Preexisting autoantibodies as predictor of immune related adverse events (irAEs) for advanced solid tumors treated with immune checkpoint inhibitors (ICIs).

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are now standard of care in many cancers. They can generate immune-related adverse events (irAEs), but no biomarkers are available to identify patients who are more likely to develop irAEs. We assess the association between pre-existing autoantibodies and occurrence of irAEs. PATIENTS AND METHODS: We prospectively collected data from consecutive patients receiving ICIs for advanced cancers, in a single center between May 2015 and July 2021. Autoantibodies testing was performed before ICIs initiation including AntiNeutrophil Cytoplasmic Antibodies, Antinuclear Antibodies, Rheumatoid Factor anti-Thyroid Peroxidase and anti-Thyroglobulin. We analyzed the associations of pre-existing autoantibodies with onset, severity, time to irAEs and with survival outcomes. RESULTS: Of the 221 patients included, most had renal cell carcinoma (n = 99; 45%) or lung carcinoma (n = 90; 41%). Grade ≥2 irAEs were more frequent among patients with pre-existing autoantibodies: 64 (50%) vs. 20 (22%) patients (Odds-Ratio= 3.5 [95% CI=1.8-6.8]; p < 0.001) in the positive vs negative group, respectively. irAEs occurred earlier in the positive group with a median time interval between ICI initiation and irAE of 13 weeks (IQR = 8.8-21.6) vs. 28.5 weeks (IQR=10.6-55.1) in the negative group (p = 0.01). Twelve patients (9.4%) experienced multiple (≥2) irAEs in the positive group vs. 2 (2%) in the negative group (OR = 4.5 [95% CI: 0.98-36], p = 0.04). After a median follow-up of 25 months, median PFS and OS were significantly longer among patients experiencing irAE (p = 0.00034 and p = 0.016, respectively). CONCLUSION: The presence of pre-existing autoantibodies is significantly associated with the occurrence of grade ≥2 irAEs, with earlier and multiple irAEs in patients treated with ICIs.

Copper(I) targeting in the Alzheimer's disease context: a first example using the biocompatible PTA ligand.

Copper(I) coordinating ligands in the Alzheimer's disease context have remained unexplored, despite the biological relevance of this redox state of the copper ion. Here, we show that the PTA ligand can remove copper from Aß, prevent reactive oxygen species production and oligomer formation, two deleterious events in the disease's etiology.

[Hospital pathway of patients with breast cancer]. / Trajectoires hospitalières des patientes atteintes de cancer du sein en Poitou-Charentes.

Health care network should promote better quality, equity and care efficacy. On the subject of breast cancer, literature has shown inequality in care depending on geographical areas and health centres locations. This article illustrates a method of analysis of female non in situ non metastatic breast cancer patients hospital care pathway, from the 2002 and 2003 Poitou-Charentes' county Diagnosis Related Groups (DRG's) data bases. The treatments several phases are described along with their combination. The number of chemotherapy and radiotherapy sessions per patient are each analysed for comparison between Health Centres, Health Centres Status, and in view of the referentials recommendations. Several health pathways options are quantified: Mono/pluri Health Centres sites, inside/outside a geographical department, inside/outside Poitou-Charentes county. Nine hundred and nine patients hospital care pathways are described. Surgery was more often partial (66%), with Health Centres variation between 17 and 68%. Among the 308 patients who had chemotherapy, 78% received between 4 and 6 sessions, with variation per Health Centre between 65 and 90%. Radiotherapy is difficult to trace because of the Health Centres non systematic radiotherapy sessions linkage, and private Health Centres lack of information (no DRG's). 91% of identified radiotherapy benefiting patients had 25 to 35 sessions, in conformation with recommendations depending on the surgery performed with Health Centres variation ratio between 76 and 96%. Hospital care pathways options between two type of treatments were identified. 90% of the hospital care pathways took place in the same geographical department, and 30% took place in public Health Centres alone. Despite radiotherapy tractability limits, proper DRG's data collection allows the description of health pathways between Health Centres and allows health practice disparity identification. Using this tool, in accordance with the Cancer Plan, can therefore help health networks in evaluating care pathway in cancer and many other fields.

Particle-size distribution of polycyclic aromatic hydrocarbons in urban air in southern Spain.

