Evolution of bone metastases in patients receiving at least three months of checkpoint inhibitors.

BACKGROUND: To investigate the evolution of bone metastases in patients receiving immune checkpoint inhibitors (ICI). METHODS: A single-center retrospective study included cancer patients with bone metastases treated with ICI at our institution between January 2014 and September 2019. Clinical and biological data were collected from medical records and independent expert review of imaging was performed. Target and non-target lesions were identified and followed up to 1 year. Patients were then classified as bone responder or non-responder. Comparisons between groups were performed with Student's t test or Mann-Whitney test. RESULTS: Among 1108 patients screened, 192 patients had bone metastases and 48 patients were included in the final analysis, with lung cancer, renal carcinoma and melanoma as most represented cancer type. Half of the patients experienced stability, condensation or peripheral sclerosis of bone lesions. Initial progression before stabilization with or without sclerosis of bone lesion occurred for 19% of patients (pseudoprogression). There was an association between bone response and global oncological outcomes. Bone responder patients had a significant decrease in morphine and co-analgesic prescription as well as a significant decrease in alkaline phosphatases compared to non-responder patients. CONCLUSION: Bone response was observed in half of patients with available imaging and follow-up after 3 months of ICI treatment, with sclerosis observed in one-third of bone lesions at month 3, in all tumor types. Up to 20% of patients experienced a pseudoprogression of bone lesions such as previously described in primary tumor and other metastatic sites. Bone response was associated with improvement of pain and survival.

[Aggressive tumor progression during immunosuppressive therapy with abatacept]. / Une progression tumorale fulgurante sous abatacept.

INTRODUCTION: Co-stimulatory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibits T-cell activation. Clinically, CTLA-4 has been targeted in opposite ways: its blockade enhances antitumor immunity in the field of oncology, whereas CTLA-4 agonists such as abatacept are used for the treatment of immuno-inflammatory diseases as rheumatoid arthritis (RA). OBSERVATION: We herein report the case of a 69-year-old man with a history of severe RA successfully treated with abatacept, who showed unusually rapid progression of undifferentiated multi-metastatic carcinoma. DISCUSSION: Although no significant increase in malignancy has been reported in abatacept-treated patients, several case reports have documented the possible association with the acceleration of the progression of malignancy. Here, abatacept may have altered immune surveillance and hence allowed tumor growth.

[Carbon dioxide laser treatment of genital intraepithelial neoplasia: A retrospective study]. / Traitement des néoplasies intraépithéliales génitales par laser CO2 : étude rétrospective.

INTRODUCTION: Genital intraepithelial neoplasias (IEN) are precursors of squamous cell carcinoma. The ideal treatment must be efficacious, conservative and well-tolerated. CO2 laser is one of the recommended therapies, but its efficacy and safety have not been extensively studied. PATIENTS AND METHODS: This was a retrospective single-center study. Sixteen patients (8 women and 8 men) treated with CO2 laser for genital IEN, whether high-grade or differentiated, were included. Surgical lateral margins of 3 to 5mm were taken macroscopically during treatment. The CO2 laser session, assessment of therapeutic response and follow-up were undertaken by a dermatologist at the University Hospital of Caen. RESULTS: The mean patient age was 68.1 years and mean follow-up was 52.7 months (5-130). Lesions were isolated in 87.5% of patients. The recurrence rates of genital intraepithelial neoplasia after CO2 laser treatment were 58% for women and 40% for men. No impact on quality of life or on sexual activity was reported in over 90% of patients. CONCLUSION: Whatever the treatment recommended for intraepithelial neoplasia, recurrence is frequent. CO2 laser is an effective and well-tolerated conservative therapeutic option. It enables rapid clinical remission, but as with all currently available treatments, long-term dermatologic follow-up remains necessary.

Whole-Genome Shotgun Sequence of Bacillus amyloliquefaciens Strain UASWS BA1, a Bacterium Antagonistic to Plant Pathogenic Fungi.

We report here the whole-genome shotgun sequence of Bacillus amyloliquefaciens strain UASWS BA1, isolated from inner wood tissues of a decaying Platanus × acerifolia tree. This strain proved to be antagonistic to several plant pathogenic fungi and oomycetes and can be developed as a biological control agent in agriculture.

Dilemmas caused by endogenous pararetroviruses regarding the taxonomy and diagnosis of yam (Dioscorea spp.) badnaviruses: analyses to support safe germplasm movement.

