (EMPM), very little is known about their immune micro-environment. We encountered several cases of tertiary lymphoid structures in EMPM in a previous study and aimed to investigate in the same series the prevalence, clinicopathological features, and the prognostic impact associated with tertiary lymphoid structures in EMPM (TLS-EMPM). Cases of EMPM, from 1995 to 2018, were retrieved from 7 French institutions from the RENAPE Network. The predictions in terms of overall survival (OS) and progression-free survival (PFS) of TLS-EMPM were analyzed. We report 52 cases of TLS-EMPM among a series of 138 cases of EMPM. TLS-EMPM was significantly associated with neoadjuvant chemotherapy, and was not a prognostic indicator for OS (p = 0.652) and PFS (p = 0.804) in our series. TLS is a component of the host immune response to EMPM significantly associated with neoadjuvant chemotherapy, but was not a predictor of prognosis for overall and progression-free survivals in this series. These findings provide another possible etiology for tertiary lymphoid structures.

Sarcoidosis: A Clinical Overview from Symptoms to Diagnosis.

Sarcoidosis is a multi-system disease of unknown etiology characterized by the formation of granulomas in various organs. It affects people of all ethnic backgrounds and occurs at any time of life but is more frequent in African Americans and Scandinavians and in adults between 30 and 50 years of age. Sarcoidosis can affect any organ with a frequency varying according to ethnicity, sex and age. Intrathoracic involvement occurs in 90% of patients with symmetrical bilateral hilar adenopathy and/or diffuse lung micronodules, mainly along the lymphatic structures which are the most affected system. Among extrapulmonary manifestations, skin lesions, uveitis, liver or splenic involvement, peripheral and abdominal lymphadenopathy and peripheral arthritis are the most frequent with a prevalence of 25-50%. Finally, cardiac and neurological manifestations which can be the initial manifestation of sarcoidosis, as can be bilateral parotitis, nasosinusal or laryngeal signs, hypercalcemia and renal dysfunction, affect less than 10% of patients. The diagnosis is not standardized but is based on three major criteria: a compatible clinical and/or radiological presentation, the histological evidence of non-necrotizing granulomatous inflammation in one or more tissues and the exclusion of alternative causes of granulomatous disease. Certain clinical features are considered to be highly specific of the disease (e.g., Löfgren's syndrome, lupus pernio, Heerfordt's syndrome) and do not require histological confirmation. New diagnostic guidelines were recently published. Specific clinical criteria have been developed for the diagnosis of cardiac, neurological and ocular sarcoidosis. This article focuses on the clinical presentation and the common differentials that need to be considered when appropriate.

Risk of Omental Metastases in Patients Undergoing Cytoreductive Surgery for Colorectal Peritoneal Metastases.

