Optimizing ReBreed21 II: Fertility and reproductive efficiency in different parities during a shortened breeding season in beef cattle.

This study evaluated the efficiency of a rapid reinsemination program allowing timed AI (TAI) every 21d (ReBreed21) in a commercial beef cow-calf operation. Nelore females from different parities (n = 2085) were synchronized for first TAI (D0 = TAI) using an estradiol/progesterone (E2/P4) protocol and assigned to one of three reinsemination programs: Resynch33 (n = 753), traditional resynch program with second TAI at D42 after first TAI; ReBreed21 (n = 687); or ReBreed21+EC (n = 670). The ReBreed females (n = 1357) received intravaginal P4 insert on D12, on D19 P4 was removed, and a dose of equine chorionic gonadotropin (eCG) was administered, then, ReBreed21 females received 0.6 mg of EC (ReBreed21+EC) or nothing (ReBreed21) and on D21, nonpregnancy (NP) was determined using Doppler ultrasound to detect corpus luteum (CL) blood flow (BF) (NP: <25 % BF pixels of total CL area) and NP cows received immediate TAI and GnRH to induce ovulation. Pregnancy diagnosis was performed at D33 after TAI following all TAIs. Cows considered pregnant at D21, based on CL BF, but NP on D33 were designated False-Positives (FP) and false negatives (FN) were number of nonpregnant cows/heifers on d21 based on the CL BF found to subsequently be pregnant on D33 divided by the total number pregnant. Pregnancy/AI (P/AI) did not differ for the first TAI (55.1 %) among the treatments. Heifers had similar P/AI at the second AI in all groups and similar to the first AI. Primiparous had greater P/AI in ReBreed21+EC and Resynch33 at s TAI compared to ReBreed21, 51.7 %, 55.8 %, 34.2 %, respectively. Multiparous had greater P/AI at second TAI in Resynch33 (60.9 %) than ReBreed21 programs (34.7 %). The percentage FP and FN among ReBreed21 programs did not differ, 13.8 and 0.2 %, respectively. Overall accumulative pregnancies on D21 of the breeding season were greater for ReBreed21 and ReBreed21+EC than Resynch33 (69.7 %, 71.6 %, and 55.5 %, respectively). However, on D42 of the breeding season, only heifers had greater pregnancies in ReBreed21 programs than Resynch33 (73.3 %, 74.3.6 %, and 63.2 %, respectively). Average days to pregnancy were less (P = 0.01) for ReBreed21 and ReBreed21+EC than Resynch33. Thus, the ReBreed21 strategy can improve the efficiency of TAI programs in beef cattle. Of interest, ReBreed21 was particularly effective in nulliparous, somewhat effective in primiparous when EC was added to the program, but relatively ineffective in multiparous beef cattle.

Timed-artificial insemination protocols for Bos indicus beef heifers: Evaluation of protocol length and variations in prostaglandin F2α treatments.

The aim was to compare reproductive outcomes of Nelore heifers submitted to timed AI (TAI) protocols, with 7 or 9 d of permanence of the intravaginal progesterone (P4) device and different times of prostaglandin F2α (PGF) administration, for first (n = 935) and second (n = 530) services. On Day -24, heifers without corpus luteum (CL) underwent a protocol for induction of ovulation. On Day 0, heifers received a P4 device (0.5 g) and 1.5 mg estradiol (E2) benzoate. In order for the TAI to be carried out on the same day, these treatments were performed 2 d later on the heifers treated with the 7-d protocol. Additionally, heifers received 0.5 mg PGF at different times, resulting in four experimental groups: 9dP4-PGFd9 (n = 365); 9dP4-PGFd7 (n = 369); 9dP4-PGFd0&9 (n = 364); 7dP4-PGFd0&7 (n = 367). These nomenclatures indicate for how many d the P4 device was kept and the specific day on which PGF was given. At P4 removal, all heifers received 0.5 mg E2 cypionate and 200 IU eCG, and TAI was performed 2 d later. Effects were considered significant when P ≤ 0.05 (superscript letters a,b) whereas a tendency was assumed when 0.05 < P ≤ 0.10. Groups 9dP4-PGFd0&9 and 7dP4-PGFd0&7 had lower percentage of heifers with CL at P4 removal. The diameter (mm) of the dominant follicle (DF) was affected by treatment at P4 removal (9dP4-PGFd9: 11.3 ± 0.3b; 9dP4-PGFd7: 11.8 ± 0.2ab; 9dP4-PGFd0&9: 12.6 ± 0.2a; 7dP4-PGFd0&7: 10.8 ± 0.2c) and at TAI (9dP4-PGFd9: 12.7 ± 0.3ab; 9dP4-PGFd7: 13.2 ± 0.2a; 9dP4-PGFd0&9: 13.4 ± 0.2a; 7dP4-PGFd0&7: 12.4 ± 0.3b). Expression of estrus (%) was affected by treatment (9dP4-PGFd9: 89.6a; 9dP4-PGFd7: 93.5a; 9dP4-PGFd0&9: 88.2ab; 7dP4-PGFd0&7: 85.6b). There were no differences among treatments for P/AI on Day 40 (30-35 d post AI), final P/AI (between Day 70 and parturition) and pregnancy loss (between Day 40 and final P/AI). When the permanence of the P4 device was compared, regardless of PGF treatments, 9-d protocols resulted in greater DF diameter at P4 removal and at TAI, and greater expression of estrus (90.4 vs. 85.6%) than the 7-d protocol. Despite that, the 7-d protocol resulted in greater P/AI on Day 40 (55.3 vs. 49.1%). In addition, there was an interaction between protocol duration and body weight, in which heavier heifers (≥ 307 kg) had greater P/AI when treated with the 7-d protocol, in comparison to 9-d. In conclusion, longer TAI protocols (9 d of P4 device duration) resulted in greater DF diameter and expression of estrus. However, the shorter TAI protocol (7 d of P4 device duration) produced greater P/AI on Day 40, particularly in heavier heifers. Within 9-d protocols, the additional dose of PGF on Day 0 or the anticipation of the PGF to Day 7 did not influence fertility.

