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Two experiments were performed to evaluate the use of an intravaginal device (IVD) impregnated with medroxyprogesterone acetate (MPA) to avoid early parturition and synchronize farrowing in sows. In both experiments with IVDs, the gestation length, stillbirth rate, birth weight, colostrum yield, lactational litter performance, and subsequent reproductive performance of sows were assessed. In Experiment 1 (Exp. 1; n = 91), sows were assigned to four treatments to evaluate the minimum required MPA dose: without IVD (CONT; control), 400 mg (MPA400), 600 mg (MPA600), and 800 mg (MPA800) of MPA in the IVD. The IVD was inserted on day 110 of gestation and removed on day 115. No sows farrowed during IVD treatment. Gestation length was increased in treatments with MPA (116.4 days) compared to the control (CONT; 114.9 days; P < 0.01), without effects on piglet birth weight (P = 0.98). A lower percentage of deaths around the farrow (P = 0.02) was observed in the CONT (1.8%) compared to MPA treatments (6.8%). The dose of 400 mg of MPA, validated in Exp. 1, was used in Experiment 2 (Exp. 2; n = 84) to evaluate the performance of sows and piglets in a sow farrowing synchronization protocol. Sows were treated with MPA from days 110-114 of gestation with or without 0.168 mg of cloprostenol sodium (PGF2α), for luteolysis induction, at IVD removal. Thus, four treatments were considered: CONT - without MPA or luteolysis induction (no interventions); PGF2α - luteolysis induction on day 114 of gestation without MPA; MPA114 - MPA treatment till 114 days of gestation without luteolysis induction; MPA114 + PGF2α - MPA treatment and luteolysis induction on day 114 of gestation. The gestation length in treatments with IVDs was longer (P < 0.01) than CONT without a difference for PGF2α treatment (P = 0.46). No impact of IVD use on piglet birth weight (P = 0.67) and deaths around the farrow (P = 0.50) were observed. The colostrum yield (P = 0.65), immunocrit (P = 0.72), piglet performance during lactation (P = 0.81), and weaning-to-estrus interval (P = 0.21) were similar among treatments. In conclusion, the use of IVDs impregnated with 400 mg of MPA between days 110 and 114 of gestation prevented early parturition with no implications for piglet survival at birth, colostrum yield, or litter performance., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest. The funding sponsors had no role in the design of the study, collection, analysis, and interpretation of data, writing of the manuscript, and the decision to publish the results., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Clonal chromosome abnormalities in Philadelphia-negative cells could concern chronic myeloid leukemia patients treated by tyrosine kinase inhibitors. The European LeukemiaNet distinguishes -7/del(7q) abnormalities as a "warning". However, the impact of clonal chromosome abnormalities, and specifically those of -7/del(7q), in Philadelphia-negative cells on clinical outcomes is unclear and based on case-reports showing morphological dysplasia and increased risk of acute myeloid leukemia, suggesting the coexistence of chronic myeloid leukemia and high-risk myelodysplastic syndrome. The aim of this study was to determine whether the impact of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells on the clinical outcome is different from that of other types of abnormalities, and we argue for an underlying associated high-risk myelodysplastic syndrome. Among 102 chronic myeloid leukemia patients with clonal chromosome abnormalities in Philadelphia-negative cells with more than a median of 6 years of follow up, patients with -7/del(7q) more frequently had signs of dysplasia, a lower cumulative incidence of deep molecular response and often needed further treatment lines, with the consequent impact on event-free and progression-free survival. Morphological features of dysplasia are associated with myelodysplastic syndrome/acute myeloid leukemia mutations and compromise the optimal response to tyrosine kinase inhibitors, irrespectively of the type of clonal chromosome abnormalities in Philadelphia-negative cells. However, mutation patterns determined by next-generation sequencing could not clearly explain the underlying high-risk disease. We hereby confirm the pejorative prognostic value of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells and suggest that myelodysplastic features constitute a warning signal that response to tyrosine kinase inhibitors may be less than optimal., (Copyright© 2019 Ferrata Storti Foundation.)

