Conventional High Dose Research Articles

Effect of Combined Low Dose Human Gonadotropic Hormone, Follicle Stimulating Hormone, and Testosterone Therapy (LFT Regimen) Versus Conventional High Dose Human Gonadotropic Hormone and Follicle Stimulating Hormone on Spermatogenesis and Biomarkers in Men With Hypogonadotropic Hypogonadism

ObjectiveIn male Congenital hypogonadotropic hypogonadism(CHH), it was observed that lower dose human gonadotropic hormone(hCG) can maintain normal intratesticular testosterone(ITT) levels. We propose this study to compare the Low-Dose hCG, follicle stimulating hormone(FSH), and Testosterone(T) [LFT Regimen] to conventional treatment to induce virilization and fertility. DesignThis open-label randomized pilot study was conducted from June 2020 to December 2021. Subjects and outcome measuresCHH were randomly assigned to either the LFT regimen (Group A)-low-dose hCG (500U thrice per week), FSH(150U thrice per week) and T(100mg biweekly) or conventional therapy(GroupB) with high hCG dose(2000U thrice per week) and the same FSH dose. The hCG dosage was titrated to reduce Anti-mullerian hormone(AMH) by 50% and normalization of plasma T in groups A and B, respectively. The primary objective was to compare the percentage of individuals who achieved spermatogenesis between the two groups. ResultsOut of 30 patients, 23(76·7%) subjects achieved spermatogenesis, and the median time was 12(9-14·9)months. There was no difference in achieving spermatogenesis between the two groups (64·3%vs87·5%,p=0·204), and even the median time for spermatogenesis was similar (15monthsvs12months,p=0·248). Both groups had non-significant median plasma AMH at spermatogenesis,[6·6ng/ml(3·3-9·76) vs 4·41ng/ml(2·3-6·47),p=0·298]. Similarly, the median plasma Inhibin B at spermatogenesis between groups were comparable[152·4pg/ml(101·7-198·0)vs149·1pg/ml(128·7-237·3),p=0·488]. ConclusionsA reasonable approach to induce fertility in male CHH is to initiate combination therapy using FSH, low-dose hCG targeting AMH <6·9 ng/ml, along with T to achieve normal range. Monitoring AMH could serve as a proxy indicator of spermatogenesis.

169Yb-based high dose rate intensity modulated brachytherapy for focal treatment of prostate cancer

PurposeThis study compares conventional 192Ir-based high dose rate brachytherapy (HDR-BT) with 169Yb-based HDR intensity modulated brachytherapy (IMBT) for focal prostate cancer treatment. Additionally, the study explores the potential to generate less invasive treatment plans with IMBT by reducing the number of catheters needed to achieve acceptable outcomes. Methods and MaterialsA retrospective dosimetric study of ten prostate cancer patients initially treated with conventional 192Ir-based HDR-BT and 5-14 catheters was employed. RapidBrachyMCTPS, a Monte Carlo-based treatment planning system was used to calculate and optimize dose distributions. For 169Yb-based HDR IMBT, a custom 169Yb source combined with 0.8 mm thick platinum shields placed inside 6F catheters was used. Furthermore, dose distributions were investigated when iteratively removing catheters for less invasive treatments. ResultsWith IMBT, the urethra D10 and D0.1cc decreased on average by 15.89 and 15.65 percentage points (pp) and the rectum V75 and D2cc by 1.53 and 11.54 pp, respectively, compared to the conventional clinical plans. Similar trends were observed when the number of catheters decreased. On average, there was an observed increase in PTV V150 from 2.84 pp with IMBT when utilizing all catheters to 8.83 pp when four catheters were removed. PTV V200 increased from 0.42 to 2.96 pp on average. Hotspots in the body were however lower with IMBT compared to conventional clinical plans. Conclusions169Yb-based HDR IMBT for focal treatment of prostate cancer has the potential to successfully deliver clinically acceptable, less invasive treatment with reduced dose to organs at risk.

