A 14-year retrospective of HER2 + metastatic breast cancer treatment at one comprehensive cancer center: Impact of the trastuzumab/pertuzumab and trastuzumab-emtansine sequence versus trastuzumab on overall survival.

Introduction: Monoclonal antibodies represent a significant improvement in the treatment of the HER2 + metastatic cancer, which is associated with a worse prognosis. The objective of this study was to compare overall survival (OS) data in patients treated with trastuzumab + pertuzumab followed by trastuzumab-emtansine (T-DM1) in the second line of metastatic treatment (Arm A) versus patients treated with trastuzumab alone (Arm B). Progression-free survival (PFS) in first-line metastatic patients was also compared in both arms. Methods: This single-center retrospective study included patients from February 2008 to August 2022. OS and PFS of both arms were described and estimated using the Kaplan-Meier method. Data were extracted from electronic medical records and CHIMIO prescribing software. Results: The total duration of metastatic treatment of the 82 patients was significantly longer in the arm A (43.2 ± 28 months vs 33.6 ± 28.9 months), as was the median time to death (59 vs 52 months). The OS data showed a significant reduction in the risk of death in the arm A (Hazard Ratio = 0.59; 95% Confidence Interval [0.37-0.94]; p = 0.02). No difference was shown for PFS. Conclusion: The trastuzumab/pertuzumab/T-DM1 combination showed a significant improvement in OS. Our results are in line with the CLEOPATRA and EMILIA studies, but long-term responders in the arm A may have impacted our results. The absence of difference in term of PFS in first metastatic line may be explained by a selection bias, as patients in the arm A potentially have more aggressive forms.

[Care pathway diversity of patients with multiple sclerosis between French regions]. / Diversité des prises en charge des patients atteints de sclérose en plaques entre régions françaises.

BACKGROUND: The aim of this study is to analyze and to compare data from 2015, focusing on hospital care for patients with multiple sclerosis from three French regions with different characteristics in terms of prevalence, size and number of multiple sclerosis competencies and resource centers. METHODS: All hospital admissions from the PMSI MCO 2015 database, with a principal or related diagnosis (PD-RD) of G35* ("multiple sclerosis") were extracted. We also extracted chemotherapy treatments administered in hospital, during admissions with a significant associated diagnosis (SAD) of G35*, if the PD or RD was coded Z512 ("non-tumor chemotherapy"). The analyzed regions corresponded to those of 2015, some of which have since merged. RESULTS: There were 95,359 hospital admissions for multiple sclerosis in France in 2015 among a total cohort of 21,102 patients, resulting in a total cost of € 54.1m. Patients with MS were managed mainly in the ambulatory setting, which accounted for 88.5 % of all admissions. The Rhône-Alpes region represented 7.6 % of national admissions for MS, 9.6 % of patients, and 14 % of inpatient days, contributing 10.4 % of the national cost of MS care. 58.4 % of stays were managed by the two main multiple sclerosis centers. The Nord-Pas-de-Calais region represented 9.8 % of national admissions, 10 % of patients, 6.6 % of inpatient days, and 9.1 % of the national cost. 29.8 % of stays were managed by the main multiple sclerosis center. The Centre region represented 2.7 % of stays, 2.8 % of patients, 3.1 % of inpatient days, and 2.8 % of the national cost. 28.4 % of stays were managed by the main multiple sclerosis center. CONCLUSION: This study highlights the diversity of multiple sclerosis hospital management and care between these three regions.

Amyloid associated with neoplasia in two captive tricolour sharkminnows Balantiocheilus melanopterus Bleeker.