The discovery of endogenous pararetroviral sequences (EPRVs) has had a deep impact on the approaches needed for diagnosis, taxonomy, safe movement of germplasm and management of diseases caused by pararetroviruses. In this article, we illustrate this through the example of yam (Dioscorea spp.) badnaviruses. To enable progress, it is first necessary to clarify the taxonomical status of yam badnavirus sequences. Phylogeny and pairwise sequence comparison of 121 yam partial reverse transcriptase sequences provided strong support for the identification of 12 yam badnavirus species, of which ten have not been previously named. Virus prevalence data were obtained, and they support the presence of EPRVs in D. rotundata, but not in D. praehensilis, D. abyssinica, D. alata or D. trifida. Five yam badnavirus species characterised by a wide host range seem to be of African origin. Seven other yam badnavirus species with a limited host range are probably of Asian-Pacific origin. Recombination under natural circumstances appears to be rare. Average values of nucleotide intra-species genetic distances are comparable to data obtained for other RNA and DNA virus families. The dispersion scenarios proposed here, combined with the fact that host-switching events appear common for some yam badnaviruses, suggest that the risks linked to introduction via international plant material exchanges are high.

First Report of Pythium intermedium Causing Root Rot on Rosa canina Rootstock in France.

Old cultivars of roses (Rosa spp.) established on Rosa canina as rootstock are grown in field collections in the repository at Gaillard in eastern France, close to the Swiss border. During June 2005 and July 2006, several rose plants in full vegetation were severely wilted, leading ultimately to plant death. Necrotic lesions were present on the roots, and marginal tissue was excised and incubated in the dark at 20°C on PARP V8 agar plates (1). Similar isolates were obtained in both years, which were inoculated within 4 days on V8 agar medium and incubated at 25°C. The pathogen colonies grew approximately 30 mm daily on V8 agar. Colonies on corn meal agar (CMA) (1) were submerged, with or without a vague radiate pattern on potato carrot agar. Main hyphae were as much as 7 µm wide. Sporangia and zoospores were not produced. Hyphal swellings as much as 25 µm in diameter were abundant, terminal, and sometimes intercalary, often forming regular, dense chains in basipetal succession at hyphal tips and readily liberated. The morphological characters matched those described for Pythium intermedium (2). DNA sequencing of the ITS rDNA (ITS1, ITS2, and 5.8S rDNA) was generated using primers ITS5 and ITS4 in primary PCR (35 cycles: 96°C for 1 min, 55°C for 1 min, and 72°C for 2 min) and sequencing reactions (1). All isolates yielded identical ITS sequences, which were identical to the ex-type strain of P. intermedium, CBS 266.38 (GenBank Accession No. AY598647). The ITS sequence was deposited as GenBank Accession No. EF078693 (National Center for Biotechnology Information, NCBI, Bethesda, MD). Pathogenicity testing was performed on 3-year-old Rosa canina rootstocks from clonal propagation in 25 cm in diameter and 40 cm deep pots of compost 297 (Ricoter, Aarberg, Switzerland). Five-day-old mycelial plugs of our isolates grown on CMA (1) were inoculated in two pots, and roots were mechanically wounded. Sterile plugs were used on two control plants set aside. All plants were kept for 2 weeks at 20°C in a glasshouse with sufficient watering. Extensive necrotic lesions developed on inoculated roots, and severe wilting and leaves drying out were also observed. The controls showed no symptoms. P. intermedium was reisolated from margins of root lesions, thus fulfilling the postulates of Koch. P. intermedium was originally isolated from dead plant material (2) but is known as a typical soil inhabitant. It also has been isolated from water and living material from numerous plant species, but never from the genus Rosa until now. To our knowledge, this is the first record of P. intermedium on Rosa spp. grafted on Rosa canina in France. References: (1) L. Belbahri et al. FEMS Microbiol Lett 255:209, 2006. (2) A. J. van der Plaats-Niterink. Stud. Mycol. 21:1, 1981.

Multiple origins of cultivated grapevine (Vitis vinifera L. ssp. sativa) based on chloroplast DNA polymorphisms.