Cardiac safety of pegylated liposomal doxorubicin after conventional doxorubicin exposure in patients with sarcoma and breast cancer.

388 Background: Lifetime cumulative doses of conventional doxorubicin (&gt;450 mg/m2) are associated with dose-dependent cardiotoxicity. In soft tissue sarcoma (STS) and breast cancer, conventional doxorubicin is often utilized in earlier lines of therapy, whereas pegylated liposomal doxorubicin (PLD) is typically reserved for recurrent and metastatic disease. PLD is associated with less cardiotoxicity than conventional doxorubicin and high doses of PLD can be administered without increased risk of cardiotoxicity in patients without prior exposure to conventional doxorubicin. Limited data exists evaluating cardiotoxicity associated with PLD treatment after conventional doxorubicin, especially when doxorubicin lifetime doses approach the established cumulative total lifetime dose of 450-550 mg/m2. This study aims to evaluate the cardiac safety of PLD use in patients who had prior exposure to conventional doxorubicin. Methods: This was a single-center, observational, retrospective cohort study conducted in patients ≥18 years with STS or breast cancer, who were exposed to conventional doxorubicin from an earlier line of treatment prior to PLD between January 2010 – May 2022. Patients participating in clinical trials were excluded. The primary outcome of the study was cardiac safety. Cardiac toxicity was defined as ≥ 10% decrease in left ventricle ejection fraction (LVEF) or new diagnosis of heart failure within 6 months after PLD cessation. Results: 494 patients were screened and 50 patients met inclusion criteria, 8 STS and 42 breast cancer patients. Median lifetime cumulative conventional doxorubicin dose in patients with STS was 450 mg/m2 with a max dose of 825 mg/m2, and 240 mg/m2 with a max dose of 300 mg/m2 in breast cancer patients. Median lifetime cumulative PLD dose was 105 mg/m2 (range: 35-150 mg/m2) in the STS group and 105 mg/m2 (range: 35-510 mg/m2) in the breast cancer group. A decrease of ≥ 10% in LVEF was not observed in the STS group. 22 breast cancer patients had available LVEF data on PLD; 3 of these patients experienced ≥ 10% in LVEF drop and one of three patients was diagnosed heart failure. The average cumulative dose of PLD administered in patients with &gt; 10% decrease in LVEF was 177 mg/m2 and had an average of 3.5 cycles. Most of STS patients initiated PLD treatment within 2 years after conventional doxorubicin while most breast patients initiated PLD treatment at least 10 years following conventional doxorubicin exposure. Conclusions: PLD administration in patients with prior exposure to conventional doxorubicin appears to be safe with limited cardiotoxicity in patients with STS and breast cancer. Future research is needed to determine if and how often routine cardiac monitoring is needed for patients on PLD without existing cardiac risk.

10-Year efficacy and co-morbidity outcomes of a phase III randomised trial of conventional vs. hypofractionated high dose intensity modulated radiotherapy for prostate cancer (CHHiP; CRUK/06/016).