Optimizing ReBreed21 I: Evaluation of endocrine and ovarian dynamics in non-bred Bos indicus heifers.

The present study evaluated follicular and endocrine dynamics during ReBreed21, a reproductive strategy that allows resynchronization of ovulation every 21 days in Bos indicus (Nelore) heifers. A synchronized estrous cycle was induced using a standard timed ovulation protocol (d -10: P4 implant inserted + 2 mg estradiol benzoate; d -2: P4 removed+ 0.5 mg cloprostenol + 0.6 mg estradiol cypionate + 200 IU equine chorionic gonadotropin (eCG); d0: 8.4 µg buserelin) without AI to ensure nonpregnancy in heifers. Day of GnRH was designated d0 of estrous cycle. On d12, heifers (n = 80) were randomized into three experimental groups: (1) ReBreed21 (n = 28) d12 P4 device inserted, d19 P4 device withdrawal plus 200 IU eCG, and d21 8.4 µg buserelin (GnRH); (2) ReBreed21+G (n = 26) same as ReBreed21 plus GnRH (16.8 µg) treatment on d12; and (3) Control (n = 26) no treatment. ReBreed21+G increased two-fold (62.9%; 18/26) percentage of heifers with synchronized follicular wave emergence compared to Control (34.6%; 9/26) whereas ReBreed21 (53.6%; 15/28) was intermediate. The ReBreeed21 groups (eCG on d19) increased (P < 0.01) follicular growth between d19 and d21 in ReBreed21 (2.3 ± 0.2 mm) and ReBreed21+G (3.4 ± 0.2 mm) compared with Control (1.2 ± 0.3 mm), resulting in greater (P < 0.01) follicle diameter on d21 for ReBreed21 (10.7 ± 0.4 mm) and ReBreed21+G (10.8 ± 0.4 mm) compared with Control (9.1 ± 0.5 mm). Structural luteolysis was similar among groups (P = 0.51), although the average day when P4 was <1 ng/mL was later (P < 0.01) for ReBreed21 (20.5 ± 0.2) and ReBreed21+G (20.7 ± 0.2) compared to Control (19.2 ± 0.4). Overall ovulation at the end of the estrous cycle was increased (P = 0.03) for ReBreed21 groups (83.3%; 45/54) compared with Control (57.7%; 15/26). Synchronized ovulation on day 22-23 was greater (P < 0.01) for ReBreed21 (78.6%; 22/28) and ReBreed21+G (76.9%; 20/26) compared with Control (30.8%; 8/26). Thus, the ReBreed21 resynchronization program produced acceptable endocrine and follicular dynamics, including synchronized ovulation at the end of the protocol in nonpregnant heifers providing good rationale for testing the fertility and practical implementation of this protocol under field conditions.

Comparison of GnRH vs. estradiol benzoate plus GnRH to initiate a progesterone-based timed-artificial insemination resynchronization protocol in lactating dairy cows.