Background: Ruminants play a great role in sustainable livestock since they transform pastures, silage, and crop residues into high-quality human food (i.e. milk and beef). Animals with better ability to convert food into animal protein, measured as a trait called feed efficiency (FE), also produce less manure and greenhouse gas per kilogram of produced meat. Thus, the identification of high feed efficiency cattle is important for sustainable nutritional management. Our aim was to evaluate the potential of serum metabolites to identify FE of beef cattle before they enter the feedlot., Results: A total of 3598 and 4210 m/z features was detected in negative and positive ionization modes via liquid chromatography-mass spectrometry. A single feature was different between high and low FE groups. Network analysis (WGCNA) yielded the detection of 19 and 20 network modules of highly correlated features in negative and positive mode respectively, and 1 module of each acquisition mode was associated with RFI (r = 0.55, P < 0.05). Pathway enrichment analysis (Mummichog) yielded the Retinol metabolism pathway associated with feed efficiency in beef cattle in our conditions., Conclusion: Altogether, these findings demonstrate the existence of a serum-based metabolomic signature associated with feed efficiency in beef cattle before they enter the feedlot. We are now working to validate the use of metabolites for identification of feed efficient animals for sustainable nutritional management.

Between March 1992 and August 1993, thirty patients with hairy cell leukemia (HCL) were treated in a single institution with 2-chlorodeoxyadenosine (2-CdA) for one course (N=27) or two courses at six month interval (N=3). Sixteen patients were previously untreated, 14 had been treated with alpha interferon (alpha IFN) (N=5), alpha IFN and splenectomy (N=8) and splenectomy, alpha IFN and Deoxycoformycin (N=1). Overall results in 29 evaluable patients were: 25 CR (86%), 3 PR (10%), one failure. The three PR patients relapsed after 18, 24 months and five years. Two were retreated successfully. Two CR patients relapsed after five years. Careful clinical survey, sequential bone marrow biopsies (BMB) with DBA44 immunostaining for assessment of response and detection of residual disease and serially evaluation of lymphocyte subsets counts were performed. Results of bone marrow biopsies study show 1) a progressive reduction in hairy cell infiltration during the first six months after therapy and not after that indicating that the best moment for the evaluation of response may be the sixth month, 2) the persistence of a very small number of DBA44+ cells (80% of BMB). There was a correlation between the presence of > 5% DBA44 positive cells on 6th month BMB and relapse. 60% had an absolute CD4+ lymphocyte count less than 0.2 10(9)/l at least on one examination after treatment. CD4+ lymphocyte level persisted less than baseline level in 8/18 patients tested after four and/or five years. Lymphopenia was less marked in splenectomized patients: 7/7 splenectomized patients tested have recovered a CD4+ lymphocyte count equal to pretherapy level compared to 3/11 non splenectomized patients (p: 0.004). Three opportunistic infections were observed early (first 6 months) after 2CdA therapy: pneumocystis pneumonia, retinitis due to toxoplasma in the patient who failed and legionella pneumonia in a patient retreated after relapse. Two patients developed a second carcinoma 6 and 12 months after therapy. Five patients died, three from a cause unrelated to HCL, one from HCL and one from infection while in second CR. At five years, overall survival is 83% and progression free survival is 66%. Our study shows 1) long-lasting response in the majority of patients after 2-CdA, 2) a correlation between persistent minimal residual disease detected with DBA44 immunostaining and occurrence of relapse and 3) a profound and persistent CD4+ lymphopenia more marked in non splenectomized patients.