BACKGROUND: Complete cytoreductive surgery of macroscopic tumor is a potentially curative treatment for patients with colorectal peritoneal metastases. OBJECTIVE: This study aims to determine the risk of microscopic tumor involvement of the greater omentum in patients with normal-looking omentum at the time of cytoreductive surgery for colorectal peritoneal metastases. DESIGN: This was a cohort study. SETTINGS: The prospective BIG-RENAPE database (NCT02823860) was analyzed. PATIENTS: All patients who underwent a complete cytoreductive surgery with greater omentectomy for colorectal peritoneal metastases at a single institution between January 2005 and December 2017 were included. MAIN OUTCOME MEASURE: Data regarding involvement of the greater omentum were extracted from surgical and pathological records. RESULTS: Of 337 patients who underwent cytoreductive surgery for colorectal peritoneal metastases, 241 (71.51%) presented macroscopic omental invasion. Among the 96 patients who underwent a complete cytoreductive surgery with no macroscopic evidence of disease in the greater omentum during surgical exploration, 17 patients (17.70%) had microscopic evidence of tumor in the omentum. Patients with pathological evidence of omental tumor involvement were more likely to have a higher peritoneal cancer index (median 9 vs 4, p = 0.006). LIMITATIONS: No survival analysis could be provided regarding the impact of omentectomy. CONCLUSION: In patients with a normal-looking omentum during surgery for colorectal peritoneal metastases, microscopic tumor was present in 17%. Routine greater omentectomy should be considered in these patients to ensure complete cytoreduction. See Video Abstract at http://links.lww.com/DCR/B262.ClinicalTrials.gov Identifier: NCT02823860 RIESGO DE METÁSTASIS OMENTALES EN PACIENTES SOMETIDOS A CIRUGÍA CITORREDUCTORA, POR METÁSTASIS PERITONEALES COLORRECTALES: La cirugía citorreductora completa del tumor macroscópico, es un tratamiento potencialmente curativo, en pacientes con metástasis peritoneales colorrectales.Determinar el riesgo de afectación tumoral microscópica del epiplón mayor, en pacientes con epiplón de aspecto normal, al momento de la cirugía citorreductora por metástasis peritoneales colorrectales.Este fue un estudio de cohorte.Se analizó la base de datos prospectiva BIG-RENAPE (NCT02823860).Se incluyeron a todos los pacientes sometidos a una cirugía citorreductora completa con omentectomía mayor, por metástasis peritoneales colorrectales, de una sola institución, entre enero de 2005 y diciembre de 2017.Se extrajeron los datos de la afectación del epiplón mayor, de los registros quirúrgicos y patológicos.De 337 pacientes sometidos a cirugía citorreductora por metástasis peritoneales colorrectales, 241 (71.51%) presentaron invasión omental macroscópica. Entre los 96 pacientes sometidos a cirugía citorreductora completa, sin evidencia macroscópica de enfermedad en el epiplón mayor, durante la exploración quirúrgica, 17 pacientes (17,70%) tuvieron en el epiplón, evidencia microscópica de tumor. Los pacientes con evidencia patológica de afectación del tumor omental, fueron más propensos a tener un índice de cáncer peritoneal más alto (mediana 9 frente a 4, p = 0,006).No se pudo obtener ningún análisis de supervivencia, sobre el impacto de la omentectomía.En pacientes con epiplón de aspecto normal, durante la cirugía por metástasis peritoneales colorrectales, estuvo presente el tumor microscópico, en el 17% de los casos. Se debe considerar una omentectomía mayor de rutina en estos pacientes, para asegurar una citorreducción completa. Consulte Video Resumen http://links.lww.com/DCR/B262.Identificador de ClinicalTrials.gov: NCT02823860.

Frequency of MET exon 14 skipping mutations in non-small cell lung cancer according to technical approach in routine diagnosis: results from a real-life cohort of 2,369 patients.

BACKGROUND: Mesenchymal epithelial transition receptor (MET) alterations, including MET exon 14 skipping mutation, are oncogenic in non-small cell lung cancer (NSCLC) and may confer sensitivity to targeted therapy. Given the rarity and the diversity of exon 14 skipping mutations, diagnosis may be challenging on small-biopsy specimens. METHODS: Between March 2014 and May 2018, tissue samples from patients with metastatic NSCLC were analysed for MET exon 14 skipping mutation as part of routine practice in the Pathology Department of the Hospices Civils de Lyon, France. Over the study period, Sanger sequencing and/or two different DNA-based next generation sequencing (NGS) assays were used. RESULTS: Genomic alterations of MET exon 14 were detected in 2.6% (62/2,369) samples of NSCLC analysed for MET exon 14 mutations. Patients were mainly women (38/62, 61%) without smoking history (22/39, 56%) and the median age was 75 years. MET exon 14 skipping mutations were diagnosed by NGS in 50 cases and by classical Sanger sequencing in 12 cases. The frequency of MET mutations was 15.4% when Sanger sequencing was performed at the request of the clinician and 4.1% when the DNA-based NGS assay coverage included the 3' and 5' parts of the MET exon 14 and performed systematically. CONCLUSIONS: The frequency of genomic alterations is highly dependent on patient selection and the technical approach.