Amyloid associated with pancreatic adenocarcinoma was discovered in two captive adult tricolour sharkminnows Balantiocheilus melanopterus Bleeker found dead in a freshwater display. Enlarged abdomens expanded by bloody ascitic fluid and grossly visible masses of abnormal tissue were present surrounding sections of the stomach and intestine. Histologically, the masses were composed of areas of well-organized exocrine pancreatic acini interspersed with cords of poorly differentiated, spindle-shaped cells that compressed and effaced normal parenchyma. These cells possessed small numbers of cytoplasmic zymogen granules; the exocrine nature of these cells was confirmed using transmission electron microscopy (TEM). Fibrovascular connective tissue of the hepatopancreas and mesenteries was expanded by lightly eosinophilic, hyaline, homogeneous acellular material. Similar material greatly expanded the tunica media of large blood vessels in the hepatopancreas. After staining with Congo red or thioflavin T, this material exhibited red-green dichroism under polarized light or bright green fluorescence under ultraviolet light (255 nm), respectively. The non-branching fibrils, of indeterminate length, had an approximate diameter of 10-20 nm using TEM. Although exocrine pancreatic neoplasia is relatively common in fish, the presence of amyloid is not. To our current knowledge, the latter has not yet been described in association with a neoplastic lesion in fish.

Diseases of captive yellow seahorse Hippocampus kuda Bleeker, pot-bellied seahorse Hippocampus abdominalis Lesson and weedy seadragon Phyllopteryx taeniolatus (Lacépède).

Seahorses, pipefish and seadragons are fish of the Family Syngnathidae. From 1998 to 2010, 172 syngnathid cases from the Toronto Zoo were submitted for post-mortem diagnostics and retrospectively examined. Among the submitted species were yellow seahorses Hippocampus kuda Bleeker (n=133), pot-bellied seahorses Hippocampus abdominalis Lesson (n=35) and weedy seadragons Phyllopteryx taeniolatus (Lacépède; n=4). The three most common causes of morbidity and mortality in this population were bacterial dermatitis, bilaterally symmetrical myopathy and mycobacteriosis, accounting for 24%, 17% and 15% of cases, respectively. Inflammatory processes were the most common diagnoses, present in 117 cases. Seven neoplasms were diagnosed, environmental aetiologies were identified in 46 cases, and two congenital defects were identified.

Viral haemorrhagic septicaemia virus IVb experimental infection of rainbow trout, Oncorhynchus mykiss (Walbaum), and fathead minnow, Pimphales promelas (Rafinesque).

Viral haemorrhagic septicaemia virus (VHSV) in the Great Lakes has had a dramatic impact on fish husbandry because of the implications of the presence of a reportable disease. Experimental infections with VHSV IVb were conducted in rainbow trout, Oncorhynchus mykiss (Walbaum), and fathead minnows, Pimphales promelas (Rafinesque), to examine their susceptibility and the clinical impact of infection. Triplicate groups of rainbow trout (n = 40) were injected intraperitoneally (i.p.) with 100 microL 10(6.5)50% tissue culture infective doses (TCID(50)) or waterborne exposed to graded doses (10(4.5), 10(6.5), and 10(8.5) TCID(50) mL(-1)) of VHSV IVb. Duplicate groups of fathead minnows (n = 15) were i.p. injected with (10(6.5) TCID(50) 100 microL) or waterborne exposed (10(6.5) TCID(50) mL(-1)). All experiments were performed with single-pass well water maintained at 12 degrees C. Following either i.p. or waterborne exposure, VHSV RNA was detectable in both rainbow trout and fathead minnows by nested reverse transcription polymerase chain reaction (nRT-PCR) as early as 4-7 days post-infection (p.i.). Infected fathead minnow and rainbow trout exhibited lesions characteristic of VHS at 9 and 15 days p.i., respectively. Route of exposure had little effect on the onset of clinical signs. Cumulative mean mortality in rainbow trout was 4.4%, 2.6%, 2.6% and less than 1% in the i.p., high, medium and low dose waterborne exposures, respectively. Cumulative average mortality of 50% and 13% occurred in i.p. and waterborne-exposed fathead minnows, respectively. VHSV was detected from pooled rainbow trout tissue by RT-PCR and virus isolation at 38 days p.i., but not at 74 days p.i., regardless of the exposure route. Immunohistochemistry (IHC) with a rabbit antibody to VHSV IVb revealed the viral tissue tropisms following infection, with the identification of viral antigen in myocardium and necrotic branchial epithelium of both species and in gonadal tissue of fathead minnows. Rainbow trout, but not fathead minnows, are relatively refractory to experimental infection with VHSV IVb.