The domestication of the Eurasian grape (Vitis vinifera ssp. sativa) from its wild ancestor (Vitis vinifera ssp. sylvestris) has long been claimed to have occurred in Transcaucasia where its greatest genetic diversity is found and where very early archaeological evidence, including grape pips and artefacts of a 'wine culture', have been excavated. Whether from Transcaucasia or the nearby Taurus or Zagros Mountains, it is hypothesized that this wine culture spread southwards and eventually westwards around the Mediterranean basin, together with the transplantation of cultivated grape cuttings. However, the existence of morphological differentiation between cultivars from eastern and western ends of the modern distribution of the Eurasian grape suggests the existence of different genetic contribution from local sylvestris populations or multilocal selection and domestication of sylvestris genotypes. To tackle this issue, we analysed chlorotype variation and distribution in 1201 samples of sylvestris and sativa genotypes from the whole area of the species' distribution and studied their genetic relationships. The results suggest the existence of at least two important origins for the cultivated germplasm, one in the Near East and another in the western Mediterranean region, the latter of which gave rise to many of the current Western European cultivars. Indeed, over 70% of the Iberian Peninsula cultivars display chlorotypes that are only compatible with their having derived from western sylvestris populations.

First Report of Downy Mildew on Greenhouse and Landscape Coleus Caused by a Peronospora sp. in Louisiana and New York.

In May 2005, two commercial greenhouse flower growers, one in Louisiana (LA) and one in New York (NY), submitted coleus, Solenostemon scutellarioides (L.) Codd, plants for diagnosis after observing stunted growth, inward curling and twisting of leaves, and leaf abscission on multiple cultivars. Downy mildew-like growth was observable with hand lens or a microscope on the abaxial leaf surfaces of affected plants. Irregular necrotic spotting was present on some, but not all, plants on which sporulation was evident. Microscopic examination of LA material led to tentative identification of the pathogen as Peronospora lamii A. Braun (2). The pale brown conidia ranged from 17 to 26 × 15 to 26 µm (average 23 × 19 µm). Conidiophores ranged from 345 to 561 × 9 to 15 µm. No oospores were found. Additional coleus plants with downy mildew were subsequently found in three retail nurseries in LA in early summer. In NY, infected coleus plants were observed in landscapes in Farmington, Rochester, Ithaca, and in two commercial greenhouses between August and October 2005. NY samples sent to the USDA/APHIS in Beltsville, MD were examined, and the fungus was found to have morphology consistent with P. lamii. Two pathogenicity trials were conducted in NY. Conidia were rubbed from an infected coleus leaf onto the leaves of six healthy potted coleus plants of five cultivars and two basil plants that were placed in a shaded plastic tent in the greenhouse where temperatures ranged from 17 to 22°C. A household humidifier was used to supply mist inside the tent for 5 h per day. Six noninoculated plants of each coleus cultivar and two basil plants, placed in the same environment, served as controls. Downy mildew sporulation and some curling and twisting of leaves were observed 14 days after inoculation on all inoculated plants for three of the five cultivars (Florida Rustic Orange, Aurora Peach, and Aurora Mocha). Cvs. Florida Sun Rose and Lava showed no symptoms or signs of downy mildew. An irregularly shaped brown lesion developed on one inoculated basil leaf, and downy mildew sporulation was evident on the abaxial surface 35 days after inoculation. All noninoculated control plants remained disease free. In a second trial, conidia were rinsed from infected coleus leaves and sprayed onto the abaxial leaf surfaces of three coleus cv. Aurora Mocha plants. Three noninoculated plants served as controls and all were placed in a humidity tent. Leaf twisting and downy mildew sporulation were observed 13 days later on all inoculated plants, and control plants showed no sporulation or symptoms. A downy mildew causing disease of greenhouse-grown basil in Europe, originally identified as P. lamii on the basis of morphology, has recently been reported to be taxonomically distinguishable from P. lamii when tested by molecular methods (1). ITS sequences of coleus downy mildew from NY and LA were nearly identical (99% homology) to those of basil downy mildew from Switzerland and Italy (1). To our knowledge, this is the first report of downy mildew occurrence on coleus. References: (1) L. Belbahri et al. Mycol. Res. 109:1276, 2005. (2) S. M. Francis. Peronospora lamii. Descriptions of Pathogenic Fungi and Bacteria. No. 688. CMI, Kew, England, 1981.

A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up.