The size distribution of polycyclic aromatic hydrocarbons (PAH) was determined for airborne particles from a large city with high vehicular traffic. The analytical method was optimised and validated using NIST standard reference material (SRM 1649a Urban Dust). The 16 priority PAH listed in the US-EPA were Soxhlet-extracted from filtered particulate matter and then fractionated using on-column chromatography. The aromatic fraction was quantified by gas chromatography-mass spectrometry. Real samples of particles collected in Seville (Spain) were analysed using the validated method. Values for the total concentration of PAH in the air, as well as the concentrations of each PAH in six particle-size ranges were obtained. Values of the PAH in TSP, PM10, PM2.5 and PM1 were assessed.

Preoperative chemoradiotherapy versus preoperative radiotherapy in rectal cancer patients: assessment of acute toxicity and treatment compliance. Report of the 22921 randomised trial conducted by the EORTC Radiotherapy Group.

The European Organisation for Research and Treatment of Cancer (EORTC) 22921 four-arm randomised trial questioned the value of preoperative chemoradiation (XRT-CT) versus preoperative radiation (XRT) and the value of additional postoperative chemotherapy (CT) versus none in T3-T4 M0 resectable rectal cancer patients. We report on the preoperative toxicity, treatment compliance and early deaths (all deaths up to 30 days after surgery) of the two treatment modalities in patients who were entered into trial before January 2001. In the XRT Group (group A), patients received 45 Gy, 25 fractions over 5 weeks. In the XRT-CT Group (group B), two 5-day courses of CT were added to the first and fifth weeks of XRT. For each CT course: 5-fluorouracil (5-FU) 350 mg/m2/day and Leucovorin (LV) 20 mg/m2/day were given. 398 and 400 patients started treatment in groups A and B, respectively. Grade 2+acute diarrhoea occurred in 17.3 and 34.3% of patients in groups A and B, respectively (P<0.005). The other side-effects remained unchanged or were only marginally increased. The compliance with RT was 98.5 and 95.5% in groups A and B, respectively. In group B, 78.7 and 71.1% of the patients received 95-105% of the planned CT doses at the first and second courses, respectively. 6 patients died preoperatively, 2 from toxicity in group B. 8 patients (1%) died within the 30 days after surgery in both groups. At the doses recommended in the protocol, the addition of 5-FU-LV to preoperative XRT slightly increased the amount of acute toxicity. However, the compliance with the radiation protocol or the feasibility of surgery did not decrease.

[Chemoradiotherapy in the adjuvant treatment of gastric adenocarcinomas: real progress?]. / Chimioradiothérapie dans le traitement adjuvant des adénocarcinomes gastriques: réelle avancée?

Frequency of local and distant failures after gastrectomy has led to extended lymph nodes dissection to obtain a better locoregional control. However, five year survival rates were not significantly different between patients undergoing D2 and D1 lymphadenectomy, and higher morbidity and post operative deaths were reported in large randomised trials (respectively 25% vs 48% and 4 vs 13%). Additionally, several metanalysis failed to demonstrate a significant survival advantage with adjuvant chemotherapy. The results of the first trial demonstrating one advantage to adjuvant post-operative chemoradiotherapy should modify the standard care. Disease free and overall survival after surgery alone and after surgery and concurrent chemoradiotherapy were respectively 31% vs 48% and 41% vs 50%. The intergroup trial demonstrate that better local control improve survival if radiation fields include stamps, tumour bed, proximal nodal chains and nodes corresponding to D2 extended lymph nodes dissection. Treatment was feasible with few severe toxic effects (1%). Of the 281 patients, 17% stopped treatment because toxic effects. Technical modalities of radiotherapy and post-operative nutrition support, which are critical points of interest for this treatment, are also discussed.

Prognostic impact of cathepsin D and c-erbB-2 oncoprotein in a subgroup of node-negative breast cancer patients with low histological grade tumors.