The Pathologic Peritoneal Cancer Index (PCI) Strongly Differs From the Surgical PCI in Peritoneal Metastases Arising From Various Primary Tumors.

BACKGROUND: The surgical peritoneal cancer index (sPCI) is calculated based on a subjective evaluation of the extent of peritoneal disease during surgery. The pathologic PCI (pPCI) may be a more accurate and objective method for determining the PCI. This study aimed to compare the sPCI and pPCI and to study the potential pitfalls and clinical implications of using the pPCI. METHODS: This prospective study (July to December 2018) included all patients undergoing cytoreductive surgery (CRS). The pPCI was calculated for each patient and compared with the sPCI. The impact of potential confounding factors on the difference between pPCI and sPCI was evaluated. RESULTS: Among 191 patients undergoing CRS at four centers, the pPCI and sPCI were concordant for 37 patients (19.3%). The pPCI was lower than the sPCI for 125 patients (65.4%) and higher for 29 patients (15.1%). The concordance between the two groups was maximum for gastric cancer (38.8%) and colorectal cancer (27.6%) and least for mesothelioma (6.7%) and rare primary tumors (5.6%) (p = 0.04). The difference was 0 to 3 points for 119 patients (62.3%), 4 to 5 points for 27 patients (14.1%), and more than 5 points for 45 patients (23.5%). The rate of concordance was not influenced by the use of neoadjuvant chemotherapy (NACT) (p = 0.4), but the difference was greater when NACT was used (p = 0.03). CONCLUSIONS: The pPCI strongly differs from the sPCI for patients undergoing CRS for peritoneal disease and may provide a more accurate evaluation of the peritoneal disease extent. Further studies are needed to determine its prognostic value compared with sPCI, and consensus guidelines are needed for calculating it.

Prognostic impact of combined progression index based on peritoneal grading regression score and peritoneal cytology in peritoneal metastasis.

AIMS: The peritoneal regression grading score (PRGS) and peritoneal cytology (PC) assess response to chemotherapy in peritoneal metastasis (PM) in a setting of palliative treatment by pressurized intraperitoneal aerosol chemotherapy (PIPAC). Progression has been defined as an increase of PRGS between first and third PIPAC procedures (iPRGS). iPRGSand positive peritoneal cytology were not associated with prognostic impact. These results may be explained by a lack of statistical power. Also, it is not known whether the mean or the highest PRGS among taken peritoneal biopsies bears the highest clinical value. We therefore conducted the largest prospective study to investigate the prognostic impact of PGRS, PC, and their combination, designated as combined progression index (CPI). METHODS AND RESULTS: Patients with PM who underwent >3 PIPAC (n = 112) between December 2016 and February 2019 were prospectively included. A significant difference in OS and PFS according to CPI (used highest value of PRGS) was found (OS: CPI-, 83.3, 95% CI [49.8; NA] vs. CPI+, 48.1, 95% CI [38.5; 66.4] months; and PFS (respectively, 59.7, 95% CI [43.0; 96.0] vs. 33.7, 95% CI [30.4; 44.2] months). PRGS or PC had no independent prognostic impact. CPI+ was an independent predictor of worse prognosis, in OS (HR = 5.24, 95% CI [2.07; 13.26]), and PFS (HR = 4.41, 95% CI [1.40; 13.88]). CONCLUSIONS: The CPI based on highest PRGS and PC was found to be independently associated with a worse prognosis for OS and for PFS in the setting of peritoneal metastasis. These results indicate that it should be of interest to systematically take peritoneal fluid for cytological examination and to implement the CPI in the therapeutic decision-making process in the context of PIPAC.

Bone decalcification to assess programmed cell death ligand 1 expression in bone metastases of non-small cell lung cancers.