BACKGROUND AND AIMS: Mutant tumour derived DNA has been detected in the sera of colorectal cancer patients. We investigated if mutant serum KRAS2 was detectable preoperatively in a large group of patients with colorectal neoplasia. A prospective study of 94 patients who underwent putative curative resection for colorectal carcinoma (CRC) was performed to ascertain if serum mutant KRAS2 could be used postoperatively as a disease marker. METHODS: Preoperative sera from 78 patients were analysed (group A). Sera from 94 patients were obtained three monthly for up to three years during the postoperative period (group B). Codon 12 and 13 KRAS2 mutations were analysed in matched tumour and serum samples. RESULTS: In the preoperative group (group A), KRAS2 mutation was found in 41/78 (53%) tumours and in 32/78 (41%) preoperative sera. Of 41 tumour KRAS2 mutation positive cases, 31/41 (76%) had an identical serum mutation detectable. In group B, the postoperative follow up group, 60/94 cases were primary tumour KRAS2 mutation positive. Of these 60, 16/60 (27%) became persistently serum mutant KRAS2 positive postoperatively. Ten of 16 (63%) of these developed a recurrence compared with only 1/44 (2%) patients who remained serum mutant negative (odds ratio 71.7 (95% confidence interval 7.7-663.9; p=0.0000). None of 34 tumour mutation negative cases became serum mutant KRAS2 positive postoperatively, despite recurrence in 9/34 patients. The relative hazard of disease recurrence in postoperative serum mutant KRAS2 positive patients was 6.37 (2.26-18.0; p=0.000). CONCLUSIONS: Serum mutant KRAS2 can be detected preoperatively in all stages of colorectal neoplasia. Postoperatively, serum mutant KRAS2 is a strong predictor of disease recurrence, stronger even than Dukes' stage of disease, and thus shows potential for use in clinical practice as a marker of preclinical disease recurrence.

[Epidemiology of childhood asthma in the department of Calvados]. / Epidémiologie de l'asthme infantile dans le département du Calvados.

A survey was conducted in 1707 sixth grade school children in the Calvados department of France. A self-administered questionnaire was filled out by the children in the presence of a school nurse. The cumulative prevalence of asthma was 14.9%. There was no significant difference between children living in urban or rural areas. There was however a significant difference by sex: 18% of the boys had asthma and 11% of the girls. The cumulative prevalence of wheezing was 25.4% (current prevalence 12.9%). The current prevalence of dry nocturnal cough, respiratory infections excluded, was 33.3%; that of exercise-induced asthma, 27%. Severity was evaluated on the basis of the number of wheezing episodes since the beginning of the school year (> 3 episodes: 4.5%), the number of awakenings at night per week (several per week: 2.2%), and aggravations severe enough to bother speech (4.3%). The rate of missed school days was 18.5% and that of asthma-related hospitalization 1.8%. One asthmatic child out of 4 had undergone pulmonary function tests and 1 out of 2 had a specific treatment for asthma. The high prevalence of childhood asthma in Calvados, with high morbidity, a significant number of missed school days, the exceptional nature of satisfactory pulmonary function testing, and the inconsistency of specific treatments, emphasizes the need for educational programs for parents and their family and improved physician training.

K-ras mutations are found in DNA extracted from the plasma of patients with colorectal cancer.

BACKGROUND & AIMS: Circulating DNA can be isolated from the plasma of healthy subjects and from patients with cancer. The aim of this study was to detect K-ras mutations in DNA extracted from the plasma of patients with colorectal cancer. METHODS: Tumor and plasma DNA were extracted from 14 patients with colorectal cancer (stages A-D), and K-ras alterations were detected using a polymerase chain reaction assay that uses sequence-specific primers to amplify mutant DNA. These results were confirmed with another polymerase chain reaction assay that creates an enzyme restriction site in the absence of a K-ras mutation followed by direct sequencing and additional cloning techniques. RESULTS: Seven patients (50%) had a codon 12 K-ras mutation within their primary tumor, and identical mutations were found in the plasma DNA of 6 patients (86%). Mutant DNA was not detected in the plasma specimens of 7 patients whose tumors tested negative for K-ras alterations or in healthy control subjects. Similar results were obtained using all three molecular biological techniques. CONCLUSIONS: K-ras abnormalities can be detected in circulating DNA extracted from the plasma specimens of patients with colorectal cancer. If these results are confirmed in larger studies, genetic analysis of plasma DNA may have clinical applications in the future.

[Transformation of NIH/3T3 cells and SW 480 cells displaying K-ras mutation]. / Transformation de cellules NIH/3T3 et cellules SW 480 porteuses d'une mutation K-ras.