Purpose: To analyze retrospectively survival and prognostic factors of patients with non-Hodgkin's lymphoma (NHL) autografted from 1979 to 1995 in a single institution., Patients and Methods: A total of 120 patients, 64 with aggressive and 56 with low-grade NHL, were autografted. The carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) regimen was used in 104. The autograft was marrow in 101 patients. Marrow was purged in vitro by mafosfamide for 63 patients (adjusted dose [AD] in 32; unique dose [UD] in 31); 27 patients received a CD34+-selected graft. Following intensification, 45 patients received additional radiotherapy on previous sites of involvement., Results: Outcome at 5 years for patients transplanted with low-grade NHL in first complete remission (CR1), in first partial remission (PR1), and in second complete remission (CR2) or beyond showed an event-free survival (EFS) of 75% +/- 12%, 46% +/- 18%, and 57% +/- 24%, a relapse incidence (RI) of 21% +/- 12%, 49% +/- 19%, and 43% +/- 25%, and a transplant-related mortality (TRM) of 5% +/- 5%, 10% +/- 7%, and 0%, respectively. For patients with aggressive NHL transplanted in CR1, in PR1, in CR2 or beyond, and in resistant relapse or in primary refractory disease, the EFS was of 73% +/- 9%, 58% +/- 19%, 29% +/- 16%, and 10% +/- 9%, the RI 22% +/- 9%, 14% +/- 9%, 77% +/- 18%, and 66% +/- 20%, and the TRM 6% +/- 6%, 32% +/- 21%, 11% +/- 10%, and 71% +/- 22%, respectively. In patients autografted upfront in first remission, additional radiotherapy was associated with a higher EFS, in univariate (P = .03) and multivariate analysis (P = .02, relative risk [RR] = .021). The role of graft purging with mafosfamide on the outcome reflected by the dose of colony-forming unit-granulocyte-macrophage (CFU-GM) per kilogram infused postpurging was assessed by univariate analysis: patients in first remission who received lower doses of CFU-GM had a lower RI and a higher EFS., Conclusion: This retrospective analysis suggests that marrow purging and posttransplant radiotherapy improve the outcome of patients with NHL autografted in first remission.

We report on seven adult leukemic patients who were autografted in spite of a prior history of invasive pulmonary aspergillosis (IPA). Their median age was 41 years (range: 19-61); six patients were male and one female. All seven had acute myeloblastic leukemia (AML) and underwent an autologous marrow transplantation (ABMT) with a marrow purged in vitro by mafosfamide. IPA was suspected prior to ABMT on clinical and radiological features. CT scan confirmed nodular infiltrates and cavitations in six cases. Microbiological documentation consisted of: identification of the fungus from bronchoalveolar lavage: one case, positive antigenemia: one case, positive antibodies: two cases. Prior ABMT patients received amphotericin B for a median total dose of 1915 mg (range: 970-3300). No patient underwent surgery. The median time from diagnosis of IPA to ABMT was 7.3 months (range: 3-10). During ABMT all patients received prophylactic amphotericin B and itraconazole. No patient died from toxicity and no IPA reactivation was observed in any patients. Post-graft, itraconazole was kept on for a median of 3 months (range: 3-5). This study demonstrates that IPA occurring during the management of AML patients is not necessarily a contraindication to subsequent ABMT.

A systematic survey of human cytomegalovirus (CMV) was performed in 29 allogeneic bone marrow transplant (BMT) recipients. At day 100 a lip biopsy was performed and histological grading according to Sale's score was compared with the immunohistochemical detection of the immediate early protein IE2 of HCMV. In 10 patients without chronic graft-versus-host disease (GVHD), 3 had lip biopsy grade 1, 7 had grade 0 Sale's score and in 19 patients with chronic GVHD, 11 had grade 2, 1 had grade 1 and 7 had grade 0. On the same lip biopsies, we found IE2 protein in 8 of the 19 patients with chronic GVHD. None of the lip biopsies from patients without chronic GVHD expressed the protein, suggesting that HCMV expression is strongly associated with chronic GVHD and Sale's grade 2. To conclude, in our group of patients with a risk for HCMV infection, detection of the protein IE2 was a good predictive criterion of chronic GVHD with a sensitivity of 61% and a specificity of 100%.

Low grade malignant follicular lymphoma is characterized by its slow course over many years. However, despite a median survival of 4 to 8 years the cure rate is lower than 10 percent and even nil for some authors. The best therapeutic approach of the disease is unknown, and many teams of oncologists are in favour of a more intense chemotherapy. We present a study of 10 patients selected for their young age and for the presence of detrimental prognostic factors (index 3 of Coiffier's classification in 8/10 patients). Nine patients received BCNU, cytosine arabinoside, etoposide and melphalan, followed by reinjection of autologous bone marrow purged in vitro by mafosfamide in the adjusted dose CFUGM LD 95. Eight of these 9 patients are in complete, unmaintained remission 15 to 43 months after the bone marrow transplantation (including 3 patients in a more than 2 years' remission). The 10th patient had autologous bone marrow transplantation in 1979; after treatment with heavy TACC chemotherapy followed by reinjection of unpurged bone marrow, he remained in complete remission for 9 years, then relapsed; he is now alive with a progressive tumour. Although the follow-up was relatively short for a particularly slow disease, this study shows that, owing to autologous bone marrow transplantation as early as the first complete remission, one of the heaviest types of chemotherapy can be delivered in patients with non-Hodgkin's lymphoma, unless precluded by toxicity. At the moment, this protocol is experimental and can be used only in young subjects at high risk. Further studies on larger series of patients and with a longer follow-up are needed to evaluate the effectiveness of this new type of treatment compared with conventional chemotherapies.