As for molecular alterations of lung adenocarcinoma, it is critical that pathologists are able to give PD-L1 expression status before first-line of treatment. The present study compared PD-L1 expression (clone 22-C3) in decalcified using EDTA or formic acid and non-decalcified lung cancer metastases bone samples. Amongst the 84 bone samples analysed for PD-L1 expression, and independently of decalcification, TPS ≥ 1% was 25.0% and ≥ 50% was 11.4%. There was no significant difference between decalcified samples (n = 45) and non-decalcified samples (n = 39) for both TPS ≥ 1% (p = 0.32) and TPS ≥ 50% (p = 1). To conclude, we confirm decalcified bone metastasis specimens may be used for PD-L1 IHC in routine practice. These results also highlight potentially interesting specificities of the bone microenvironment that should be further studied.

Rapid detection of EGFR mutations in decalcified lung cancer bone metastasis.

Detection of molecular alterations in lung cancer bone metastasis (LCBM) is particularly difficult when decalcification procedure is needed. The Idylla™ real-time (RT)-PCR is compared to the routine method used in our laboratory, which combines next generation and Sanger sequencing, for the detection of EGFR mutations in LCBM. LCBM subjected to EDTA or formic acid decalcification were analysed for EGFR mutational status using two methods: first, the Ion Torrent Ampliseq next generation sequencing (NGS) assay +/- Sanger sequencing was used prospectively; then, the fully-automated, RT-PCR based molecular testing system Idylla™ EGFR Mutation Test was applied retrospectively. Out of the 34 LCBM assayed, 14 (41.2%) were unsuitable for NGS analysis and five remained unsuitable after additional Sanger EGFR sequencing (5/34, 14.7%). Using Idylla™, valid results were observed for 33/34 samples (97.1%). The concordance between the NGS +/- Sanger sequencing method and the RT-PCR method was 89.7% (26/29), one false positive EGFR S768I mutation and two false negative results were observed using Idylla™; one of these false negative cases was diagnosed by Sanger sequencing with a rare exon 19 EGFR mutation not covered by the Idylla™ EGFR Mutation Test design. Detection of EGFR mutations in decalcified LCBM is challenging using NGS, more than half of samples showing invalid results. Alternative methods should thus be preferred to spare clinical samples and decrease delay. The Idylla™ EGFR Mutation Test shows a good performance on decalcified bone samples and could be used as a first step. In case of negative results, a sequencing approach is mandatory to check the presence of rare EGFR mutations sensitive to EGFR tyrosine kinase inhibitors.

The value of BRCA-1-associated protein 1 expression and cyclin-dependent kinase inhibitor 2A deletion to distinguish peritoneal malignant mesothelioma from peritoneal location of carcinoma in effusion cytology specimens.

OBJECTIVE: Diffuse malignant peritoneal mesothelioma (DMPM), represents 30% of all malignant mesothelioma, and is characterised by a difficult diagnosis and different presentations. Immunohistochemistry has improved the diagnostic sensitivity and specificity in the differential diagnosis between metastatic adenocarcinoma and malignant mesothelioma, and loss of BRCA-1-associated protein 1 (BAP1) expression is correlated with BAP1 somatic or constitutional genetic defects. Furthermore, cyclin-dependent kinase inhibitor 2A (CDKN2A) is frequently lost in DMPM. In the present study, we assessed the value of integrating BAP1 in the panel of antibodies used for the diagnosis of DMPM in cytological samples. Since p16 fluorescent in situ hybridisation (FISH) assay could constitute an additional useful adjunct, results of BAP1 immunostaining and p16 FISH assays have been compared. METHODS: Forty-eight DMPM patients and 71 peritoneal carcinomatosis patients were included. BAP1 immunohistochemical and CDKN2A FISH techniques were performed on tissue specimens of DMPM (n = 48) and peritoneal carcinomatosis (n = 71) then on cell-block of DMPM (n = 16), peritoneal carcinomatosis (n = 25) and peritoneal benign effusion (n = 5). RESULTS: Loss of BAP1 expression was observed in 56.3% of DMPM while none of the peritoneal carcinoma specimens showed BAP1 loss of expression. CDKN2A loss was observed in 34.9% DMPM and 2.1% peritoneal carcinoma. Although BAP1 immunostaining was successful in 100% of cytological DMPM samples, CDKN2A deletion status could be obtained for 75% of DMPM cases. CONCLUSION: BAP1 immunostaining represents an objective and reproducible diagnostic biomarker for peritoneal mesothelioma in effusion cytology specimens and should be preferred to CDKN2A FISH analysis on these precious samples.