The present study compared 2 strategies to initiate a progesterone (P4)-based timed-artificial insemination (TAI) protocol for lactating dairy cows: only GnRH or estradiol benzoate (EB) plus GnRH. Lactating Holstein cows (n = 487; 184 primiparous and 303 multiparous) from 2 commercial dairy herds were used for their second or greater services postpartum. Weekly nonpregnant cows at pregnancy diagnosis 32 d after a previous AI were randomly assigned to 1 of 2 experimental groups that differed only in the strategy to initiate (d 0) the TAI protocol. On d 0, every cow received a 2.0 g P4 implant, and in Group EB+GnRH, cows were treated with 2.0 mg i.m. of EB and 16.8 µg i.m. of buserelin acetate (GnRH), while in Group GnRH, cows received only 16.8 µg i.m of GnRH. Seven d later (d 7), 0.530 mg i.m. of cloprostenol sodium (PGF) was administered in all cows, followed by a second dose on d 8, concomitant with 1.0 mg i.m. of estradiol cypionate (EC) and P4 implant withdrawal. The TAI was performed on d 10 (48 h after P4 device withdrawal) in both experimental groups. Only conventional Holstein semen was used throughout the study. The percentage of cows with corpus luteum (CL) on d 0 (73%) and overall ovulation rate after d 0 (54%) did not differ between groups. The CL regression between d 0 and the first PGF treatment was greater in EB+GnRH than GnRH group (42 vs. 31%). Consequently, the proportion of cows with CL at PGF was greater when only GnRH was used on d 0 compared with EB plus GnRH (86 vs. 82%), and the mean number of CL at PGF was greater (1.23 vs. 1.11). The expression of estrus near TAI was greater in GnRH group (84 vs. 77%), and cows showing estrus had greater (44 vs. 10%) pregnancy per AI (P/AI) on d 32 for both treatments. There was no effect of the presence of CL on d 0 or at PGF, nor of ovulation after d 0 or CL regression between d 0 and d 7 on fertility. However, fertility was critically impaired when cows did not have CL at both times, d 0 and at PGF treatment. There was no interaction between treatment and other variables, and the P/AI was similar in cows receiving EB plus GnRH or only GnRH on d 0 (37.8 vs. 36.6%). In summary, although there was no detectable difference in P/AI between treatments, this study demonstrated potential negative physiological outcomes caused by EB treatment on d 0 (greater incidence of luteolysis after d 0 and fewer cows with CL at PGF treatment). In conclusion, there was no benefit of adding EB at the initiation of a P4-based TAI protocol on fertility compared with using GnRH alone, despite differences in ovarian dynamics and expression of estrus.

A real-life study of daratumumab-bortezomib-dexamethasone (D-VD) in lenalidomide exposed/refractory multiple myeloma patients: a report from the Triveneto Myeloma Working Group.

Treatment of lenalidomide refractory (Len-R) multiple myeloma (MM) patients still represents an unmet clinical need. In the last years, daratumumab-bortezomib-dexamethasone (D-VD) combination was extensively used in this setting, even though only a small fraction of Len-R patients was included in the pivotal trial. This real-life study aimed to evaluate the efficacy and safety of the D-VD regimen in a cohort that exclusively enrolled Len exposed or refractory MM patients. The study cohort included 57 patients affected by relapsed/refractory MM. All patients were previously exposed to Len, with 77.2% being refractory. The overall response rate (ORR) was 79.6% with 43% of cases obtaining at least a very good partial response (VGPR). The D-VD regimen showed a favorable safety profile, with low frequency of grade 3-4 adverse events, except for thrombocytopenia observed in 21.4% of patients. With a median follow-up of 13 months, median progression-free survival (PFS) was 17 months. No significant PFS differences were observed according to age, ISS, LDH levels, type of relapse, and high-risk FISH. Len exposed patients displayed a PFS advantage as compared to Len refractory patients (29 vs 16 months, p = 0.2876). Similarly, patients treated after Len maintenance showed a better outcome as compared to patients who had received a full-dose Len treatment (23 vs 13 months, p = 0.1728). In conclusion, our real-world data on D-VD combination showed remarkable efficacy in Len-R patients, placing this regimen as one of the standards of care to be properly taken into account in this MM setting.

Research on timed AI in beef cattle: Past, present and future, a 27-year perspective.

This review aimed to (1) summarize the results from fixed-timed artificial insemination (TAI) fertility studies performed during the last 27 years; (2) compile and evaluate, as examples from the literature base, the direct comparisons made of specific manipulations to synchronization protocols; (3) evaluate the impact of the TAI programs on the reproductive performance during the breeding season, and (4) provide perspective on the future of TAI programs in beef cattle. A search of the literature published from 1995 to 2021 was conducted to identify experiments in which synchronization of ovulation and TAI in beef cattle was performed. The primary outcome of interest was fertility expressed as pregnancies per TAI. The literature included two search engines, the SIS Web of Science and the US National Library of Medicine Institutes of Health through PubMed. After the initial search and screening, a total of 228 manuscripts were selected containing a total of 272,668 TAI. A dramatic increase in the number of publications and TAIs occurred throughout the years. Most of them were from Brazil and United States, followed by Canada, Argentina, Uruguay, and Australia. Two main types of TAI programs were identified: GnRH-based and E2/P4-based protocols. In terms of GnRH-based programs, two variations were evaluated in the present manuscript. First, we evaluated the effect of the progesterone implant during the protocol. The progesterone implant increased pregnancy/TAI (P/TAI) from 44.3 to 54.3%. Second, the use of a second prostaglandin F2α treatment in 5-d CO-synch program increased the P/TAI from 53.2 to 60.9%. In E2/P4-based programs, use of GnRH at TAI increased P/TAI from 54.7 to 59.2% in cows. However, no increase was detected in heifers. Other research showed that use of TAI can increase the overall proportion of the cows pregnant at end of the breeding season and produce earlier calvings compared with bulls. In conclusion, there have been a large number of excellent research studies that have been performed during the last 27 years on TAI in beef cattle. This technology is being utilized successfully in the beef cattle industry. This success is largely because of the valid research that underlies the application of the technology and the economic value of the technology.