Short- and long-term response to corticosteroid therapy in chronic beryllium disease.

Chronic beryllium disease (CBD) is a granulomatous disorder that affects the lung after exposure to beryllium. The present study reports short- and long-term evolution of granulomatous and fibrotic components in eight patients with severe CBD receiving corticosteroid therapy. Eight patients with confirmed CBD were studied at baseline, after initial corticosteroid treatment (4-12 months), at relapse and at the final visit. Beryllium exposure, Glu(69) (HLA-DPB1 genes coding for glutamate at position beta69) polymorphism, symptoms, pulmonary function tests (PFT), serum angiotensin-converting enzyme (SACE) and high-resolution computed tomography (HRCT) quantification of pulmonary lesions were analysed. The CBD patients were observed for a median (range) of 69 (20-180) months. After stopping beryllium exposure, corticosteroids improved symptoms and PFT (vital capacity +26%, diffusing capacity of the lung for carbon monoxide +15%), and decreased SACE level and active lesion HRCT score. In total, 18 clinical relapses occurred after the treatment was tapered and these were associated with SACE and active lesion HRCT score impairment. At the final visit, corticosteroids had completely stabilised all parameters including both HRCT scores of active lesions and fibrotic lesions in six out of eight patients. Corticosteroids were beneficial in chronic beryllium disease. They were effective in suppressing granulomatosis lesions in all cases and in stopping the evolution to pulmonary fibrosis in six out of eight patients.

A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus.

Family and population studies indicate that predisposition to insulin-dependent (type I) diabetes mellitus (IDDM) is polygenic. It has been shown that the absence of the aspartic acid in position 57 (Asp57) of the DQ beta chain is positively correlated to IDDM. However, Asp57-negative haplotypes do not always confer susceptibility and conversely, some Asp57-positive haplotypes seem to be disease associated. It has been suggested that other HLA class II sequences, probably belonging to the HLA DQA1 gene, confer susceptibility to IDDM. This report, based on extensive oligonucleotide dot blot hybridization of PCR-amplified DQA1 and DQB1 genes, reinforces the importance of the Asp57-negative DQ beta chain, but also introduces the possibility that a DQ alpha chain bearing an arginine in position 52 (Arg52) confers susceptibility to IDDM. A molecular model of susceptibility to IDDM is proposed. This model strongly suggests that the disease susceptibility correlates quantitatively with the expression at the cell surface of a heterodimer, composed of a DQ alpha-chain bearing an Arg52 and a DQ beta chain lacking an Asp57. In view of the respective positions of the two residues and their charge, we might anticipate that both residues DQ beta Asp57 and DQ alpha Arg52 are critical for modulation of susceptibility, presumably via viral-antigenic peptide and/or autoantigen presentation.

Activating KIR genes are associated with CMV reactivation and survival after non-T-cell depleted HLA-identical sibling bone marrow transplantation for malignant disorders.

Combinations of HLA and killer immunoglobulin-like receptors (KIR) may affect outcome in T-cell depleted haematopoietic stem cell transplantation (HSCT). The KIR gene family includes inhibitory (KIR2DL and 3DL) and activating receptors (KIR2DS). Ligands are HLA-C (KIR2D) and HLA-Bw4 (KIR3DL1) for inhibitory KIR and are still unknown for activating KIR. The impact of activating KIR genotypes from donor and recipient is poorly documented in HSCT outcome. Here, HLA and KIR genotypes were determined in 131 pairs from non-T-cell depleted HLA-identical sibling HSCT. No effect of 'missing KIR ligand' was detected on acute graft-versus-host disease (GVHD), relapse, survival or infections even in myeloid malignancies. However, additional activating KIR genes in the donor compared to the recipient's genotype or an identity between donor and recipient activating KIR genotypes was associated with a lower transplant-related mortality (TRM) (P=0.005) and in a multivariate analysis with a better survival (P=0.02, HR=0.28; P=0.013, HR=0.29) and a lower incidence of cytomegalovirus (CMV) reactivation (P=0.009, HR=0.36). These data highlight the impact of donor-activating KIR genes on TRM, overall survival and CMV reactivation in HLA-identical sibling HSCT.