304 Background: Five-year results from the CHHiP trial indicated that moderate hypofractionation of 60 Gray (Gy)/20 fractions (f) was non-inferior to 74Gy/37f (Lancet Oncology, 2016). Reporting of long-term efficacy and side effects is essential in a patient population that remain at risk of recurrence years after treatment. Here we report specific co-morbidity data collected at 10 years and an update of efficacy. Methods: Between October 2002 and June 2011, 3216 men with node negative T1b-T3a localised prostate cancer with risk of seminal vesical involvement ≤30% were randomised (1:1:1 ratio) to 74Gy/37f (control), 60Gy/20f or 57Gy/19f. Patients received 3-6 months of androgen deprivation prior to radiotherapy. The primary endpoint was time to biochemical failure (Phoenix consensus guidelines) or clinical failure (BCF). The non-inferiority design specified a critical hazard ratio (HR) of 1.208 for each hypofractionated schedule compared to control. Data on specific radiotherapy related co-morbidities were collected at 10-year follow-up and are presented as frequency and percentages. Analysis was by intention-to-treat; HRs quoted are unadjusted. Results: With a median follow up of 12.1 years, 10-year BCF-free rates (95% CI) were 74Gy: 76.0% (73.1%, 78.6%); 60Gy: 79.8% (77.1%, 82.3%) and 57Gy: 73.4% (70.5%, 76.1%). For 60Gy/20f, non-inferiority was confirmed: HR60=0.84 (90% CI 0.72, 0.97) with borderline significance for superiority (HR=0.84 (95% CI 0.70, 1.00). As in the primary analysis, for 57Gy/19f, non-inferiority could not be declared: HR57=1.13 (90% CI 0.98, 1.30). 10-year overall survival (95% CI) was 78.5% (75.9%, 81.0%), 82.9% (80.4%, 85.0%) and 79.9% (77.3%, 82.2%) in the 74Gy, 60Gy and 57Gy groups. Bone fractures were reported in 2% (15/700), 2% (19/771) and 3% (22/719) of patients in the 74Gy, 60Gy and 57Gy groups respectively at 10 years. The most common intervention reported was a sigmoidoscopy with 12% (79/681), 8% (60/739) and 9% (65/702) in the 74Gy, 60Gy and 57Gy groups respectively. Of those patients who underwent a sigmoidoscopy it was due to symptoms for 81% (63/78) 81% (48/59) and 85% (55/65) of patients in the 74Gy, 60Gy and 57Gy group respectively. Frequencies of all other pre-specified co-morbidities or related interventions (ureteric obstruction, bowel strictures, trans-urethral resection of prostate, urethrotomy, urethral dilatation or long term catheterisation or treatment of proctopathy with steroid, sucralfate, formalin, laser coagulation or rectal diversion) were &lt;1% in all groups. Conclusions: With a median follow-up of 12 years, oncological outcomes following 60Gy/20f continue to be non-inferior to those with 74Gy/37f. Late co-morbidities were very low across all treatment groups. These data support the long-term safety of moderate hypofractionation. Clinical trial information: 97182923 .

Hemophagocytic lymphohistocytosis in trisomy 21: successful treatment with interferon inhibition

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of immune dysregulation primarily driven by the cytokine interferon gamma. It can be either a genetic or acquired disorder associated with infection, malignancy, and rheumatologic disorders. Trisomy 21 can express a wide range of phenotypes which include immune dysregulation and shares inherent pathophysiology with a group of disorders termed interferonopathies. Knowledge of this overlap in seemingly unrelated conditions could provide a basis for future research, and most importantly, alternative therapeutic interventions in acute life threatening clinical scenarios. Herein, we describe two patients with trisomy 21 presenting with HLH that was refractory to conventional treatment. Both patients were successfully managed with novel interventions targeting the interferon pathway.Case presentationWe describe a 17-month-old male and 15-month-old female with trisomy 21 presenting with a myriad of signs and symptoms including fever, rash, cytopenias, and hyperferritinemia, both ultimately diagnosed with HLH. Each had relapsing, refractory HLH over time requiring several admissions to the hospital receiving conventional high dose corticosteroids and interleukin-1 inhibition therapy. Successful steroid-free remission was achieved after targeting interferon inhibition with emapalumab induction followed by long-term maintenance on baricitinib.ConclusionTo our knowledge, these are the first reported cases of relapsed, refractory HLH in patients with trisomy 21 successfully treated with emapalumab and transitioned to a steroid-sparing regimen with oral baricitinib for maintenance therapy. Trisomy 21 autoimmunity and HLH are both thought to be driven by interferon gamma. Targeting therapy toward interferon signaling in both HLH and autoimmunity in trisomy 21 may have potential therapeutic benefits. Further investigation is needed to determine if trisomy 21 may predispose to the development of HLH given this common pathway.

An Ultra-Low Dose of ∆9-Tetrahydrocannabinol Alleviates Alzheimer's Disease-Related Cognitive Impairments and Modulates TrkB Receptor Expression in a 5XFAD Mouse Model.