A Fondazione Italiana Linfomi cohort study of R-COMP vs R-CHOP in older patients with diffuse large B-cell lymphoma.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the most commonly used regimen for the upfront treatment of diffuse large B-cell lymphoma (DLBCL). However, it is associated with cardiotoxicity, especially in older patients. Substituting doxorubicin with non-PEGylated liposomal doxorubicin (R-COMP) may reduce the risk of cardiac events, but its efficacy has never been demonstrated in prospective trials. We describe the characteristics and outcome of patients with DLBCL aged ≥65 years prospectively enrolled in the Elderly Project by the Fondazione Italiana Linfomi and treated with full doses of R-CHOP or R-COMP per local practice. Starting from 1163 patients, 383 (55%) were treated with R-CHOP and 308 (45%) with R-COMP. Patients treated with R-COMP were older (median age, 76 vs 71 years), less frequently fit at simplified geriatric assessment (61% vs 88%; P < .001), and had a more frequent baseline cardiac disorders (grade >1, 32% vs 8%; P < .001). Three-year progression-free survival (PFS) was similar between R-CHOP and R-COMP (70% and 64%); 3-year overall survival was 77%, and 71% respectively. R-CHOP was associated with better PFS vs R-COMP only in the Elderly Prognostic Index (EPI) low-risk group. The two groups had similar rates of treatment interruptions due to toxicities or of cardiac events (P = 1.00). We suggest R-COMP is a potentially curative treatment for older patients with intermediate- or high-risk EPI, even in the presence of a baseline cardiopathy. R-CHOP is confirmed as the standard therapy for low risk patients.

Effect of progesterone from corpus luteum, intravaginal implant, or both on luteinizing hormone release, ovulatory response, and subsequent luteal development after gonadotropin-releasing hormone treatment in cows.

This study aimed to determine the effect of circulating progesterone (P4) concentrations produced by a corpus luteum (CL) or released by an intravaginal P4 implant (IPI) on GnRH-induced LH release, ovulatory response, and subsequent CL development, after treatment with 100 µg of gonadorelin acetate (GnRH challenge). Nonlactating multiparous Holstein cows were synchronized and GnRH was used to induce ovulation (d -7). Over 4 replicates, cows that ovulated (n = 87) were randomly assigned to a 2 × 2 factorial arrangement (presence or absence of CL and insertion or not of an IPI at GnRH challenge), creating 4 groups: CL_IPI, CL_NoIPI, NoCL_IPI, and NoCL_NoIPI. On d -1.5, NoCL_IPI and NoCL_NoIPI received 2 doses of 0.53 mg of cloprostenol sodium (PGF2α), 24 h apart to regress CL. On d 0, cows were treated with 100 µg of GnRH and, simultaneously, cows from IPI groups received a 2-g IPI maintained for the next 14 d. Diameter of dominant follicle, ovulatory response, and subsequent CL volume were assessed by ultrasonography on d -1.5, 0, 2, 7, and 14. Blood samples were collected on d -1.5, 0, 1, 2, 3, 5, 7, and 14 for analysis of circulating P4 and at 0, 1, 2, 4, and 6 h after GnRH challenge for analysis of circulating LH. In a subset of cows (n = 34), the development of the new CL was evaluated daily, from d 5 to 14. The presence of CL at the time of GnRH challenge affected the LH peak and ovulatory response (CL: 5.3 ng/mL and 58.1%; NoCL: 13.2 ng/mL and 95.5%, respectively). However, despite producing a rapid increase in circulating P4, IPI insertion did not affect LH concentration or ovulation. Regardless of group, ovulatory response was positively correlated with LH peak and negatively correlated with circulating P4 on d 0. Moreover, new CL development and function were negatively affected by the presence of CL and by the IPI insertion. In summary, circulating P4 produced by a CL exerted a suppressive effect on GnRH-induced LH release and subsequent ovulation of a 7-d-old dominant follicle, whereas the IPI insertion at the time of GnRH had no effect on LH concentration or ovulation. Finally, elevated circulating P4, either from CL or exogenously released by the IPI, compromised the development and function of the new CL, inducing short cycles in cows without CL at the time of GnRH treatment.