Dose effect of cis- and trans-encoded HLA-DQ alpha beta heterodimers in IDDM susceptibility.

Insulin-dependent diabetes mellitus (IDDM) in whites is strongly associated with particular HLA-DQ alpha beta heterodimers composed of a DQ alpha chain with an arginine at residue 52 (Arg52+) combined to a DQ beta chain lacking an aspartic acid at residue 57 (Asp57-). With the aim of confirming this association, clarifying which heterodimers account for the highest risk of IDDM and explaining the excess risk of DR3-DQw2/DR4-DQw8, 115 unrelated white IDDM patients and 108 unrelated healthy nondiabetic control subjects were studied. With polymerase chain reaction and sequence-specific oligonucleotide probes, both patients and control subjects were typed for their HLA-DQA1 and DQB1 alleles and their DQA1-DQB1 haplotype and genotype frequencies were compared. Four major findings emerged from our analysis. 1) Arg52+ DQ alpha/Asp57- DQ beta heterodimers, formed in cis and/or in trans, are strongly associated with susceptibility to IDDM; 97% of patients and 46% of control subjects had at least one such susceptibility heterodimer (relative risk [RR] 32, confidence interval [Cl] 14.25-71.86, P less than 10(-7). 2) The degree of disease susceptibility depends on the number of such DQ heterodimers that a subject can express according to his or her DQA1-DQB1 genotype. The highest RR was observed in patients with four susceptibility DQ heterodimers (RR 41, Cl 17.05-95.9). 3) Only part of the susceptibility DQ heterodimers were significantly increased in patients, conferring IDDM susceptibility of different strength. The strongest association was with the DQA1*0501-DQB1*0302 combination formed in trans position (RR 35.2, CI 12.88-96.78, P less than 10(-7).(ABSTRACT TRUNCATED AT 250 WORDS)

HLA DQB1*0301 allele is involved in the susceptibility to erythema multiforme.

Erythema multiforme (EM) is an acute, episodic inflammatory disorder of the skin and mucous membranes of various etiology that could be related to immunologic hypersensitivity response. EM has been previously reported to be associated with serologically defined HLA-DRw53 and DQw3 antigens. In this report, we reevaluate the role of HLA class II alleles in EM manifestations. With use of the polymerase chain reaction, followed by sequence-specific oligonucleotide hybridization, 35 unrelated Caucasian EM patients and 80 randomly selected healthy subjects were studied, and the DRB3, DRB4, DQA1, and DQB1 alleles were analyzed. The comparison of frequencies of these alleles indicates that (i) susceptibility to EM disease is more associated with the HLA-DQ than the HLA-DR subregions and (ii) that the DQB1*0301 is the most frequent allele among EM patients. Sixty-six percent of the patients had the DQB1*0301 allele compared to 31% of the controls (RR = 4.1; p less than 0.001). An even stronger DQB1*0301 association was found in the patient group with herpes-associated EM (76%; RR = 6.5; p less than 0.001). Our data demonstrate a clear association between an HLA-DQB1 allele and susceptibility to EM.

Anti-B cell lymphocytotoxic antibodies in kidney transplant recipients.

