Safety and efficacy of tafasitamab with or without lenalidomide added to first-line R-CHOP for DLBCL: the phase 1b First-MIND study.

Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.

The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT).

While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p = 0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits.

Lessons learned from the use of HRP-2 based rapid diagnostic test in community-wide screening and treatment of asymptomatic carriers of Plasmodium falciparum in Burkina Faso.

BACKGROUND: Rapid diagnostic tests (RDTs) are immune chromatographic tests targeting antigens of one or more Plasmodium species and offer the potential to extend accurate malaria diagnosis in endemic areas. In this study, the performance of Plasmodium falciparum-specific histidine-rich protein-2 (PfHRP-2) RDT in the detection of asymptomatic carriers from a hyperendemic region of Burkina Faso was compared with microscopy to gain further insight on its relevance in community-based interventions. METHODS: The performance of HRP-2 test was evaluated in terms of sensitivity, specificity, positive and negative predictive values, discordant values, likelihood ratios, accuracy, and precision using microscopy as the 'gold standard'. This analysis was carried out in a controlled, parallel, cluster-randomized (18 clusters; 1:1) study in children and adults. The effect of systematic treatment of P. falciparum asymptomatic carriers during three consecutive monthly community screening campaigns on the incidence of symptomatic malaria episodes over a 12-month period was compared with no treatment of asymptomatic carriers. RESULTS: Sensitivity of HRP-2 test in asymptomatic carriers was higher in campaign 1 (92.4%) when compared to campaign 2 (84.0%) and campaign 3 (77.8%). The sensitivity of HRP-2 test increased as parasite density increased across all the age groups. Highest sensitivity (≥97.0%) was recorded at parasite densities of 1,000-4,999/µl, except for children aged 10 to 14 years. The specificity of HRP-2 test was comparable across age groups and highest in campaign 3 (95.9%). The negative predictive values were high across the three campaigns (≥92.7%) while the positive predictive values ranged from 23.2 to 73.8%. False-positive and false-negative rates were high in campaign 1 and campaign 3, respectively. CONCLUSION: The performance of HRP-2 test in detecting asymptomatic carriers of P. falciparum varied by age and parasite density. Although the use of HRP-2 test is beneficial for the diagnosis of acute malaria, its low sensitivity in screening asymptomatic carriers may limit its utility in pre-elimination interventional settings. The use of a practical and more sensitive test such as loop-mediated isothermal amplification in combination with a cost effective HRP-2 test may be worth exploring in such settings.

Dynamics of malaria transmission and susceptibility to clinical malaria episodes following treatment of Plasmodium falciparum asymptomatic carriers: results of a cluster-randomized study of community-wide screening and treatment, and a parallel entomology study.

BACKGROUND: In malaria-endemic countries, large proportions of individuals infected with Plasmodium falciparum are asymptomatic and constitute a reservoir of parasites for infection of newly hatched mosquitoes. METHODS: Two studies were run in parallel in Burkina Faso to evaluate the impact of systematic identification and treatment of asymptomatic carriers of P. falciparum, detected by rapid diagnostic test, on disease transmission and susceptibility to clinical malaria episodes. A clinical study assessed the incidence of symptomatic malaria episodes with a parasite density >5,000/µL after three screening and treatment campaigns ~1 month apart before the rainy season; and an entomological study determined the effect of these campaigns on malaria transmission as measured by entomological inoculation rate. RESULTS: The intervention arm had lower prevalence of asymptomatic carriers of asexual parasites and lower prevalence of gametocyte carriers during campaigns 2 and 3 as compared to the control arm. During the entire follow-up period, out of 13,767 at-risk subjects, 2,516 subjects (intervention arm 1,332; control arm 1,184) had symptomatic malaria. Kaplan-Meier analysis of the incidence of first symptomatic malaria episode with a parasite density >5,000/µL showed that, in the total population, the two treatment arms were similar until Week 11-12 after campaign 3, corresponding with the beginning of the malaria transmission season, after which the probability of being free of symptomatic malaria was lower in the intervention arm (logrank p < 0.0001). Similar trends were observed in infants and children <5 years and in individuals ≥5 years of age. In infants and children <5 years old who experienced symptomatic malaria episodes, the geometric mean P. falciparum density was lower in the intervention arm than the control arm. This trend was not seen in those individuals aged ≥5 years. Over the year, monthly variation in mosquito density and entomological inoculation rate was comparable in both arms, with September peaks in both indices. CONCLUSION: Community screening and targeted treatment of asymptomatic carriers of P. falciparum had no effect on the dynamics of malaria transmission, but seemed to be associated with an increase in the treated community's susceptibility to symptomatic malaria episodes after the screening campaigns had finished. These results highlight the importance of further exploratory studies to better understand the dynamics of disease transmission in the context of malaria elimination.

A controlled, parallel, cluster-randomized trial of community-wide screening and treatment of asymptomatic carriers of Plasmodium falciparum in Burkina Faso.