Some node-negative breast cancer patients, with initially good prognosis, relapse from their cancer and are poorly identified. In the present study, based on prospective data of 197 tumors, we measured cathepsin D (cath D, n=197), pS2 protein (n=125), c-erbB-2 oncoprotein (n=100) and epidermal growth factor receptor (EGF-R, n=99) to better define the risk of relapse of node-negative patients in comparison with that defined by the clinical and histological factors. The median follow-up in surviving patients was 75 months. Univariate analysis indicated that patients with histological grade III tumors (the Scarff, Bloom and Richardson classification) had a much poorer prognosis than those with histological grade I or II tumors (P=0.0027 for relapse-free survival and P=0.0156 for overall survival). When the population of node-negative patients was divided by tertiles, high cath D levels showed a significant association with an early relapse (P=0.0316). Using cut-off values, patients with high cath D (> or =25 pmol/mg protein) or c-erbB-2 oncoprotein (> or =4 Human Neu Unit/microg protein) levels, had a significant worse relapse-free survival (P=0.0147 and 0.0417, respectively). No prognostic information was supported by pS2 protein or EGF-R measurements. In multivariate analysis, histological grade, cath D and c-erbB-2 oncoprotein remained independent predictors of recurrence (P=0.005, 0.0361 and 0.0321, respectively). By combining low levels of cath D and c-erbB-2 oncoprotein in histological grade I or II tumors, we identified a subgroup of patients with a 100% relapse-free survival probability at 6 years of follow-up. Moreover, the subgroup of patients with histological grade I or II tumors and high values of both cath D and c-erbB-2 oncoprotein showed a prognosis as poor as the subgroup defined by histological grade III alone, respectively 66% and 70% relapse-free survival at 6 years of follow-up. In conclusion, the combination of conventional prognostic factor (histological grade) and biochemical factors (cath D and c-erbB-2 oncoprotein) enabled us to identify, in this preliminary study, a subgroup of patients having an increased risk of relapse in a group (node-negative patients with low histological grade tumors) considered as good prognosis.

[Retrospective analysis of results of treatment of 91 oral cavity cancers from 1982 to 1992]. / Analyse rétrospective des résultats du traitement de 91 cancers de la cavité buccale de 1982 à 1992.

PURPOSE: To analyse retrospectively the results of different treatment regimens of carcinomas of the floor of the mouth and tongue. MATERIALS AND METHODS: Between 1982 and 1992, 61 patients with carcinoma of the floor of the mouth and 30 with tongue cancer (25 stage I, nine stage II, 28 stage III, 29 stage IV) were treated in the radiotherapy department of Poitiers. Nine patients with stage I tumours were treated with 70 Gy low-dose rate brachytherapy only, without nodal dissection. Stages II and III were treated with combined surgery with neck dissection; and radiotherapy of stage II with nodal metastasis and for all stage III cases. Stage IV cases were treated either surgically if possible, or with combined chemotherapy and radiation. RESULTS: The five-year overall survival rate was 87.3% for stage I, 68.5% for stage II, 45.3% for stage III, and 0% for stage IV patients. Most relapses appeared in the first two years after treatment. Eight patients (32%) with stage I cancer developed nodal relapses, isolated in five cases. Complications of radiotherapy were acceptable. Four cases of osteonecrosis were observed after radiotherapy. All of these appeared simultaneously with a local relapse. CONCLUSION: These results are comparable with reports in the literature. The remarkable observation of our study is the high incidence of nodal recurrences after local treatment of stage I tumours. Therefore, local treatment is insufficient for early-stage tumours. The question of neck dissection for the early stage is discussed.

Accuracy of alignment in breast irradiation: a retrospective analysis of clinical practice.

The objective of the study was to determine the accuracy of patient positioning in radiotherapy for breast cancer. Portal images were obtained using a fast electronic megavoltage radiotherapy imaging system in 30 cases of breast cancer. Quantitative analysis of 530 megavolt portal images and comparison with 30 digitized simulation films were performed. Five linear measurements were taken for each simulation and verification film. Central lung distance (CLD) is the distance from the dorsomedial beam edge to the inner thoracic wall in the central plane of the beam. Cranial lung distance (CrLD) is the distance from the dorsomedial beam edge to the inner thoracic wall in the plane of the beam at 4 cm from the central plane. Central beam edge to skin distance (CBESD) is the distance from the skin to the ventrolateral beam edge in the central plane of the beam. The central irradiated width (CIW) is defined as the distance from the dorsomedial beam edge to the skin. The craniocaudal distance (CCD) is defined as the distance from a particular landmark to the caudal field border. Concerning patient position in the field, mean standard deviations of the difference between simulation and treatment images were 3.9 mm for the CLD, 3.2 mm at +4 cm, 3.6 mm for the CIW, 3.3 mm for the CBESD, 3.8 mm for the CCD. In 90% of all set-up for treatment, errors were less than 1 cm. The variation of the CLD was the largest set-up error. This parameter is clinically the most significant. Future treatment delivery should be improved by introducing patient positioning devices such as thermoplastic shells. The electronic portal imaging device (EPID) appears to be an adequate tool to study the accuracy of treatment set-ups like this.

[Retrospective analysis of the reproducibility of the daily set-up of the irradiation fields of cancer of the rectum using a megavoltage imaging system]. / Analyse rétrospective de la reproductibilité de la mise en place quotidienne des champs d'irradiation de cancer du rectum par imagerie de contrôle de haute énergie.

