Initial experience of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in a French hyperthermic intraperitoneal chemotherapy (HIPEC) expert center.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new intraabdominal technique to approach non-resectable peritoneal carcinomatosis (PC). PIPAC can be performed alone or alternated with systemic chemotherapy to increase tumor regression. We describe our initial experience performed in an expert hyperthermic intraperitoneal chemotherapy (HIPEC) French center to demonstrate the safety and the feasibility of PIPAC. METHODS: Between January 2016 and March 2019, PIPAC was proposed to 43 consecutive patients affected by digestive, ovarian, peritoneal and mammary carcinomatosis. Initially PIPAC was proposed to patients non eligible for cytoreductive surgery for palliative purposes. In five patients we associated PIPAC to systemic chemotherapy to improve tumor regression and enhance the chance of patients to undergo HIPEC. Three PIPAC treatments were supposed to be performed for each patient with an interval of 6 weeks in between each procedure. Peritoneal biopsies were always performed to evaluate microscopic tumor regression. In case of postoperative clinical deterioration or quick tumor progression during the cycles, PIPAC was interrupted. Depending on the primary tumor, chemotherapies used were oxaliplatin or a combination of cisplatin and doxorubicin. RESULTS: Twenty-six (60.4%) patients have already had a surgical resection or intervention of primary cancer removal. In 5 patients abdominal access was impossible. Of the 38 patients operated, seventy-one procedures were performed. In the series, one patient died because of tumor progression. Only one major complication occurred intraoperatively. Two of thirteen patients receiving oxaliplatin had postoperative abdominal pain and needed more drugs assumption and a longer hospitalization. Three patients after a three cycles procedure underwent HIPEC. Nine of the patients who had at least two PIPACs had last biopsies showing a major or complete tumor response. CONCLUSION: PIPAC is a safe and feasible procedure that can be performed in patients with peritoneal carcinomatosis initially not eligible for surgery to reduce tumor invasion or for palliation to reduce symptoms. Contraindications are bowel obstruction and multiple intraabdominal adhesions.

Assessing the benefit of the 72-hour antibiotic therapy reassessment documentation.

OBJECTIVES: To assess the documentation of the 72-hour antibiotic therapy reassessment in medical records. METHODS: One-day prevalence evaluation of curative antibiotic therapies≥72hours. The documentation of the reassessment was defined according to three criteria: (1) "clear" documentation (clinical or microbiological comment associated with a comment on the need to adjust the antibiotic therapy or on the lack of need); (2) "tacit" documentation (only based on a clinical or microbiological comment); (3) no documentation. RESULTS: We assessed 114 antibiotic therapies in 26 hospital departments. A clear reassessment at 72hours was observed in only 45 (39%) records and 31 (27%) records had no reassessment. The planned duration of treatment was written in 63 (55%) records. At 72hours, among the 71 antibiotic therapies with a microbiological documentation, 69 (97%) were active and 44 (62%) had a narrow spectrum. Among the 48 antibiotic therapies with a broad spectrum on day 1, only 21 (44%) benefited from a de-escalation at 72hours. A clearly recorded reassessment at 72hours was associated with de-escalation (P=0.025) and the prescription of a planned duration of treatment was associated with antibiotic therapy compliance with local or national guidelines (P=0.018). CONCLUSION: Although reassessment was observed in 73% of records, it was correctly recorded at 72hours in only 39% of cases. The documentation of the reassessment and the prescription of a planned duration were associated with a better quality of antibiotic prescription (de-escalation, compliance with guidelines) and are relevant indicators for monitoring the proper use of antibiotics.

Papillomavirus genotyping on formaldehyde fixed paraffin-embedded tissues in vulvar intraepithelial neoplasia.