The spontaneous release of a glyconucleoprotein complex in the supernatant of eukaryote cell cultures is a general phenomenon independent of cell lysis. The DNA recovered from this glyconucleoprotein material contains most part of the genome. The SW 480 cell line, originating from a human colon carcinoma, presents a point mutation of the K-ras gene on both alleles. These cells in culture release the mutated K-ras gene. When crude SW 480 cell supernatant is given, without any other adjonction, to NIH/3T3 mouse cells, transformed foci appear as numerous as those occurring after a transfection provoked by a cloned E.J. ras gene administered as a calcium precipitate. The presence of a mutated ras gene in the transfected foci of the 3T3 cells has been checked by hybridization, after PCR, with an oligonucleotide probe specific to the mutation. This result was confirmed by sequencing the PCR product.

Prognosis of rectal cancer in France.

We studied changes in the prognosis of cancer of the rectum (excluding the rectosigmoid junction) from 1978 to 1986 in the French department of Calvados on the basis of the 616 cases in the cancer registry. Taken as whole, survival has improved slightly with time (P < 0.01), but the improvement is only significant for men (P < 0.02), patients under 70 years (P < 0.01) and patients living in urban areas (P < 0.05). With regard to tumour characteristics, the improvement was significant only for patients with Dukes' stage C tumours at surgery (P < 0.02). To determine the reasons for the improvement in survival, the year of diagnosis and all other prognostic factors were studied in a multivariate model. Diagnostic conditions such as age and tumour stage did not vary from 1978 to 1986; in contrast, the rates of tumour resection and adjuvant radiation therapy increased, possibly explaining at least part of the improvement, particularly for patients with Dukes' stage C tumours.

[Assessment of the practice of adjuvant radiotherapy in cancer of the rectum in the department of Calvados]. / Evaluation de la pratique de la radiothérapie adjuvante dans le cancer du rectum dans le département du Calvados.

The effectiveness of adjuvant radiotherapy (ART) in the treatment of rectal cancer (RC) is established for the local control of the tumor, but doubt remains as concerns improvement in survival. The aim of this work was to assess the present techniques and trends of ART in a French department based on a population-based study. From 1978 to 1986, 616 cases of RC were diagnosed in the department of Calvados (France). Tumor was removed in 346 patients (56 percent). Of these 346 cases, 29 percent were irradiated, 3/4 postoperatively and one forth preoperatively. Besides sex and age, the type of surgery (anal sphincter saving or not) and Dukes' tumor stade had an influence on the performance of ART. Thirty-one percent Dukes B tumors and 42.1 percent of Dukes C tumors were irradiated. The practice of ART for these tumors increased significantly from 1978 (18.5 percent) to 1986 (60 percent) (P less than 10(-4)). However, the practice and the distribution of centers performing ART were heterogenous within the department of Calvados. This heterogeneity was neither due to the environment (urban/rural) of the patient nor to the distance between the place of residence and the radiation therapy center. Such an heterogeneity could be explained only by the lack of consensus concerning the practice of ART. Such a consensus could be found considering the results of the latest controlled clinical trials, but definitive conclusions are needed about the effectiveness of ART on the improvement of survival.

Uterine height and umbilical perimeter curves in twin pregnancies.

From previous research, which gave standard curves for the evolution of uterine height and umbilical perimeter according to gestational age in the case of single pregnancies, the authors propose curves which show the variations of these two parameters in twin pregnancies. The observed differences are sufficient to allow a diagnosis of twin pregnancy as soon as the 18th week of amenorrhea. This observation is interesting because, until now, a systematic early B-scan examination has not been performed as a rule.

Intrauterine growth charts for twin fetuses.

In addition to centile curves for birth weight and height of single infants, the authors offer similar biometric references for twins derived from a large French data base. The aim of the work is to assist in discovering small-for-date twins. In the actual prenatal environment, the curves show a decrease in the evolution of these growth parameters in comparison with the single pregnancy standards as early as the 30th week of pregnancy.

[Uterine height and umbilical circumference - an index of uterine development]. / Hauteur utérine et périmètre ombilical, indices de développement utérin.

The importance of clinical follow-up of the growth in size of the uterus in the screening of intrauterine underdevelopment of the fetus and also other ovulatory anomalies has been stressed by the authors, and the acceptable standards for uterine heighth and umbilical circumference at the various stages of pregnancy have been assessed. Reference curves establishing the limits that correspond to 10th and 90th percentiles have been determined. An individual diagram that would permit to visualize successive measurements in any pregnant woman has been proposed. The authors have recommanded the use of an index of uterine development the abnormal values of which should be included in the evaluation of risk.