Alzheimer’s disease (AD) is the most common form of dementia, but there is still no available treatment. Δ9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent. Using THC in conventional high doses may have deleterious effects. Therefore, we propose to use an ultra-low dose of THC (ULD-THC). We previously published that a single injection of ULD-THC ameliorated cognitive functioning in several models of brain injuries as well as in naturally aging mice. Here, 5xFAD AD model mice received a single treatment of ULD-THC (0.002 mg/kg) after disease onset and were examined in two separate experiments for cognitive functions, neurotropic, and inflammatory factors in the hippocampus. We show that a single injection of ULD-THC alleviated cognitive impairments in 6- and 12-month-old 5xFAD mice. On the biochemical level, our results indicate an imbalance between the truncated TrkB receptor isoform and the full receptor, with AD mice showing a greater tendency to express the truncated receptor, and ULD-THC improved this imbalance. We also investigated the expression of three AD-related inflammatory markers and found an ameliorating effect of ULD-THC. The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset.

Comparing the Efficacy of Double Dose Hepatitis B Vaccine with Conventional Dose Hepatitis B Vaccine in CLD Patients

Aim: To compare the efficacy of double dose hepatitis B vaccine with conventional dose hepatitis B vaccine in hepatitis C related chronic liver disease patients. Study design: Interventional study (randomized controlled clinical trial) Place and duration of study: Outpatient Department of Medicine, Services Hospital, Lahore from 12th August 2019 to 12th February 2020. Methodology: One hundred and ten patients of both male and female age group 30 to 70 years diagnosed with chronic liver disease on the basis of changed liver echo texture on ultrasound were included. Patients were divided into two groups, each group having 55 patients. One group was given double dose (2ml) while the other was given conventional dose (1ml). Both groups were compared for efficacy in terms of prevention of CLD. Results: The mean age of conventional group was 33.8±9.6 years while 33.7±9.1 years in the double dose group with male predominance (69.10%). Hypo-responsiveness was detected in 23.6% and 32.7% of conventional low dose group and double dose group respectively. There were gender variations in mean Anti-HBs levels. It was 129.80±70.53 mIU/mL in males and 113.26±75.57 mIU/mL in female patients (P= 0.039). Mean titers of anti-HBs in conventional dose group and high dose group were 127.82±67.59 mIU/mL and 121.56±77.00 mIU/mL, respectively (P= 0.52). Conclusion: Double dose hepatitis B vaccination in chronic HCV infected patients efficiently increases the response rate and hence protection against chronic hepatitis B. Keywords: Double dose hepatitis B vaccine, conventional hepatitis B vaccine, chronic hepatitis.

POEMS syndrome: 2021 Update on diagnosis, risk-stratification, and management.

POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. Risk factors include low serum albumin, age, pleural effusion, pulmonary hypertension, and reduced eGFR. For those patients with a dominant plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3-6months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

Low Adenovirus Vaccine Doses Administered to Skin Using Microneedle Patches Induce Better Functional Antibody Immunogenicity as Compared to Systemic Injection.

Adenovirus-based vaccines are demonstrating promising clinical potential for multiple infectious diseases, including COVID-19. However, the immunogenicity of the vector itself decreases its effectiveness as a boosting vaccine due to the induction of strong anti-vector neutralizing immunity. Here we determined how dissolvable microneedle patches (DMN) for skin immunization can overcome this issue, using a clinically-relevant adenovirus-based Plasmodium falciparum malaria vaccine, AdHu5–PfRH5, in mice. Incorporation of vaccine into patches significantly enhanced its thermostability compared to the liquid form. Conventional high dose repeated immunization by the intramuscular (IM) route induced low antigen-specific IgG titres and high anti-vector immunity. A low priming dose of vaccine, by the IM route, but more so using DMN patches, induced the most efficacious immune responses, assessed by parasite growth inhibitory activity (GIA) assays. Administration of low dose AdHu5–PfRH5 using patches to the skin, boosted by high dose IM, induced the highest antigen-specific serum IgG response after boosting, the greatest skewing of the antibody response towards the antigen and away from the vector, and the highest efficacy. This study therefore demonstrates that repeated use of the same adenovirus vaccine can be highly immunogenic towards the transgene if a low dose is used to prime the response. It also provides a method of stabilizing adenovirus vaccine, in easy-to-administer dissolvable microneedle patches, permitting storage and distribution out of cold chain.