PURPOSE: To evaluate a ionization chamber on-line portal imaging system in routine clinical radiotherapy of rectum cancers. PATIENTS AND METHODS: Megavolt portal images were obtained using a fast electronic megavoltage radiotherapy imaging system in 13 cases of pelvic fields. A total of 208 portal images and 13 simulator films were used to determine the values of set-up deviations in the X-Z-directions of a fixed co-ordinate system, and of the rotation fields (R). RESULTS: Mean standard deviations of the difference between simulation and treatment images were 3.2 mm and 0.9 mm for X and Z, 3.6 mm for the rotation fault. The standard deviations were, respectively, 7.1 mm, 7.1 mm and 1.5 mm. The cumulative frequency distributions revealed that 80% and 95% of the absolute differences were less than 10 mm and 17.5 mm, respectively. CONCLUSION: These results indicate the difficulty of a reproducible daily set-up. A weekly control could be proposed in order to increase the quality of pelvic site treatment. The introduction of masks to improve the set-up is also discussed.

[The role of radiotherapy in the treatment of primary lymphoma of the brain. Presentation of the results of a series from the French Society of Neurosurgery and the literature]. / Place de la radiothérapie dans le traitement des lymphomes primitifs de l'encéphale. Présentation des résultats des séries de la SFNC et de la littérature.

One hundred eighty three patients (73.8%) in the SFNC series received radiation therapy alone, for 60 patients and with additional chemotherapy for 129 patients. From this review, a dose-response relationship with an improved survival time with doses greater than 50 Gy could not be demonstrated (p = 0.97). The multivariate risk analysis identified the radiation therapy as one of the factors which has the most favorable impact on survival. Radiation therapy remains the treatment method of choice. These results are compared with data from the literature.

[Immunoenzymatic assays of c-erbB-2 oncoprotein and epidermal growth factor receptor in breast cancer: correlation with clinical and biological parameters]. / Dosages immunoenzymatiques de l'oncoprotéine c-erbB-2 et du récepteur du facteur de croissance de l'épiderme dans le cancer du sein: corrélation avec les paramètres cliniques et biologiques.

Two new immunoenzymatic assays for c-erbB-2 oncoprotein and epidermal growth factor receptor (EGF-R) (Oncogene Science) in human breast cancer were validated. Correlations between these assays and some clinical and biological parameters were also studied. The repeatability and reproducibility of standard curves for the two methods gave a coefficient of variation (CV) of less than 4% and about 10% respectively. The accuracy of c-erbB-2 oncoprotein and EGF-R assays was examined by using dilution and recovery tests throughout the standard curves. The linear relations between theoretical and measured values, for these tests, had slopes close to 1 and an intercept near 0. The median value for EGF-R, measured on solubilized membranes of 290 primary tumors, was 0.12 fmol/micrograms protein, the mean value was 0.37 (range 0 to 35.7). For c-erbB-2 oncoprotein, the median value, measured using the same population, was 2.75 human neu unit/micrograms protein, the mean value was 7.85 (range 1 to 125). There was an inverse relationship between EGF-R values and those for the estrogen receptor (ER), progesterone receptor and pS2 protein as well as menopausal status. C-erbB-2 oncoprotein concentrations were positively correlated with ER, pS2 protein and cathepsin D. Furthermore, a significant positive correlation was observed between EGF-R levels and c-erbB-2 oncoprotein levels. In conclusion, immunoenzymatic assays of EGF-R and c-erbB-2 oncoprotein are easy to use, sensitive and reliable. The accurate standardisation of immunoenzymatic assays could contribute to the clinical use of EGF-R and c-erbB-2 oncoprotein as prognostic factors in breast cancer.

[2d and 3d line hormonal therapy in postmenopausal metastatic breast tumor. Comparison of medroxyprogesterone acetate and aminoglutethimide in tamoxifen-resistant patients]. / Terapia ormonale di seconda e terza linea nel tumore mammario metastatico in post-menopausa. Confronto tra il medrossiprogesterone acetato e l'aminoglutetimide in pazienti divenute resistenti al tamoxifen.