PURPOSE: Few studies have described the epidemiology of human papillomavirus (HPV) in vulvar intraepithelial neoplasia (VIN). The aim of this study was to genotype HPV on formalin fixed paraffin-embedded tissues in VIN lesions. METHODS: A 5-year retrospective study was conducted by including all patients attending the teaching hospital of Nice with a diagnosis of VIN between 1st January 2010 and 31st December 2014. For all patients, HPV genotyping was performed with the PapilloCheck® microarray kit, routinely used on cervical cytology samples, and optimized for formaldehyde fixed paraffin-embedded tissues in VIN. RESULTS: Forty patients were included in the study: 39 patients had usual VIN and one presented with differentiated VIN. Among the 39 patients with usual VIN, the prevalence of HPV was 90% (35/39). Thirty-two patients had high grade VIN (82%) and seven low grade VIN (18%). In high grade VIN, the most represented HPV types were: HPV 16 (21/32 66%), HPV 56 (3/32 9%) and HPV 33 (2/32 6%). In low grade VIN, the most represented HPV types were: HPV 16 (4/7 57%) and HPV 6 (3/7 43%). Interestingly, 5/39 (13%) of patients diagnosed with usual VIN also had co-existing lichen sclerosus. CONCLUSIONS: We have optimized a HPV genotyping technique, routinely used on cervical cytology samples, and on paraffin fixed embedded tissue showing VIN. Moreover, we have identified five patients with lichen sclerosus co-existing with usual VIN. This association has rarely been reported and proves that these two entities can coexist.

[Lymphedema of the lower limbs: Initial manifestation of gastric linitis plastica]. / Lymphœdème des membres inférieurs révélant une linite gastrique.

BACKGROUND: Primary lymphedemas are constitutional abnormalities of the lymphatic system. Secondary lymphedemas occur after damage to the lymphatic system, mainly after cancer treatments or tumour mass compression. There are many other causes, including filariasis, which is nonetheless very rare in France. PATIENTS AND METHODS: A 52-year-old man presented with a two-month history of increased size of the left leg. He was asymptomatic and in good general condition. Clinical examination revealed non-pitting lymphedema and ipsilateral hydrocele without loco-regional compressive lymph node. Initial extensive explorations were unremarkable. Lymphoscintigraphy revealed low tracer fixation in the left leg. The symptoms continued to worsen, with exacerbation and bilateralization of the lymphedema. Two months later, axillary lymph nodes appeared corresponding to metastasis from a signet-ring cell carcinoma. Despite two lines of chemotherapy, the patient died 8 months later due to multiple metastatic disease. DISCUSSION: Our case is remarkable because the lymphedema was not related to extrinsic compression and was the first symptom of gastric cancer. In the absence of compression, endo-lymphatic micro-metastases could constitute the causative process. Acquired lymphedema of the lower limbs must be recognized as a potential early symptom of gastric carcinoma and should therefore prompt further investigations.

[Clinical pharmacist influence at hospital to prevent overdosed prescription of acetaminophen]. / Impact du pharmacien clinicien à l'hôpital pour prévenir les posologies supra-thérapeutiques du paracétamol.

OBJECTIVES: The recommended daily dose of acetaminophen is limited to 60mg/kg/day with a maximum of 3g daily dose in adults weighing less than 50kg or in patients undergoing certain risk factors. This study aimed at assessing the fulfillment of those recommendations and the possible impact on the liver dysfunction at supra-therapeutic doses of acetaminophen. METHODS: This study was performed one day in 9 services. Patients characteristics, acetaminophen dose, daily dose administered, physiopathological aspects, markers of liver damage were collected. RESULTS: Among 542 prescriptions analyzed, 343 of them contained acetaminophen. The median age of patients studied was 81 years and one third weighed less than 50kg. The main risk factor of supra-therapeutic prescriptions was the lack of dose acetaminophen based on weight with 14% patients concerned and this risk raised at 17% when the pathophysiological conditions were included. The presence of pharmacists in medicals departments was more effective than the use of informatics programs limiting the dose systematically to 3g/day, or a distant pharmaceutical validation from care services to reduce the risk of acetaminophen overdose. According to the statement of administrations, only 4 of 49 patients received doses above 60mg/kg/day with a low impact on liver function tests. CONCLUSION: The continuous presence in pharmaceutical care services was the most effective measure to ensure effective implementation of acetaminophen recommendations.

[Distribution of human papillomavirus genotypes amongst HIV-negative and HIV-positive women diagnosed with ASC-US cytology. Preliminary data of a local retrospective study]. / Répartition des génotypes de papillomavirus humain dans les frottis ASC-US de patientes infectées ou non par le VIH-1. Résultats préliminaires d'une enquête rétrospective locale.