Clinical efficacy and safety in patients treated with teicoplanin with a target trough concentration of 20\u2009\u03bcg/mL using a regimen of 12\u2009mg/kg for five doses within the initial 3\u2009days

BackgroundA trough concentration (Cmin) ≥20 μg/mL of teicoplanin is recommended for the treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections. However, sufficient clinical evidence to support the efficacy of this target Cmin has not been obtained. Even though the recommended high Cmin of teicoplanin was associated with better clinical outcome, reaching the target concentration is challenging.MethodsPharmacokinetics and adverse events were evaluated in all eligible patients. For clinical efficacy, patients who had bacteremia/complicated MRSA infections were analyzed. The primary endpoint for clinical efficacy was an early clinical response at 72–96 h after the start of therapy. Five dosed of 12 mg/kg or 10 mg/kg was administered as an enhanced or conventional high loading dose regimen, respectively. The Cmin was obtained at 72 h after the first dose.ResultsOverall, 512 patients were eligible, and 76 patients were analyzed for treatment efficacy. The proportion of patients achieving the target Cmin range (20–40 μg/mL) by the enhanced regimen was significantly higher than for the conventional regimen (75.2% versus 41.0%, p < 0.001). In multivariate analysis, Cmin ≥ 20 μg/mL was an independent factor for an early clinical response (odds ratio 3.95, 95% confidence interval 1.25–12.53). There was no significant difference in the occurrence of adverse events between patients who did or did not achieve a Cmin ≥ 20 μg/mL.ConclusionA target Cmin ≥ 20 μg/mL might improve early clinical responses during the treatment of difficult MRSA infections using 12 mg/kg teicoplanin for five doses within the initial 3 days.

A randomised assessment of image guided radiotherapy within a phase 3 trial of conventional or hypofractionated high dose intensity modulated radiotherapy for prostate cancer

Background and purposeImage-guided radiotherapy (IGRT) improves treatment set-up accuracy and provides the opportunity to reduce target volume margins. We introduced IGRT methods using standard (IGRT-S) or reduced (IGRT-R) margins in a randomised phase 2 substudy within CHHiP trial. We present a pre-planned analysis of the impact of IGRT on dosimetry and acute/late pelvic side effects using gastrointestinal and genitourinary clinician and patient-reported outcomes (PRO) and evaluate efficacy. Materials and methodsCHHiP is a randomised phase 3, non-inferiority trial for men with localised prostate cancer. 3216 patients were randomly assigned to conventional (74 Gy in 2 Gy/fraction (f) daily) or moderate hypofractionation (60 or 57 Gy in 3 Gy/f daily) between October 2002 and June 2011. The IGRT substudy included a second randomisation assigning to no-IGRT, IGRT-S (standard CTV-PTV margins), or IGRT-R (reduced CTV-PTV margins). Primary substudy endpoint was late RTOG bowel and urinary toxicity at 2 years post-radiotherapy. ResultsBetween June 2010 to July 2011, 293 men were recruited from 16 centres. Median follow-up is 56.9(IQR 54.3–60.9) months. Rectal and bladder dose-volume and surface percentages were significantly lower in IGRT-R compared to IGRT-S group; (p < 0.0001). Cumulative proportion with RTOG grade ≥ 2 toxicity reported to 2 years for bowel was 8.3(95% CI 3.2–20.7)%, 8.3(4.7–14.6)% and 5.8(2.6–12.4)% and for urinary 8.4(3.2–20.8)%, 4.6(2.1–9.9)% and 3.9(1.5–9.9)% in no IGRT, IGRT-S and IGRT-R groups respectively. In an exploratory analysis, treatment efficacy appeared similar in all three groups. ConclusionIntroduction of IGRT was feasible in a national randomised trial and IGRT-R produced dosimetric benefits. Overall side effect profiles were acceptable in all groups but lowest with IGRT and reduced margins. ISRCTN97182923.