Thirty-three patients with severe aplastic anemia were treated with antilymphocyte globulin (ALG, Mérieux) and androgens (with or without corticosteroids) between 1981 and 1989; 24 patients (72.7%) were responders after one course of ALG, eight were nonresponders, and only one patient had an early death. Eighteen of the 24 responses occurred within 2 months of ALG treatment. Of note is the good response rate we obtained for very severe aplastic anemia (four responders of five evaluable patients). With a median follow-up of 36 months (range 1-97), a survival rate of 77.6% +/- 1.2% was obtained at 30 months. No predictive factor of survival could be identified except response to treatment (p = 0.0001). The duration of the disease before treatment was inversely related to survival, although this difference did not reach statistical significance (p = 0.06). Four initial responders relapsed after 14, 24, 38, and 57 months. Three of these patients received a second course of ALG and two responded. In contrast, four of the non-responders received a second course of ALG, with only one response. Toxicity of androgens was mild. No patient developed a PNH clone or myelodysplastic syndrome. Major toxicity of corticosteroids was femoral osteonecrosis in three patients. In our experience, the combination of ALG and androgens in SAA, with or without corticosteroids, was associated with a higher response rate and better survival than in many previously published reports. This could have been due to the intensive supportive care during the initial weeks of treatment. We suggest that it may also result from the addition of androgens to ALG, although this issue may only be resolved in a randomized study.

In contrast to intermediate- and high-grade non-Hodgkin's lymphomas (NHL), patients with follicular lymphomas retain a poor prognosis in the long run. Several reports suggested that they are incurable by conventional chemotherapy. 10 patients with follicular NHL were autografted for consolidation of early remission. One of these patients treated in 1979 received the TACC regimen with unpurged marrow. The other 9 (8 in first, 1 in second remission) treated since July 1987 received the BEAM regimen followed by autologous bone marrow transplantation (ABMT) with marrow purged in vitro by mafosfamide at levels individually adjusted. There were no toxic deaths. 8 patients remain in unmaintained CR 15 to 43 months post-ABMT-2 are beyond 2 years. The patient autografted in 1979 has relapsed 9 yr later. ABMT is feasible with no indue toxicity for consolidation of follicular NHL early in first remission, as an alternative aggressive strategy. Further studies and a longer follow-up will be needed to evaluate its antitumor efficacy.

This report describes an 18-year-old man with disseminated malignant histiocytosis (MH). The patient initially attained complete remission (CR1) with conventional chemotherapy and then relapsed 14 months later. In second complete remission (CR2) 2 years and 8 months after initial diagnosis, an autologous bone marrow transplantation (ABMT) was undertaken following conditioning with the BEAM regimen. Bone marrow collected in CR2 was incubated with mafosfamide at a dose adjusted to the individual sensitivity of normal CFU-GM according to our current protocol. At the time of writing, 4 years post-transplant, this patient remains disease free. This is the first report of ABMT with marrow treated in vitro by mafosfamide in MH.

Forty-three adult patients with idiopathic thrombocytopenic purpura (ITP) were treated by slow intravenous infusions of vinblastine. Nineteen had ITP of recent onset (i.e. of less than 6 months duration) and had contraindication to steroids (3 patients), refractoriness to steroids (6 patients) or to steroids and high dose intravenous immunoglobulins (IVIg, 10 patients). Of the 19 patients, 10 achieved complete response (CR), 2 achieved partial response (PR), 2 had minor response (MR) and the remaining 5 patients had no response (NR). Six of the complete responders remained in CR after 12 to 48 months, whereas all other responders relapsed within 3 months, in spite of maintenance therapy. Twenty-four patients had chronic ITP (i.e. of 6 months duration or more) and had showed no or only transient response to steroids and/or splenectomy, and in many of them, to other therapeutic approaches. Four achieved CR, 4 PR, 6 MR and 10 NR. All but 3 responses were shorter than 3 months, in spite of maintenance therapy. Most responses to slow infusions of vinblastine began after the first infusion. Main side effects included leukopenia in 9 patients (but with absolute neutropenia in only one) and peripheral neuropathy in 2 patients. Interval from diagnosis was the only prognostic factor of response to treatment. We conclude that slow infusions of vinblastine may be a useful approach in ITP of recent onset, when contraindication or refractoriness to steroids and/or IVIg exists. In our experience, this treatment has limited benefit in chronic ITP. In addition, it remains to be demonstrated that slow infusions of vinca alkaloids have any superiority over intravenous bolus injections of the same drugs.