Relationships among total mixed ration nutritional components and reproductive performance in high-producing dairy herds.

The main objective of the present study was to determine whether composition of total mixed ration influences reproductive performance in high-producing commercial dairy farms. Dairy producers and nutritional consultants from 48 dairy farms located in Wisconsin agreed to provide reproductive data and dietary information on high milk production pens during the main breeding period for the previous 12 mo. Dietary components (percentage of dry matter) were crude protein (CP), rumen degradable (RDP) and undegradable (RUP) protein, neutral detergent fiber (NDF), nonfiber carbohydrates (NFC), starch, and fat. Reproductive data were service rate (SR), overall pregnancy per artificial insemination (P/AI) and P/AI at the first service, 21-d pregnancy rate (PR), days open, and percentage of cows pregnant by 150 d in milk (PREG150). Participating herds had lactating Holstein cows (range = 143 to 2,717) housed in freestall facilities. Statistical analyses were performed with CORR and GLIMMIX of SAS (SAS Institute Inc.). Daily average milk production of herds was 38.9 ± 0.60 kg/d (30.0 to 50.4 kg/d). Overall SR was 58.5% (39-73) and P/AI was 36.1% (22-49). Overall 21-d PR was 20.3% (10-42%). Correlation between SR and PR was 0.59, whereas correlation of overall P/AI and P/AI at first service with PR were both 0.72. Similarly, for PREG150, correlation with overall P/AI (0.63) and P/AI at first service (0.66) were greater than with SR (0.48). There was large variation in diet composition, with CP varying from 16.0 to 18.7%, NDF from 24.9 to 35.1%, NFC from 31.7 to 46.6%, starch from 20.1 to 30.8%, and fat from 3.1 to 6.7%. Overall, there were no detectable associations of CP, RDP, and RUP with reproductive measures. The strongest relationship was a decrease in reproductive performance with increasing dietary NFC including overall P/AI (-0.48), P/AI at first service (-0.51), and PREG150 (-0.33). Starch also had a negative relationship with P/AI at first service (-0.35). Conversely, greater NDF was positively associated with P/AI at first service (0.34). Fat content was also positively associated with P/AI at first service (0.34). When NFC was divided in tertiles (<40, 40 to 42.2, and >42.2% NFC), the highest tertile had lower overall P/AI (39 vs. 36 vs. 31%), P/AI at first service (43 vs. 40 vs. 33%), and PREG150 (54 vs. 53 vs. 47%). In conclusion, farms with greater dietary NFC may have compromised reproductive performance. Correspondingly, herds with greater NDF content may achieve high milk production with potentially positive associations with reproduction. Other relationships of dietary components on reproduction were not as obvious in this herd-level analysis.

Biological features and outcome of diffuse large B-cell lymphoma associated with hepatitis C virus in elderly patients: Results of the prospective 'Elderly Project' by the Fondazione Italiana Linfomi.

Up to 10%-15% of diffuse large B-cell lymphoma (DLBCL) are related to hepatitis C virus (HCV) infection, in particular in elderly patients. The Fondazione Italiana Linfomi has recently published a multicentre prospective observational study, the 'Elderly Project', on the outcome of DLBCL in patients aged ≥65 years, evaluated using a simplified comprehensive geriatric assessment. The aim of this study was to compare biological and clinical features of HCV positive (HCV+) with HCV negative (HCV-) cases. A total of 89 HCV+ patients were identified out of 1095 evaluated for HCV serology (8.1%). The HCV+ patients were older, less fit, and had frequent extranodal involvement. The cell-of-origin determination by Nanostring showed that HCV+ cases less frequently had an activated B-cell profile compared to HCV- patients (18% vs. 43%). In all, 86% of HCV+ patients received rituximab-cyclophosphamide, doxorubicin, vincristine (Oncovin) and prednisone (R-CHOP)-like immunochemotherapy. Grade 3-4 liver toxicity occurred in 3% of cases. Among centrally reviewed cases confirmed as DLBCL, the 3-year overall survival of HCV+ patients was very similar to HCV- (63% vs. 61%, p = 0.926). In all, 20 HCV+ patients were treated with direct-acting antiviral agents (DAAs), with good tolerance and sustained virological response in all cases. The 3-year progression-free survival for this subgroup was excellent (77%), suggesting DAAs' possible role in reducing the risk of relapse by eliminating the viral trigger.

What are the factors associated with pregnancy loss after timed-artificial insemination in Bos indicus cattle?