Addition of the Anti-CD33 Monoclonal Antibody Mylotarg to Fludarabine/High Dose Cytarabine - Based Induction Significantly Improves Outcome in Patient Affected By FLT3-ITD Positive Cytogenetically Normal Acute Myeloid Leukemia

Background: The addition of the anti-CD33 targeting antibody Mylotarg (MY) to conventional "3+7" induction has been shown to improve the outcome of patients affected by acute myeloid leukemia (AML) without adverse cytogenetic alterations. Early reports suggested that MY was particularly effective among low risk patients, such as core binding factor AML, particularly if included in a high dose cytarabine-based induction therapy. The role of MY for intermediate risk patients appears to be less clear. Cytogenetically defined intermediate risk patients may be further stratified considering two frequent molecular aberrations: FLT3 "internal tandem duplication" (FLT3-ITD) mutation, associated with poor prognosis and NPM1 mutation (NPM1-mut), associated with a good prognosis. The concomitant presence of NPM1-mutpartially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild type allelic ratio. NPM1 and FLT3 mutational status assessment is strongly recommended for risk stratification at diagnosis by the last ELN 2017 guidelines. Aims: To investigate the efficacy of MY added to an intensive fludarabine, high dose cytarabine and Idarubicin-based induction regimen (FLAI) as frontline treatment for younger (&amp;lt;65 years), cytogenetically normal AML patients according to NPM1 and FLT3-ITD mutational status. Methods:One-hundred and forty eight consecutive AML patients, treated in 3 Italian Hematology centersbetween 2008 and 2018and harboring at least one molecular alteration among NPM1-mut and FLT3-ITD, were included in the analysis. Thirty three patients carried isolated FLT3-ITD, 50patients showed concomitant FLT3-ITD and NPM1-mut and 65 isolated mutated NPM-1.Median age was 50 years(range: 18-65). All patients received FLAI induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm on days1 to 5 plus idarubicin 10 mg/sqm on days 1-3-5), with or without low dose MY(3 mg/sqm, added in 42 patients), followed by a second induction without fludarabine and with idarubicin at the increased dose of 12 mg/sqm. Before 2017, patients with isolated FLT3-ITD mutation were scheduled for allogeneic stem cell transplantation (HSCT), if an HLA-matched sibling donor was available, whereas after 2017 only patients with high allelic burden isolated FLT3-ITD mutation received HSCT in first CR. The other patients received conventional high dose cytarabine consolidation for a total of 3 cycles. Results: Overall, 60-days mortality was 3%, and was not significantly influenced by receiving or not MY during induction. After one induction cycle, 126 patients achieved CR (85%) with no difference between patients receiving or not MY. After a median follow up of 70months, 3-year overall survival (OS) was 59.5% (median not reached). OS duration was significantly longer in NPM1 mutated patients (p &amp;lt;0.05).Patients with isolated FLT3-ITD mutation had a significantly worse prognosis (3-year OS 38.3%, p&amp;lt;0.05). The addiction of MY did not significantly improve outcome in the whole cohort but did show a significant positive effect on survival among FLT3-ITD patients (3-year OS 66.7% vs 46.6% for FLT3-ITD patients receiving or not MY, respectively, p&amp;lt;0.03, Fig. 1). This effect was more evident among the 33 NPM1 negative/FLT3-ITD patients: in this subgroup, patients who received MY had an overall good outcome that was similar to patients with double mutation who received the same therapy(median OS not reached in both groups, p=n.s.). On the contrary, among patients who did not receive MY, NPM1 negative/FLT3-ITD positive patients had a poor outcome, significantly inferior to double positive patients receiving the same regimen(3-Year OS 39.8% and 57.3%, respectively, p&amp;lt;0.05). The favorable effect of MY among FLT3-ITD patients was not influenced by FLT3-ITD allelic burden.Of note, the proportion of patients receiving HSCT in first CR, as expected, was higher among patients harboring isolated FLT3-ITD mutation, but there was no significant difference among patients receiving or not MY. Conclusions: Despite the potential bias due to the retrospective nature of the analysis, our data seem to indicate that Mylotarg, added to an intensive fludarabine/high dose cytarabine-based induction, provides a significant improvement in anti-leukemic efficacy in patients carrying FLT3-ITD mutation, especially if concomitant NPM1 mutation is not present. Disclosures Candoni: Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Merck SD: Honoraria, Speakers Bureau. Bocchia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria.