BACKGROUND: In malaria-endemic countries, large proportions of infected individuals are asymptomatic, constituting a reservoir of parasites for infection of newly hatched mosquitoes. This study evaluated the impact of screening and treatment of asymptomatic carriers of Plasmodium falciparum. METHODS: Eighteen villages were randomized (1:1) to study arms and inhabitants participated in four community screening campaigns: three before the rainy season ~1 month apart, and the fourth after the rains at ~12 months. On day 1 of campaigns 1-3, asymptomatic carriers in the intervention arm were identified by rapid diagnostic test and treated with artemether-lumefantrine. Outcomes were symptomatic malaria with parasite density >5,000/µL per person-year in children < 5 years and change in haemoglobin between days 1 and 28 of campaign 1. RESULTS: At 12 months, the number of symptomatic malaria episodes with a parasite density >5,000/µL per person-year in children < 5 years was not significantly different between arms (1.69 vs 1.60, p = 0.3482). Mean haemoglobin change in asymptomatic carriers during campaign 1 was greater in the intervention vs control arm (+0.53 g/dL vs -0.21 g/dL, p < 0.0001). ANCOVA demonstrated that mean asymptomatic carriage at the cluster level was lower in the intervention vs control arm at day 1 of campaigns 2 (5.0% vs 34.9%, p < 0.0001) and 3 (3.5% vs 31.5%, p < 0.0001), but showed only a small difference at day 1 of campaign 4 (34.6% vs 37.6%, p = 0.2982). Mean gametocyte carriage was lower in the intervention vs control arm at day 1 of campaigns 2 and 3 (0.7% vs 5.4%, p < 0.0001; 0.5% vs 5.8%, p < 0.0001), but was similar at day 1 of campaign 4 (4.9% vs 5.1%, p = 0.7208). CONCLUSIONS: Systematic screening and treatment of asymptomatic carriers at the community level did not reduce clinical malaria incidence in the subsequent transmission season, indicating greater levels of parasite clearance are required to achieve a sustained impact in this setting.

Prediction of pre-eclampsia: comparative analysis of two screening tests.

Pre-eclampsia is a major cause of maternal and perinatal morbidity and mortality. Unfortunately, in spite of extensive research worldwide, still we lack an effective screening test for pre-eclampsia. The aim of the current study is to assess the importance of micro-albuminuria and uterine artery Doppler resistance index as a screening test for pre-eclampsia during antenatal period. The study is a prospective audit. The study population consisted of 160 antenatal mothers attending the outpatient department. Test for micro-albuminuria was done at 14 weeks, 18 weeks, 28 weeks and 34 weeks of gestation. Uterine artery Doppler resistance index (0.58 taken as cut-off) was recorded at 18 weeks of gestation. The subjects were followed up till delivery for development of pre-eclampsia. Sensitivity, specificity, positive and negative predictive value (along with confidence interval and diagnostic odd's ratio) of the tests were calculated. Sensitivity, specificity, positive and negative predictive value of micro-albuminuria was recorded as 66.67%, 93.24%, 44.44% and 97.18% respectively. Those of uterine artery Doppler resistance index were 33.33%, 95.96%, 40% and 94.67% respectively. Diagnostic odd's ratio of micro-albuminuria and uterine artery Doppler resistance index were 27.600 and 11.833 respectively. Confidence interval and diagnostic odd's ratios show that uterine artery Doppler study is a better screening test amongst the two. Both the tests being non-invasive in nature and having high specificity and high negative predictive value can be utilised in community-based antenatal care for identifying women who need intensive vigilance.

A case of endometrioma causing ureteric obstruction.

A 32 years old married woman presented at the outpatients' department with the complaints of pain lower abdomen and irregular heavy menstrual bleeding for last 6 months. She was married for 7 years and attended an infertility clinic. Diagnostic laparoscopy was carried out there which revealed an endometrioma arising from right overy. On bimanual examination a mass was palpable in the right fornix. USG and Intervenous pyelography were advised. The diagnosis was confirmed endometrioma from right ovary and right sided ureter as hydro-ureter and there was hydronephrosis. She was operated and the endometrioma was resected out. She was discharged on 10th postoperative day with the advice to take tablet danazol (400) orally daily for 2 months.

Pre-operative assessment of benign and malignant ovarian tumours using colour Doppler ultrasonography.

Ultrasonography of 56 women with adenexal masses who were admitted for laparotomy were done mainly by transvaginal route. Though Gray scale morphologic evaluations of masses were done routinely, only colour Doppler imaging criteria were taken into consideration in this study. These are pulsatility index (PI), resistance index (RI), peak systolic velocity (PSV), timed average maximal velocity (TAMXV), vessels localisation and dicrotic notch. Histopathological examination was done and considered as gold standard. In 83.78% cases of benign tumour PI is equal or greater than 1, whereas it was less than 1 in 84.21% in malignant ovarian tumour. The sensitivity, specificity, PPV and NPV were respectively 84.21%, 83.78%, 72.72% and 91.11%. RI in benign tumours were equal to or more than 0.4 in 81.08% and less than 0.4 in 68.42% in case of malignant tumours. The sensitivity, specificity, PPV and NPV were respectively 68.42%, 81.08%, 65% and 83.33%. Considering the TAMXV>12 cm/second as a criterion for malignancy the sensitivity, specificity, PPV and NPV were respectively 89.45%, 89.19%, 80.95% and 94.28%, and also considering septal/central localisation of vessels as a criterion for malignancy, it was found the sensitivity, specificity, PPV and NPV were 89.47%, 62.16%, 54.84% and 92% respectively. Considering absence of dicrotic notch for malignant tumours we found sensitivity, specificity, PPV and NPV were 89.47%, 81.08%, 70.83% and 93.75% respectively. The above findings of the PI, TAMXV and dicrotic notch evaluation show most useful was colour Doppler parameters for pre-operative screening for ovarian malignancy in this study.

Leiomyoma in a young woman with Mayer-Rokitansky-Huster-Hauser syndrome.

A 20 years old, unmarried woman attended OPD with the complaints of amenorrhoea (primary) and lower abdominal pain for last 3 months. Per abdominal examination revealed a mobile mass in the lower abdomen at the level of pubic symphysis. Per rectal examination revealed a midpelvic mass. Per vagina examination revealed vaginal opening was blind. On laparotomy a solid mass (8cm x 7cam) with bosselated surface was seen arising from the uterine bulb on the left side, which appeared and histopathologically correlated to be leiomyoma. The patient was discharged with a plan for further surgery of vaginoplasty.