Pregnancy loss (PL) has important impacts on the profitability of livestock production systems, although it is not widely reported, particularly in Bos indicus cattle. The present study retrospectively evaluated PL after timed-artificial insemination (TAI) in Bos indicus (Nelore) beef cows corresponding to several factors, such as parity, body condition score (BCS), presence of corpus luteum (CL) at the beginning of TAI protocols, expression of estrus, and hormonal manipulations during the TAI protocol. Data from two experiments performed during three breeding seasons (BS) were reanalyzed. Both experiments evaluated adding GnRH treatment at TAI in a 7-d estradiol (E2) plus progesterone (P4)-based protocol, with intravaginal P4 implant removal on Day 7 combined with treatment with 0.5 or 1.0 mg E2 cypionate and 300 IU eCG, and TAI on Day 9. In addition, during BS 2 and 3 (Exp 2), cows were randomized to receive or not a PGF treatment on Day 0 (beginning of the TAI protocol). In all BS, presence of CL and BCS were evaluated at the beginning of TAI protocols, follicle size and expression of estrus were evaluated at TAI. The PL was assessed between the first pregnancy diagnosis (∼35d) and parturition. There were no effects of hormonal manipulations within TAI protocols of different BS on PL. There was no interaction between GnRH treatment at TAI and the other variables within BS, and there was no main effect of GnRH treatment on PL (without = 10.1% [102/1007] vs. with = 10.4% [114/1100]). The addition of PGF on Day 0 had no effect on PL (11.5% [102/886] vs. 10.5% [89/850]), as well as EC dose to induce final ovulation (10.8% [89/827] vs. 11.2% [102/909] for 0.5 and 1.0 mg, respectively). Primiparous had greater PL than multiparous cows (14.0% [77/550] vs. 8.9% [139/1557]), and cows not expressing estrus near TAI had greater PL than those expressing estrus (13.5% [57/422] vs. 9.7% [156/1617]). There was no interaction between follicle size at TAI and GnRH treatment on PL. However, probability of PL decreased linearly as follicle size at TAI increased. There were no effects of service number (first TAI or resynchronization), BCS, or presence of CL on D0 on PL. In addition, PL was not affected by sire within any of the BS. In conclusion, some factors that are known to impact pregnancy per AI also influenced PL, such as parity and expression of estrus, although, other aspects such as BCS, number of services, and presence of CL on D0 did not affect PL. Moreover, commonly implemented treatments to increase fertility (e.g., PGF on Day 0 and increasing EC dose to 1.0 mg) did not affect PL. Finally, the GnRH treatment at TAI had no effect on PL and did not interact with any of the variables, an important result, since GnRH at TAI also increases fertility in Bos indicus beef cows.

Diffuse large B-cell lymphoma in octogenarians aged 85 and older can benefit from treatment with curative intent: a report on 129 patients prospectively registered in the Elderly Project of the Fondazione Italiana Linfomi (FIL).

Octogenarian patients with diffuse large B-cell lymphoma are managed mainly with palliation, but recent improvement in their overall condition makes potentially curative treatment a possibility. Studies have shown that half of selected octogenarians may be cured using reduced-dose anthracycline chemoimmunotherapy. However, patients aged >85 (late octogenarians [LO]) were underrepresented, and selection criteria were poorly defined. We analyzed the clinical characteristics and outcomes of LO enrolled in the FIL Elderly Project in terms of the treatment received (palliative vs. curative) and of their simplified geriatric assessment (sGA), then compared them with early octogenarians (EO) aged 80- 84 and with those aged 65-79 classified as UNFIT or FRAIL according to sGA enrolled in the same study. Of the 1,163 patients, 370 were >80 and 129 LO. Clinical characteristics were similar between LO and EO, but LO more frequently received palliation (50% vs. 23%; P=0.001) and had worse 2-year overall survival (OS) (48% vs. 63%; P=0.001) and 2-year progression-free survival (PFS) (43% vs. 56%; P=0.01). Patients receiving anthracycline did better than patients receiving palliation (P<0.001), without any difference between full or reduced doses. Rituximab within palliation improved outcome (2-yr OS with or without rituximab 42% vs. 22%; P=0.008). Elderly Prognostic Index (EPI) performed better than sGA in identifying different risk categories, and high-risk EPI retained an independent unfavorable effect on OS and PFS, together with treatment without anthracycline. In conclusion, late octogenarians can benefit from a curative approach with reduced-dose anthracycline and from rituximab within palliation. EPI may help in patient selection more than sGA can.

The elderly prognostic index predicts early mortality in older patients with diffuse large B-cell lymphoma. An ad hoc analysis of the elderly project by the Fondazione Italiana Linfomi.