Conventional oral and secondary high dose vaginal metronidazole therapy for recurrent bacterial vaginosis: clinical outcomes, impacts of sex and menses.

PurposeOral metronidazole therapy is the standard of care for bacterial vaginosis (BV), yet it has alarming rates of recurrence and refractory responses among recurrent BV (RBV) patients. This study addresses whether high dose vaginal metronidazole therapy (HDM) is beneficial in RBV patients who fail after standard of care (SOC) therapy, whether diagnostic test scores proximal to the HDM predict clinical outcome, and whether menses, coitus, or race influences therapy outcome.Patients and methodsA total of 90 patients with RBV were given SOC and tracked 74 for up to 9 months. Refractory or recurrent patients (57) with symptomatic BV were given HDM and followed for up to 8 months. Patients were evaluated by Amsel criteria, Nugent score, and a qPCR assay that assesses the Lactobacillus content.ResultsHDM achieved at least short-term remission in 68% of the patients who were refractory to or recurred after SOC and provided a 10-day increase in the mean duration of remission among patients who eventually recurred (p=0.027). Patients with prolonged dysbiosis (pH >5 or Amsel 4) before symptomatic recurrence were more likely to recur after subsequent HDM. Most recurrence happened within 10 days of menses, but sex in this cohort was not associated with clinical outcome. Mean diagnostic BV scores of African American patients in remission were inferior to scores of a small cohort of Caucasian patients in remission.ConclusionEncouraging results obtained with HDM justify a prospective, randomized study to determine if follow-up HDM is beneficial among a broader cohort of women failing conventional oral metronidazole therapy.

POEMS Syndrome: 2019 Update on diagnosis, risk-stratification, and management.

Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal PCD, and at least one of the minor criteria. Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. Risk factors include low serum albumin, age, pleural effusion, pulmonary hypertension, and reduced eGFR. For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3 to 6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

The Use of Minimal Ovarian Stimulation to Achieve Autologous Pregnancy in Extremely Poor Prognosis Patients [36T

INTRODUCTION: Patients with extreme advanced reproductive age and/or markedly diminished ovarian reserve are often recommended to undergo oocyte donation following failure to obtain embryos or achieve pregnancy with conventional high dose ovarian stimulation protocols. We present a cohort of patients who were recommended to use oocyte donation who underwent minimal stimulation for the purposes of embryo banking subsequently achieving ongoing pregnancy. METHODS: Retrospective cohort. RESULTS: A total of 20 self-referred patients after only being offered donor oocyte at an outside fertility clinic. Characteristics of this cohort included mean age 40.1 ± 0.74 years, Anti-Müllerian hormone 0.89 ng/mL ± 0.19, and the average number of conventional high dose cycles prior to referral was 2.2 ± 0.3 cycles. Of the patients undergoing minimal ovarian stimulation protocols, 90% (18/20) were able to have embryos frozen after undergoing 3.8 (+/- 0.41) cycles. Of these patients, 61.1% (11/18) progressed to embryo transfer (ET). For those who underwent ET, a total of 5 ongoing pregnancies (45% pregnancy rate) were achieved with an average time to pregnancy of 1.3 ± 0.24 years. Two spontaneous pregnancies (1 ongoing and 1 miscarriage) occurred during the course of treatment. CONCLUSION: Repetitive minimal simulation protocols with embryo banking allow the opportunity for autologous pregnancy in patients who previously failed conventional stimulation protocols and were recommended donor oocytes.