OBJECTIVES: Analysis of the distribution of human papillomavirus (HPV) genotypes amongst HIV-negative and HIV-positive women diagnosed with atypical squamous cells of undetermined significance (ASC-US). PATIENTS AND METHODS: We performed a retrospective study of HPV genotype distribution in 313 ASC-US Pap smears from women who consulted at the University Hospital of Nice between 2008 and 2012. HPV genotyping results, conducted on PapilloCheck(®) HPV DNA Chip, and information on the status of HIV patients were retrospectively collected. The odds ratio were calculated by logistic regression. RESULTS: In co-infected HIV/HPV women we observed a low prevalence of HPV16, a high prevalence of oncogenic HPV low risk and a high prevalence of HPV 68 compared to non-co-infected women. By grouping HPV HR based on their prevalence in cervical cancer of the uterus and their genetic proximity we observe that HPV 18, 45, 68 (the "alpha-7") are 7.4 times more represented (CI95 [2.48 to 22.35]) than HPV 16, 31, 33, 52, 58 (the "alpha-9") in the population of women co-infected with HIV. DISCUSSION AND CONCLUSION: Given that HPV "alpha-7" are responsible for 46.3% of adenocarcinomas, the high prevalence of these HPV found in ASC-US Pap smears of co-infected women should be put in relation with the highest prevalence of glandular abnormalities found in this population. HPV genotyping could become an essential tool for gynecological care for HIV positive women.

Bronchogenic cyst of the tongue in an infant.

Bronchogenic cyst of the tongue is rare. We report the case of a 17-month baby who has a lingual lesion. MRI shows a well-defined cystic lesion. Treatment consisted of a complete resection and histology found a pseudostratified respiratory type epithelium. Only 10 pediatric cases of bronchogenic cyst of the tongue have been reported in the literature. MRI is the imaging modality of choice and treatment is always surgical. The final diagnosis is made by histology.

[Post-menopausal ovarian hyperthecosis]. / Hyperthécose ovarienne post-ménopausique.

Ovarian hyperthecosis is infrequent but it represents the first cause of post-menopausal hyperandrogenia. Pathophysiology of ovarian hyperthecosis remains poorly understood but the metabolic syndrome observed in most patients suggests that insulin resistance associated with high, postmenopausal LH levels, might play a role as in polycystic ovarian syndrome. We report here four patients who presented post-menopausal hyperandrogenia. Although high, tumoral, plasma testosterone levels, lack of focused radiological lesions except enlarged ovaries, associated to the metabolic syndrome, suggested ovarian hyperthecosis. Bilateral annexectomy allowed histological confirmation of hyperthecosis showing specific luteinized stromal cells and led to the complete suppression of the inappropriate androgen secretion.

Melanotic neuroectodermal tumor of infancy: case report and review of the literature.

Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a rare but distinct neoplastic entity in infancy. Diagnosis is usually made before the age of 12 months. The common clinical presentation is a rapidly growing mass of the pre-maxillary area. Its surface is unevenly pigmented. To affirm the diagnosis a biopsy is necessary. Few cases of malignancy have been described (5% of cases). Adequate surgical excision is the treatment of choice. Recurrence rate is about 10 to 15% within 5 years. We report in this article the case of a newborn with MNTI illustrating that an R0 surgical excision can be correlated to a favourable prognosis. In this case the 5 years follow up didn't show any local or distant recurrence.

Adrenocortical incidentaloma with uncertain prognosis associated with an inadequately treated congenital adrenal hyperplasia.

Large adrenal tumors are rarely associated with adrenal enzymatic deficiency, except in 11-ss-hydroxylase insufficiency. These tumors are exceptionally malignant. We report here the case of a patient with a congenital 21-hydroxylase deficiency (compound heterozygote for two severe mutations in the CYP21A2 gene) untreated for 20 years. His evaluation at 36 years of age showed a four-centimeter mass in the left adrenal gland, with most characteristics suggestive of malignancy (CT and positron emission tomography [PET] scan). We performed a surgical resection that established the diagnosis of adrenocortical tumor of uncertain prognosis (Weiss's score: 3). Even though malignant tumors are unusual in adrenal deficiency, our observation shows the need for a replacement therapy during adulthood, with a regular CT scan follow up in order to diagnose early isolated adrenal adenoma and remove it in case of malignancy suspicion.

Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity.