The Elderly Prognostic Index (EPI) is based on the integration of a simplified geriatric assessment, hemoglobin levels and International Prognostic Index and has been validated to predict overall survival in older patients with diffuse large B-cell lymphoma (DLBCL). In this study, we evaluated the ability of EPI to predict the risk of early mortality. This study included all patients registered in the Elderly Project for whom treatment details and a minimum follow-up of 3 months were available. Three main treatment groups were identified based on the anthracycline amount administered: cases receiving >70% of the theoretical anthracyclines dose (Full Dose [FD] group), ≤70% (Reduced Dose [RD]) and palliative therapy (PT; no anthracyclines). The primary endpoint was early mortality rate, defined as death for any cause occurring within 90 days from diagnosis. We identified 1150 patients with a median age of 76 years (range 65-94). Overall, 69 early deaths were observed, accounting for 19% of all reported deaths. The cumulative rate of early mortality at 90 days was 6.0%. Comparing early with delayed deaths, we observed a lower frequency of deaths due to lymphoma progression (42% vs. 75%; p < 0.001) and a higher frequency due to toxicity and infections (22% vs. 4%, p < 0.001, and 22% vs. 3%, p < 0.001, respectively) for early events. A multivariable logistic analysis on 931 patients (excluding PT) confirmed an independent association of high-risk EPI (odds ratio [OR] 3.60; 95% confidence interval [CI] 1.15-11.2) and bulky disease (OR 2.08; 95% CI 1.09-3.97) with the risk of early mortality. The cumulative incidence of early mortality for older patients with DLBCL is not negligible and is mainly associated with non-lymphoma related events. For patients receiving anthracyclines, high-risk EPI and bulky disease are associated with a higher probability of early mortality.

Improved fertility following a gonadotropin-releasing hormone treatment on day 2 of an estradiol and progesterone-based timed-artificial insemination protocol in lactating dairy cows.

The present study evaluated the addition of gonadotropin-releasing hormone (GnRH) concomitant or 2 d after the beginning of protocols initiated with estradiol benzoate (EB). A total of 459 multiparous and 371 primiparous lactating Holstein cows were enrolled in the study. Weekly cohorts of cows were randomly assigned to 1 of 3 experimental groups that differed in the strategy to initiate the timed AI (TAI protocol. On d 0, all cows received a 1.55-g progesterone (P4) implant. Additionally, cows in the EBd0 group received 2 mg of EB i.m.; cows in the EBd0-GnRHd0 group were treated simultaneously on d 0 with 2 mg of EB plus 100 µg of gonadorelin diacetate tetrahydrate (GnRH) i.m.; and cows in the EBd0-GnRHd2 group received 2 mg of EB on d 0 and 100 µg of GnRH 48 h later (d 2). The remaining treatments in the protocol were similar among groups and included 0.53 mg (i.m.) of cloprostenol sodium (PGF2α) on d 7, followed by a second PGF2α treatment on d 9 (at the time of P4 implant withdrawal) and 1 mg of estradiol cypionate i.m. Then, TAI was performed on d 11 (48 h after P4 removal) in all experimental groups. We detected an effect of treatment on pregnancy per AI (P/AI) on d 30, in which cows from the EBd0-GnRHd2 group demonstrated greater fertility than EBd0 cows, whereas cows in the EBd0-GnRHd0 group did not differ among EBd0 and EBd0-GnRHd0 (40.5 vs. 30.4 vs. 34.4%, respectively). In summary, GnRH treatment at the beginning of an estradiol and P4-based TAI protocol increased fertility only when GnRH was given on d 2. Moreover, a more pronounced positive effect of this strategy was observed in particular classes of cows: multiparous cows, cows with greater milk production, and those receiving the first service.

Ibrutinib improves survival compared with chemotherapy in mantle cell lymphoma with central nervous system relapse.

Central nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood-brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.

Low levels of sulfur and cobalt during the pre- and periconceptional periods affect the oocyte yield of donors and the DNA methylome of preimplantation bovine embryos.

Maternal nutrition is critical in mammalian development, influencing the epigenetic reprogramming of gametes, embryos, and fetal programming. We evaluated the effects of different levels of sulfur (S) and cobalt (Co) in the maternal diet throughout the pre- and periconceptional periods on the biochemical and reproductive parameters of the donors and the DNA methylome of the progeny in Bos indicus cattle. The low-S/Co group differed from the control with respect to homocysteine, folic acid, B12, insulin growth factor 1, and glucose. The oocyte yield was lower in heifers from the low S/Co group than that in the control heifers. Embryos from the low-S/Co group exhibited 2320 differentially methylated regions (DMRs) across the genome compared with the control embryos. We also characterized candidate DMRs linked to the DNMT1 and DNMT3B genes in the blood and sperm cells of the adult progeny. A DMR located in DNMT1 that was identified in embryos remained differentially methylated in the sperm of the progeny from the low-S/Co group. Therefore, we associated changes in specific compounds in the maternal diet with DNA methylation modifications in the progeny. Our results help to elucidate the impact of maternal nutrition on epigenetic reprogramming in livestock, opening new avenues of research to study the effect of disturbed epigenetic patterns in early life on health and fertility in adulthood. Considering that cattle are physiologically similar to humans with respect to gestational length, our study may serve as a model for studies related to the developmental origin of health and disease in humans.