In order to evaluate the effectiveness of second and third line hormone therapy for postmenopausal (spontaneous or surgical) women with metastatic tamoxifen-resistant breast cancer, 293 women aged 36 to 91 (mean 63.6) were divided into two groups submitted to a multicenter study of two treatment schedules: a) Aminoglutethimide (AG; 500 mg daily plus hydrocortisone 40 mg daily); b) Medroxyprogesterone (MPA; 1,000 mg daily per os). Of the 293 patients receiving second line hormone therapy, only 161 were available for third line treatment. In phase 1, 153 patients were treated with AG: 36% had objective responses (complete or partial); of 140 patient receiving MPA, 33% had objective responses (p = 0.045, significant). In the AG-treated group, duration of response was 11.3 +/- 8.4 months as against 8.3 +/- 5.6 months in the MPA group (p = 0.07, significant). In phase 2, 87 women previously treated with MPA received AG, and 74 previously AG-treated patients were given MPA. There were no significant differences in the results obtained. In conclusion, there were no significant differences in the results obtained by AG and MPA treatment as far as toxicity and survival was concerned but there was a statistically significant advantage for AG as second and third line management both as to objective responses and mean time until renewed progression of the disease.

Sensibilite in vitro de plasmodium falciparum a l'artemether au Cameroun en 1993

Les auteurs rapportent dans cette etude les resultats des mesures effectuees a Yaounde en 1993. Les objectifs etaient d'etudier in vitro la sensibilite a l'artemether d'isolats de plasmodium falciparum; d'etudier conjointement la sensibilite in vitro de ces isolats aux principaux antipaludiques et rechercher l'existence d'une resistance croisee potentielle entre ces molecules

Efficacite de la mefloquine dans le traitement de l'acces palustre simple a Yaounde

Cette etude a montre l'efficacite et la bonne tolerance a la dose unique de 15 mg/Kg de la mefloquine dans le traitement de l'acces palustre simple a plasmodium falciparum chez l'enfant

[Cardiotoxicity of 5-fluorouracil. Clinical picture of 4 cases and a prevention proposal]. / Cardiotoxicité du 5-fluoro-uracile. Tableaux cliniques à propos de 4 cas et proposition de prévention.

5-fluoro-uracil (5-FU) cardiotoxicity has been often reported during chemotherapy. We collect four atypical cases of cardiac side effects in patients treated by 5-FU for head and neck tumors. We review the literature about the subject, and we propose criteria to detect patients with a high risk level, and to prevent this adverse effect incidence.

Treatment and long-term outcome of chronic radiation esophagitis after radiation therapy for head and neck tumors. A report of 13 cases.

The natural history of chronic radiation esophagitis occurring in previously normal esophagus is still unknown. We describe here the long-term outcome of chronic esophagitis arising after neck irradiation for oropharynx and larynx carcinomas in 13 consecutive adult patients. The first clinical signs of radiation esophagitis were dysphagia or impossibility of oral intake, which appeared within 26 months (range 2-120 months) after the end of radiation for pyriform fossae carcinoma (N = 5), tonsil carcinoma (N = 2), larynx carcinoma (N = 2), pharynx carcinoma (N = 2), base of the tongue (N = 1), and thyroid carcinomas (N = 1). During upper endoscopy, an esophageal stenosis was found in 11 cases and was associated with ulceration in three cases. An isolated esophageal ulceration was present in only two cases. Chronic radiation esophagitis diagnosis was confirmed by histology and surgery in seven cases. In the last six cases, diagnosis was supported by the absence of first cancer relapses within a median follow-up of two years (16 months to nine years) and by endoscopic findings. Seven patients received parenteral or enteral nutrition. Ten patients were treated by peroral dilatations. These treatments allowed nearly normal oral diet in 11/13 patients. Only one patient was lost of follow-up after 20 months. Four patients died from chronic radiation esophagitis. One of these patients died from massive hemorrhage after peroral dilatation. Four patients died of a second carcinoma with no first cancer recurrence. Four patients were alive after six months to nine years of follow-up. Moderate dysphagia was still present, allowing nearly normal oral feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Second and third line hormonotherapy in advanced post-menopausal breast cancer: a multicenter randomized trial comparing medroxyprogesterone acetate with aminoglutethimide in patients who have become resistant to tamoxifen.

In order to evaluate the efficacy of two different sequences of second and third line hormonotherapy in advanced post-menopausal breast cancer, 257 women aged 36-91 years (mean age: 63.6 years) who had become resistant to tamoxifen (TAM), entered into a multicenter randomized trial comparing two different regimens: 1) Aminoglutethimide (Ag) 500 mg/day with hydrocortisone supplementation from 30 to 60 mg/day; and 2) oral medroxyprogesterone acetate (MPA) 500 mg twice a day. 250 patients were evaluated following second line hormone therapy and, after cross-over, 128 following third line hormonotherapy. No significant difference was observed, during either second or third line therapies, for toxicity, survival, or response rate; however, in both second and third line therapies the median time to progression was significantly longer with Ag therapy.