Aryl hydrocarbon receptor (AhR), or dioxin receptor, is a transcription factor that induces adaptive metabolic pathways in response to environmental pollutants. Recently, other pathways were found to be altered by AhR and its ligands. Indeed, developmental defects elicited by AhR ligands suggest that additional cellular functions may be targeted by this receptor, including cell migration and plasticity. Here, we show that dioxin-mediated activation of Ahr induces Nedd9/Hef1/Cas-L, a member of the Cas protein family recently identified as a metastasis marker. The Hef1 gene induction is mediated by two xenobiotic responsive elements present in this gene promoter. Moreover, using RNA interference, we show that Nedd9/Hef1/Cas-L mediates the dioxin-elicited changes related to cell plasticity, including alterations of cellular adhesion and shape, cytoskeleton reorganization, and increased cell migration. Furthermore, we show that both E-cadherin repression and Jun N-terminal kinases activation by dioxin and AhR also depend on the expression of Nedd9/Hef1/Cas-L. Our study unveils, for the first time, a link between pollutants exposure and the induced expression of a metastasis marker and shows that cellular migration and plasticity markers are regulated by AhR and its toxic ligands.

Adrenal tuberculosis after a pheochromocytoma: a misleading tumoral presentation.

Adrenal gland involvement could account for 6% of active tuberculosis. The diagnosis of this extrapulmonary form of tuberculosis is difficult, especially when presenting as unilateral adrenal tumor. This report describes an unusual case of adrenal tuberculosis presenting as a tumor occurring shortly after surgical removal of an adrenal pheochromocytoma located in the opposite gland, in a 63-year-old woman with a previous history of breast cancer. At initial presentation, the patient suffered from symptomatic paroxysmal hypertension. A pheochromocytoma in the left adrenal was diagnosed and resected. One year later, while physical examination and biological parameters were unremarkable, an enhanced adrenal computed tomography (CT) scan showed a right adrenal mass mimicking the CT features of the resected pheochromocytoma. A peripheral tissular rim delineating a central hypodensity characterized this tumor. Magnetic resonance imaging (MRI) showed the same findings on gadolinium-enhanced T1-weighted slices, while the mass was not seen on T2-weighted images. No tumoral signal loss was observed on out of phase images when using the in phase-out of phase T1-weighted sequence. Because of the tumoral evolution and the uncertainty of the nature of that lesion, the patient underwent a second adrenalectomy. Definitive diagnosis was provided by culture of tissue sample, which resulted in the identification of Mycobacterium tuberculosis. In an era of tuberculosis resurgence, this unusual case underscores the necessity of keeping in mind adrenal tuberculosis as a possible differential diagnosis in adrenal tumors of uncertainty nature. It stresses the importance of culture of biopsy tumor, whenever feasible, to avoid unnecessary operations. In the near future, interferon-gamma assay could be a valuable means to recognize extrapulmonary forms of tuberculosis.

[Prescribing guidance pocket chart on the initiation of warfarin therapy in a geriatric hospital: a useful but challenging tool]. / Diffusion d'une fiche d'aide à la prescription pour l'initiation d'un traitement par warfarine dans un hôpital gériatrique: intérêt et difficultés de mise en place.

Elderly patients are at high risk of over-anticoagulation and of haemorrhagic risk when on warfarin, especially during treatment induction. In Charles Foix Hospital, a 800-bed geriatric hospital, we specifically developed for in-patients older than 70 years (target INR 2.5) a simple low-dose warfarin induction regimen. The dosing recommendations were summarized on a prescribing guidance pocket chart. Eighteen months after the distribution of the chart, we conducted a one-year observational study in order to evaluate: i/ the time needed to achieve the warfarin maintenance dose; ii/ the prescriber'adherence to the recommendations; iii/ the benefit for elderly patients receiving warfarin therapy. The mean time needed to achieve the warfarin maintenance dose was 12.3 +/- 7.0 days for the 89 patients included in the study: 10.6 +/- 5.9 days for the 30 patients whose prescribers followed the recommendations versus 13.5 +/- 7.6 days for the 59 patients whose prescribers did not follow the recommendations. There is a trend to a more frequent over-anticoagulation in patients whose prescribers did not follow the recommendations. The duration of the heparin-warfarin overlap was significantly shorter when the recommendations were followed. Finally, the reasons for non-adherence to the recommendations were analyzed. This study illustrates an assessment of practice in an health care institution.

Genetic and environmental factors influencing first service conception rate and late embryonic/foetal mortality in low fertility dairy herds.