Serial serum samples from 47 renal allotransplant recipients were screened for antiperipheral blood lymphocyte, anti-B cell, and anti-Daudi cell line antibodies. Various associations of these antibodies were observed in 28 patients. Anti-Daudi did not correlate with graft survival, whereas anti-B, although they were often associated with anti-peripheral blood lymphocyte antibodies, showed the strongest correlation with chronic rejection (P = 0.00002). However anti-B cytotoxicity preceded or was concurrent with the onset of chronic rejection in only 53% of the cases. Antibodies were absent in six of nine patients with irreversible acute rejection, but they usually appeared after transplant nephrectomy. These findings suggest that anti-B cell antibodies may play a role in the rejection process. In 15 of 17 recipients (88%), anti-B cell antibodies occurred during the first trimester after transplantation. These patients showed 20% 1-year graft survival compared with 68% in those without antibodies at that time (P less than 0.005).

Despite lack of monospecific anti-DRw13 sera, a corresponding class II determinant can be defined by a DRw13 restricted anti-influenza virus T cell clone.

The study of a T3+ T4+ T8- human T cell clone COTC2 with both specific proliferative response and cytolytic activity for influenza A virus infected cells reveals that: the restricting element of this clone is strongly associated with DRw13 molecule(s) as seen by the study of a large panel of antigen presenting cells (APC) and by the observation that monoclonal antibodies (MoAb) specific for DR molecules inhibit its proliferative activity while anti-DQ MoAb do not. These results indicate that there exists a DRw13 associated determinant that can be defined at the functional level by COTC2 recognition despite the absence of monospecific anti-DRw13 serum. In contrast to the results found by other groups, the restriction of this DRw13 restricted clone follows the DRw13 serological definition irrespective of the DW type of the APC. These results indicate that the polymorphism of HLA class II molecules can be further defined at the functional level by monoclonal populations of T cells in conjunction with molecular definition.

HLA class I and class II are both associated with the genetic predisposition to primary Sjögren syndrome.

Primary Sjögren syndrome (pSS) is an autoimmune disease characterized by progressive destruction of the exocrine glands leading to mucosal and conjunctival dryness. It is marked by lymphocytic infiltration of the glands and the accumulation of several types of autoantibodies such as rheumatoid factor (RF), antinuclear, anti-SS-A (anti-Ro) and anti-SS-B (anti-LA) autoantibodies. The susceptibility to pSS and/or the presence of SS-A/SS-B autoantibodies in pSS patients is associated with DRB1*03-DQB1*02 and DRB1*02-DQB1*06 haplotypes, whereas no associations have been described with any HLA class I allele. To define the impact of HLA class I alleles in predisposition to pSS, 46 patients responding to the European criteria and 222 healthy unrelated Caucasians were analyzed for their HLA class I and class II haplotypes. Our results confirm the association of the DRB1*03-DQB1*02 haplotype with SS-A/SS-B autoantibodies positive pSS and demonstrate a significant association of the HLA-A24 with the disease. Moreover, HLA-A24 is more often associated with DRB1*11-DQB1*0301 and/or DRB1*0301-DQB1*02 in pSS patients than in the controls. The novel association of HLA class I alleles with susceptibility to pSS provides new insights to the genetic predisposition to this disease and subsequently to its physiopathology.

European genetic study on rheumatoid arthritis: is there a linkage of the interleukin-1 (IL-1), IL-10 or IL-4 genes to RA?

UNLABELLED: The genetic predisposition for rheumatoid arthritis (RA) is only partly explained by the HLA locus and most genetic factors involved in the susceptibility (and/or severity) of the disease await further identification. The first European genome scan in RA families provided suggestive evidence for linkage with a region (3.1/3q13) on chromosome 3, but many other potential RA susceptibility genes have yet to be analysed. AIMS: To perform a linkage analysis with microsatellite markers located in the vicinity of the interleukin-1 (IL-1) gene superfamily, the IL-10 gene and the IL-4 gene cluster which might be considered putative candidate loci for RA. METHODS: 107 Caucasoid European RA sibpairs from 90 nuclear families were genotyped for markers flanking the genes for the IL-1 superfamily, IL-10 and the IL-4 gene cluster. Linkage analysis based on the identity by descent (IBD) in affected siblings was analysed with the program SIBPALNA. Affected sibpairs were stratified according to the identity by state (IBS) for three markers in the HLA region (DRB1 oligotyping, D6S276 and TNFa microsatellites) and to the presence/absence of erosive disease on X-ray examination. RESULTS: Analysis of the whole family set showed an excess of allele sharing for markers of the IL-1 gene cluster (IBD 60%; P = 0.012) but not for IL-10 or IL-4. After stratification, the evidence of linkage to IL-1 was restricted to HLA concordant sibpairs (n = 32; IBD 70%; P = 0.006). Some evidence of linkage to IL-10 was also observed in HLA concordant sibpairs (IBD 66%; P = 0.03) and in sibpairs with erosive disease (n = 61; IBD 62%; P = 0.02). CONCLUSIONS: We found suggestive evidence of linkage of RA to the IL-1 locus. The increased linkage to IL-1 and IL-10 in HLA-identical sibs suggests a possible interaction between these cytokines and the HLA loci. Moreover IL-10 could interact with HLA factors in predisposing to erosive disease. These results need to be tested in additional families for consistency and replication.