Pyoderma gangrenosum is a rare skin disease of unknown pathogenesis associated, in almost 8 out of 10 cases, with a systemic disease, notably enterocolitis or hemopathy. We report the case of a 57-year old man who had been presenting with pyoderma gangrenosum for 5 years when he developed a rheumatoid-like seronegative chronic polyarthritis. The occurrence, some time later, of a supraclavicular adenopathy led to the diagnosis of Hodgkin's disease. To our knowledge, the pyoderma-chronic polyarthritis-Hodgkin's lymphoma association has never been reported. Treatment of the lymphoma resulted in complete disappearance of cutaneous and articular symptoms. The fact that neither the skin disease nor the polyarthritis recurred during a 3-year follow-up after treatment was discontinued, incites us to discuss the possibility that the pyoderma and the polyarthritis observed in this patient were neoplastic diseases.

This retrospective study concerns 13 patients in whom Hodgkin's disease was diagnosed during pregnancy or immediately after delivery (group I) and 12 patients with Hodgkin's disease who had one or several pregnancies while under treatment (group II). In group I, Hodgkin's disease was diagnosed in early pregnancy in 4 patients who all had therapeutic abortion: 3 remain in prolonged complete remission and 1 had a late relapse; 9 cases were diagnosed in late pregnancy or after delivery: 3 were treatment failures, 2 had a relapse and 4 remain in complete remission. In group II patients, 3 pregnancies occurred during initial chemotherapy and were interrupted; 5 pregnancies occurred during subsequent radiotherapy or (for earlier patients) maintenance chemotherapy, and 4 of them were interrupted; 9 pregnancies occurred within 2 years of completing treatment, and 7 after 2 years. Of the 12 patients in group II, only 2 had a relapse whereas 10 remain in complete remission. Although they should be interpreted with caution, these data suggest that Hodgkin's disease diagnosed in late pregnancy or after delivery might be more active, and they justify therapeutic abortion when diagnosis is made in early pregnancy. They do not indicate a high risk of relapse in treated Hodgkin's disease patients during a subsequent pregnancy, even if it occurs shortly after treatment.

16 adult idiopathic thrombocytopenic purpura (ITP) patients, with mean age 51 years, were treated by 5 weekly slow intravenous infusions of vinblastine (0.1 mg/kg). When a complete or partial response (CR or PR) was obtained, slow infusions were repeated at 2-weekly then monthly intervals, as maintenance therapy. In 4 cases with ITP of recent onset, but presenting contraindication or failure to prednisone and high dose intravenous immunoglobulins, CR was obtained in all patients after 4 to 15 days (mean 9.5). Only one of these patients relapsed. In 12 cases of refractory chronic ITP (of whom 10 had been splenectomized), there were 2 CR, 6 PR and 4 failures. The 8 responding patients had a mean interval to response of 20 days. The 6 PR were short and did not exceed 15 days. Our results do not support a superiority of this treatment compared to other modes of administration of vinca alkaloids in ITP (intravenous bolus, vinca loaded platelets).

A male patient, aged 23 years, with no notable previous history, was admitted to hospital because of fever, splenomegaly, and pancytopenia. The bone marrow was infiltrated by mature looking histiocytes displaying erythrophagocytosis. Other findings included polyclonal hypergammaglobulinemia, elevated transaminases, hypofibrinogenemia, and hypertriglyceridemia. A diagnosis of virus-associated hemophagocytic syndrome was made and virology studies attributed it to herpes simplex virus type 1. Therapy with acyclovir, high dose i.v. immunoglobulins, and vinblastine was unsuccessful. With the addition of prednisone, a remission, with disappearance of histiocytic marrow involvement, was obtained but was of short duration, and the outcome was fatal.