Progesterone release profile and follicular development in Nelore cows receiving intravaginal progesterone devices.

This study aimed to evaluate the progesterone (P4) release profile provided by four commercially available intravaginal P4 devices, as well as the effect of circulating P4 concentrations exclusively from these devices on the development of the dominant follicle (DF) in Nelore (Bos indicus) cows. Therefore, non-lactating multiparous Nelore cows were enrolled in an experimental design, over three replicates, starting on Day -9 with the insertion of a reused P4 device (2 g - original P4 load) for 7 d, followed by two treatments of cloprostenol sodium (PGF; 0.482 mg), 24 h apart, on Days -3 and -2. Just before device removal, on Day -2, a norgestomet ear implant was inserted and, 2 d later (Day 0), at the time of norgestomet withdrawal, cows were randomly assigned to receive one of the intravaginal devices: Primer (0.5 g); Prociclar (0.75 g); Sincrogest (1 g); or CIDR (1.9 g), and 2 mg of estradiol benzoate (EB) im. Blood samples were collected immediately before P4 device insertion, 12 h later and daily over 15 d (1 d after P4 device removal). Ultrasound examinations were performed on Days 0, 7, 8, 9, 10, 12, and 14 to evaluate ovarian dynamics. Results are presented as mean ± SEM and differences were considered when P ≤ 0.05. Overall, the devices resulted in distinct circulating P4 concentrations over 10 d, varying according to their initial P4 load and P4 impregnated surface area. Primer provided the lowest circulating P4 concentrations over time, whereas, CIDR had the greatest concentration. Sincrogest and Prociclar were similar, producing intermediary circulating P4. There was no effect of treatment on the DF diameter on any specific day, nor on follicular growth rate from Day 7-10. However, the Primer device resulted in a greater mean DF diameter over time. Additionally, greater circulating P4 concentrations, mainly during the first 3 d of device insertion, were associated with smaller DF diameters regardless of the treatment. In conclusion, results from this study provided a better understanding of the P4 profile of intravaginal P4 devices, as well as, their effect on DF development in Bos indicus cows. These data contribute to optimize the use of P4 devices in the reproductive management of beef cattle.

Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.

BACKGROUND: Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed. METHODS: In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score. RESULTS: After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%). CONCLUSIONS: This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.

Accessory corpus luteum regression during pregnancy II: reproductive outcomes.

The objective of this study was to evaluate the effect of accessory corpus luteum (CL) induction on fertility in dairy cows. On day 5 after artificial insemination (AI), lactating Holstein cows were assigned unequally to receive gonadotrophin-releasing hormone treatment (GnRH) (n = 641) or no treatment (control; n = 289). Cows had their blood sampled for progesterone (P4), and ovaries were scanned by ultrasound on days 5, 12, 19, 26, 33, 47, and 61 after AI. Pregnancy diagnosis was performed on days 26, 33, 47, and 61. On day 12, cows treated with GnRH were allocated to ipsilateral (n = 239) or contralateral (n = 241) groups based on the side of accessory CL formation relative to previous ovulation. Accessory CL cows had greater P4 than controls. In total, 52.7% (78/148) of pregnant cows in contralateral group had accessory CL regression earlier (

Accessory corpus luteum regression during pregnancy I: timing, physiology, and P4 profiles.

Inappropriate corpus luteum (CL) regression can produce pregnancy loss. An experimental model was utilized to investigate regression of accessory CL during pregnancy in dairy cows. Cows were bred (day 0) and treated with gonadotrophin-releasing hormone 6 days later to form accessory CL. Transrectal ultrasound (every other days) and blood samples for progesterone (P4; daily) were performed until day 56 of pregnancy. On day 28, 13 cows were confirmed pregnant, and accessory CL were found contralateral (n = 9) or ipsilateral (n = 4) to previous ovulation. On day 18, CL biopsy was performed to analyze mRNA expression for interferon-stimulated genes (ISGs). Luteolysis occurred more frequently in cows that had contralateral accessory CL (88.9% (8/9)) than in cows with ipsilateral accessory CL (0% (0/4)). Luteolysis of contralateral accessory CL occurred either earlier (days 19-23; 2/8) or later (days 48-53; 6/8) in pregnancy and occurred rapidly (24 h), based on daily P4. After onset of earlier or later accessory CL regression, circulating P4 decreased by 41.2%. There was no difference in luteal tissue mRNA expression for ISGs on day 18 between accessory and original CL and between CL that subsequently regressed or did not regress. On day 56, an oxytocin challenge dramatically increased prostaglandin F2α metabolite (PGFM) in all cows but produced no pregnancy losses, although cows with previous accessory CL regression had greater PGFM. In summary, ipsilateral accessory CL did not regress during pregnancy, whereas most contralateral CL regressed by 63 days of pregnancy, providing evidence for local mechanisms in regression of accessory CL and protection of CL during pregnancy.