Mitochondrial DNA polymorphism in the French population.

One hundred unrelated individuals of French origin were screened for mtDNA variation as restriction fragment length polymorphisms (RFLPs) with the restriction enzymes HpaI, BamHI, HaeII, MspI, AvaII and HincII. Twenty enzyme morphs were detected, four of which (AvaII-37Fr, -38Fr, HincII-18Fr and -19Fr) are new. Of the 17 mitotypes detected, five are new and they were named 1-19Fr, 6-18Fr, 100Fr-2 (2-1-2-4-1-2), 101Fr-2 (2-1-1-1-38Fr-2) and 102Fr-2 (2-1-1-4-37Fr-2). All new morphs and mitotypes derive from those already known due to a single nucleotide substitution. The French population was compared with other European, Mediterranean and Caucasian populations. Calculation of the genetic distances showed close genetic affinity with European-Mediterranean populations and especially with Calabrians, Majorcans and northern Italians (at negative values).

Mitochondrial DNA polymorphisms of a west Algerian population (Oran region).

Mitochondrial DNA codes for enzymes involved in the cellular energetic pathway. The polymorphism of this genome has been extensively analyzed for disease associations, but can also be used to characterize anthropological distances between populations. This study presents the results of mitochondrial DNA (mtDNA) sequence variation for a population sample of 50 unrelated individuals originating from western Algeria. The samples were studied with the recently developed long PCR technique followed by RFLP analysis using six restriction endonucleases: HpaI, BamHI, HaeII, MspI, AvaII and HincII. One new morph for HpaI (named HpaI-9Alg) was detected, and was found to be derived from the combination of the already known morphs 3 and 4. mtDNA restriction endonuclease fragment patterns were analyzed for potential site gain or loss and classified into 18 mtDNA types by the sequence-comparison method. Three mtDNA types (97Alg; 2-1-7-1-1, 98Alg; 2-1-1-8-37 and 99Alg; 9Alg-1-1-1-3) were detected for the first time. Another mtDNA marker--the presence of the 9 bp deletion in the COII/tRNA(Lys) region--was also studied in the Algerian sample. No deletions were observed. Our results indicate that the Algerians are genetically related to the Israeli-Arab population, with certain characteristics found in southern Europeans and others found in sub-Saharan Africans.

Genetic predisposition and IDDM in Greece.

Serological typing of HLA-DR antigens was performed on 116 patients with IDDM and 380 healthy controls. As expected a high incidence of HLA-DR3 and DR4 antigens was observed in patients with IDDM. However, the HLA-DR2 antigen, which rarely occurs in IDDM and is considered to confer protection against IDDM, was found in equal distribution (35%) in both patients and controls. HLA-DQ genotype analysis in 10 children with IDDM and 13 controls, all with the HLA-DR2 haplotype, showed that the great majority of affected children and normal controls carry the DR2 (16) or AZH-DQA1 *0102, DQB *0502 subtype. The high incidence of this subtype in normal individuals possibly explains why the DR2 antigen does not offer protection against IDDM in Greeks.