Pathological assessment of cytoreductive surgery specimens and its unexplored prognostic potential-a prospective multi-centric study.

BACKGROUND AND AIM: The grade/histological subtype is one of the most important prognostic markers in patients undergoing cytoreductive surgery (CRS). Our aim was to study other potential prognostic information that can be derived from the pathological evaluation of CRS specimens and provide a broad outline for evaluation of these. METHODS: This prospective study (July to December 2018) included all patients undergoing cytoreductive surgery (CRS). A protocol for pathological evaluation was laid down which was based on existing practices at the participating centers and included evaluation of the pathological PCI, regional node involvement, response to chemotherapy, morphology of peritoneal metastases (PM) and distribution in the peritoneal cavity. RESULTS: In 191 patients undergoing CRS at 4 centers, the pathological and surgical PCI differed in over 75%. Nodes in relation to peritoneal disease were positive in 13.6%. Disease in normal peritoneum adjacent to tumor nodules was seen in >50% patients with ovarian cancer and mucinous apppendiceal tumors. 23.8% of evaluated colorectal PM patients had a complete response and 25.0% ovarian cancer patients had a near complete pathological response to chemotherapy. CONCLUSIONS: Pathological evaluation of extent and distribution of peritoneal disease differs from the surgical evaluation in majority of the patients. Lymph node involvement in relation of peritoneal disease is common. The morphological presentation of PM in ovarian cancer and mucinous appendiceal tumors merits evaluation of more extensive resections in these patients. Standardized methods of synoptic reporting of CRS specimens could help capture vital prognostic information that may in future influence how these patients are treated.

Osteoclast-Derived Autotaxin, a Distinguishing Factor for Inflammatory Bone Loss.

OBJECTIVE: The severity of rheumatoid arthritis (RA) correlates directly with bone erosions arising from osteoclast (OC) hyperactivity. Despite the fact that inflammation may be controlled in patients with RA, those in a state of sustained clinical remission or low disease activity may continue to accrue erosions, which supports the need for treatments that would be suitable for long-lasting inhibition of OC activity without altering the physiologic function of OCs in bone remodeling. Autotaxin (ATX) contributes to inflammation, but its role in bone erosion is unknown. METHODS: ATX was targeted by inhibitory treatment with pharmacologic drugs and also by conditional inactivation of the ATX gene Ennp2 in murine OCs (ΔATXC tsk ). Arthritic and erosive diseases were studied in human tumor necrosis factor-transgenic (hTNF+/- ) mice and mice with K/BxN serum transfer-induced arthritis. Systemic bone loss was also analyzed in mice with lipopolysaccharide (LPS)-induced inflammation and estrogen deprivation. Joint inflammation and bone erosion were assessed by histology and micro-computed tomography. The role of ATX in RA was also examined in OC differentiation and activity assays. RESULTS: OCs present at sites of inflammation overexpressed ATX. Pharmacologic inhibition of ATX in hTNF+/- mice, as compared to vehicle-treated controls, significantly mitigated focal bone erosion (36% decrease; P < 0.05) and systemic bone loss (43% decrease; P < 0.05), without affecting synovial inflammation. OC-derived ATX was revealed to be instrumental in OC bone resorptive activity and was up-regulated by the inflammation elicited in the presence of TNF or LPS. Specific loss of ATX in OCs from mice subjected to ovariectomy significantly protected against the systemic bone loss and erosion that had been induced with LPS and K/BxN serum treatments (30% reversal of systemic bone loss [P < 0.01]; 55% reversal of erosion [P < 0.001]), without conferring bone-protective properties. CONCLUSION: Our results identify ATX as a novel OC factor that specifically controls inflammation-induced bone erosions and systemic bone loss. Therefore, ATX inhibition offers a novel therapeutic approach for potentially preventing bone erosion in patients with RA.