The objective of this study was to identify factors affecting variation in conception rate to first artificial inseminations (AI) (CR: number of pregnant cows on D80-100/inseminated cows) and the incidence of embryonic/foetal loss (LEM) between 21 and 80 days of pregnancy (number of cows non-pregnant on D80-100/pregnant on D21) in 44 low fertility dairy herds of the west-central region of France. Reproductive status was assessed using progesterone milk concentration on D0 = Day of AI and D21-24, plasma PSPB concentration on D30-35, rectal palpation on D80-100 and observed return to oestrous. The final data set contained 1285 Prim'Holstein cows, 5.0% (64/1285) were inseminated in the luteal phase (progesterone > or = 3 ng/ml on D0), 61.3% (787/1285) were pregnant on D21-24 (progesterone < 3 ng/ml on D0 and > or = 5 ng/ml on D21-24), 15.4% lost their embryo/foetus between D21-24 and D80-100 (198/1285) and 45.8% (589/1285) were pregnant on D80-100. The incidence of late embryonic/foetal loss (LEM) was 25.2% (198/787). Multivariate logistic regression models including the random herd effect were used to analyse the relationship between AI centre, AI sire, cow's sire, parity, interval between calving and AI, milk production, milk protein content, body condition score (BCS) on D0, season of calving, season of AI, estimated genetic index on CR and LEM incidence. CR was significantly related to parity (p < 0.05), milk production after calving (p < 0.05) and estimated genetic value (p < 0.01). A significant difference in CR was observed for calving to AI interval > or = 70 days versus > or = 90 days, but the overall effect of the interval was not significant (p = 0.11). LEM incidence was affected by period of AI (p < 0.05), milk production (p < 0.05) and BCS (p < 0.05), but was not related to estimated genetic index. In conclusion, in these low fertility herds, the incidence of LEM was high and 25% of the cows lost their embryo after 21 days of pregnancy. LEM was affected by specific factors (season, BCS), which were not related to CR. The absence of a relationship between estimated genetic index and LEM in spite of its effect on CR indicates that estimated genetic merit has a greater effect on early embryonic loss or fertilisation failure than on later stages of embryo development.

Mutations within the MGC4607 gene cause cerebral cavernous malformations.

Cerebral cavernous malformations (CCM) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and focal neurological deficits due to cerebral hemorrhages. CCM loci have already been assigned to chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3) and have been identified in 40%, 20%, and 40%, respectively, of families with CCM. Loss-of-function mutations have been identified in CCM1/KRIT1, the sole CCM gene identified to date. We report here the identification of MGC4607 as the CCM2 gene. We first reduced the size of the CCM2 interval from 22 cM to 7.5 cM by genetic linkage analysis. We then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions, such as tuberous sclerosis or neurofibromatosis. We performed a high-density microsatellite genotyping of this 7.5-cM interval to search for putative null alleles in 30 unrelated families, and we identified, in 2 unrelated families, null alleles that were the result of deletions within a 350-kb interval flanked by markers D7S478 and D7S621. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these two distinct deletions overlapped and that both of the two deleted the first exon of MGC4607, a known gene of unknown function. In both families, one of the two MGC4607 transcripts was not detected. We then identified eight additional point mutations within MGC4607 in eight of the remaining families. One of them led to the alteration of the initiation codon and five of them to a premature termination codon, including one nonsense, one frameshift, and three splice-site mutations. All these mutations cosegregated with the disease in the families and were not observed in 192 control chromosomes. MGC4607 is so far unrelated to any known gene family. Its implication in CCMs strongly suggests that it is a new player in vascular morphogenesis.

[Practical approach to usual rheumatologic and traumatic diseases in elderly patients]. / Approche pratique des affections rhumatologiques et traumatiques courantes du sujet âgé

Rheumatologic and traumatic pathology is particularly important in elderly patients because it may compromise autonomy. The severity of the loss of autonomy is variable and it may be temporary or permanent. Therefore rapid and suitable care is necessary, old age in itself being an emergency factor. The purpose of this article is to develop an approach that based on presenting symptoms such as pain, mild or severe disability, or a modification of behavior in an elderly patient will enable:--to correctly evaluate the clinical findings which will guide the imaging--to not exclude a traumatic origin even if it doesn't seem obvious--to adapt the radiological examinations depending on the therapeutic possibilities--to demonstrate that plain radiographs are usually sufficient--to not deny access to CT or MRI systematically on the basis of old age. Knowledge of specific geriatric issues and correlation with imaging findings will usually improve the quality and quantity of life of elderly patients.