Acute Renal Colic Due to Immunoglobulin Free Light Chain Kidney Stones: A Case Report of an Unusual Complication of Multiple Myeloma.

Kidney failure is common in patients with a monoclonal gammopathy, most frequently due to hypercalcemia or myeloma cast nephropathy. Immunoglobulin crystallization is an uncommon phenomenon that also results in kidney injury. We report the case of a 74-year-old man with recurrent renal colic and acute kidney injury. He presented with κ light chain Bence-Jones proteinuria, hypogammaglobulinemia, anemia, and high plasma κ light chain level, leading to the diagnosis of κ light chain multiple myeloma. One calculus was collected and its analysis revealed a unique protein structure consisting of κ immunoglobulin free light chain. Genetic sequencing of the κ light chain identified a subgroup of variable domain previously identified as prone to crystallization. Eight cycles of cyclophosphamide-bortezomib-dexamethasone chemotherapy resulted in a partial hematologic response and kidney recovery without recurrence of renal colic. This rare case of urinary light chain nephrolithiasis highlights the importance of genetic and molecular analysis of the immunoglobulin variable domain to better understand the wide spectrum of monoclonal gammopathies.

The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinomas and pseudomyxoma peritonei.

The vermiform appendix is the primary site of several distinctive benign and malignant neoplasms. Some can produce the clinical syndrome of pseudomyxoma peritonei (PMP). A consensus on their terminology was reached by an international panel of pathologists and clinicians working under the auspices of the Peritoneal Surface Oncology Group International (PSOGI), and this review discusses the application of the PSOGI classification to routine reporting. We discuss diagnosis and differential diagnosis together with implications for patient management, covering low-grade appendiceal mucinous neoplasms, high-grade appendiceal mucinous neoplasms, serrated polyps, adenomas and adenocarcinomas. We do not cover goblet cell tumours or neuroendocrine neoplasms in this paper.

The role of 18F-FDG-PET/ceCT in peritoneal mesothelioma.

PURPOSE: The aim of this study was to assess glucose metabolism of multicystic peritoneal mesothelioma and epithelioid peritoneal mesothelioma by fluorine-18 fluorodeoxyglucose (F-FDG)-PET/contrast-enhanced computed tomography (ceCT) and to assess its prognostic impact. MATERIALS AND METHODS: Twenty-three (14 women) patients, without previous treatment, underwent F-FDG-PET/ceCT before peritoneal mesothelioma cytoreductive surgery and intraperitoneal chemotherapy. F-FDG-PET/ceCT was interpreted prospectively as positive or negative. Maximum standardized uptake value (SUVmax) of each lesion was measured retrospectively on the basis of postsurgery data. At laparotomy, disease extension was estimated with the Peritoneal Cancer Index. The median follow-up was 27 months (95% confidence interval: 12.9-37.8); progression-free survival (PFS) was recorded. RESULTS: Nine patients were affected by multicystic and 14 were affected by epithelioid peritoneal mesothelioma. PET showed mild focal uptake in one case of multicystic peritoneal mesothelioma, whereas in eight patients, no abnormal uptake was observed. PET was positive in 12/14 patients with epithelioid peritoneal mesothelioma. Sensitivity, specificity and accuracy were respectively 86, 89 and 87%; the qualitative assessment was statistically different (P=0.0020, χ). Multicystic peritoneal mesothelioma histology was significantly associated with lower SUVmaxlesion (P=0.0061), SUVmaxlesion/liver (P=0.0025), Peritoneal Cancer Index, younger age, and it was observed only in women.Recurrence was observed on nine patients affected by epithelioid peritoneal mesothelioma, whereas no recurrences were observed among multicystic peritoneal mesothelioma patients. SUVmaxlesion (P=0.0278) and age (P=0.0241) were significantly associated with PFS in patients with epithelioid peritoneal mesothelioma. CONCLUSION: F-FDG-PET/ceCT showed significant differences between multicystic and epithelioid peritoneal mesothelioma, whereas SUVmaxlesion was associated with PFS in the latter. Although multicentre prospective studies are necessary, F-FDG-PET/ceCT appears to be a promising tool in patients affected by peritoneal mesothelioma.

BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas.

INTRODUCTION: Malignant mesothelioma is a deadly disease that is strongly associated with asbestos exposure. Peritoneal mesotheliomas account for 10% of all the cases. BRCA1 associated protein 1 (BAP1) is a deubiquitinating hydrolase that plays a key role in various cellular processes. Germline and somatic inactivation of BRCA1 associated protein 1 gene (BAP1) is frequent in pleural mesothelioma; however, little is known about its status in peritoneal mesothelioma. METHODS: Taking advantage of the extensive French National Network for the Diagnosis of Malignant Pleural Mesothelioma and Rare Peritoneal Tumors and the French National Network for the Treatment of Rare Peritoneal Surface Malignancies, we collected biological material and clinical and epidemiological data for 46 patients with peritoneal mesothelioma. The status of BAP1 was evaluated at the mutational and protein expression levels and combined with our previous data on copy number alterations assessed in the same samples. RESULTS: We detected mutations in 32% of the malignant peritoneal mesotheliomas analyzed. In addition, we have previously reported that copy number losses occurred in 42% of the samples included in this series. Overall, 73% of the malignant peritoneal mesotheliomas analyzed carried at least one inactivated BAP1 allele, but only 57% had a complete loss of its protein nuclear expression. Better overall survival was observed for patients with BAP1 mutations (p = 0.04), protein expression loss (p = 0.016), or at least one of these alterations (p = 0.007) independently of tumor histological subtype, age, and sex. CONCLUSIONS: As in pleural mesothelioma, inactivation of BAP1 is frequent in peritoneal mesotheliomas. We found that BAP1 protein nuclear expression is a good prognostic factor and a more reliable marker for the complete loss of BAP1 activity than mutation or copy number loss.

Genomic copy number alterations in 33 malignant peritoneal mesothelioma analyzed by comparative genomic hybridization array.

Malignant peritoneal mesotheliomas (MPM) are rare, accounting for approximately 8% of cases of mesothelioma in France. We performed comparative genomic hybridization (CGH) on frozen MPM samples using the Agilent Human Genome CGH 180 K array. Samples were taken from a total of 33 French patients, comprising 20 men and 13 women with a mean (range) age of 58.4 (17-76) years. Asbestos exposure was reported in 8 patients (24.2%). Median (range) overall survival (OS) was 39 (0-119) months. CGH analysis demonstrated the presence of chromosomal instability in patients with MPM, with a genomic pattern that was similar to that described for pleural mesothelioma, including the loss of chromosomal regions 3p21, 9p21, and 22q12. In addition, novel genomic copy number alterations were identified, including the 15q26.2 region and the 8p11.22 region. Median OS was associated with a low peritoneal cancer index (P=.011), epithelioid subtype (P=.038), and a low number of genomic aberrations (P=.015), all of which constitute good prognostic factors for MPM. Our results provide new insights into the genetic and genomic background of MPM. Although pleural and peritoneal mesotheliomas have different risk factors, different therapeutics, and different prognosis; these data provide support to combine pleural and peritoneal mesothelioma in same clinical assays.