Comparative Efficacy and Safety of Low Dose versus High Dose Isotretinoin in Severe Acne Vulgaris Patients

Background: Oral isotretinoin is the recommended treatment for acne vulgaris, a skin disease especially common in teenagers and adolescents. This study was designed to compare the efficacy and safety of low dose with high dose isotretinoin in severe acne vulgaris patients.Material and Methods: This randomized controlled trial included 110 patients with a clinical diagnosis of acne vulgaris. They were divided into two groups. Both groups were matched for age (mean 18.2±3.7 vs 17.6±3.2 years), weight (mean 58±10.2 vs 60.7±9.3 Kg), gender and disease duration (3±1.1 vs 3±1.0 years). Group A received low dose oral isotretinoin (20 mg/day) while group B received standard high dose regimen (1mg/kg/day). All patients were followed up for 16 weeks to assess efficacy (assessment of complete remission) and safety (mucocutaneous side effects). All calculations were performed using SPSS v. 16 with p value &lt;0.05 considered as statistically significant.Results: There was no statistically significant difference in efficacy. However, significantly fewer mucocutaneous side effects were reported in group A (80%) as compared to group B (100%). This safety profile spectrum was observed across all pre-defined subsets i.e chielitis (78.1% vs 98.2%), dry skin (69.1% vs 92.7%), dry mouth (47.2% vs 72.7%) and facial rash (12.7% vs 30.9%).Conclusion: In patients with severe acne vulgaris, efficacy (complete remission) of low dose oral isotretinoin is almost equal to conventional high dose regimen but it is statistically superior in terms of safety (mucocutaneous side effects).

Isotretinoin induces dermcidin expression in patients with moderate to severe acne vulgaris

Background The continuous low-dose (LD) isotretinoin is a frequently used treatment regimen for acne vulgaris. However, data about its antimicrobial efficacy are lacking. Objective To study dermcidin expression and the effects of LD and conventional-dose isotretinoin (CD) on its expression in patients with moderate-severe acne vulgaris. Patients and methods Skin dermcidin expression was investigated in 30 patients with moderate-severe acne vulgaris and 15 healthy control patients using ELISA. In this case–control study, 15 patients were given continuous LD isotretinoin (0.3 mg/kg/day), and the other 15 were given the conventional high dose (0.5 mg/kg/day). Skin biopsies were taken at the start of the study and 6 months after. Results Dermcidin was significantly lower in patients with acne vulgaris (P Conclusion Dermcidin expression is reduced in acne vulgaris. CD and LD isotretinoin regimens are associated with increased dermcidin expression.

PSIV-2 Use of protected zinc oxide in lower doses in weaned pigs in substitution for the conventional high dose zinc oxide.

PSIV-2 Use of protected zinc oxide in lower doses in weaned pigs in substitution for the conventional high dose zinc oxide.

First-in-Human CLL1-CD33 Compound CAR T Cell Therapy Induces Complete Remission in Patients with Refractory Acute Myeloid Leukemia: Update on Phase 1 Clinical Trial

▪BackgroundCD19-specific chimeric antigen receptor (CAR) T cell therapy has achieved high efficacy in acute lymphoblastic leukemia patients. However, the treatment of acute myeloid leukemia (AML) has remained a particular challenge due to the heterogeneity of AML bearing cells, which renders single antigen targeting CAR T cell therapy ineffective. CLL1 and CD33 are often used as targets for AML CAR T cell therapy. CLL1 is associated with leukemia stem cells and disease relapse, and CD33 is expressed on the bulk AML disease. Previously, we demonstrated the profound anti-tumor activity of CLL1-CD33 compound CAR (cCAR) T cells. Here we present the efficacy of cCAR in preclinical study and update the success in level 1 dose escalation clinical trial on relapsed/refractory AML patients.MethodsWe engineered a cCAR comprising of an anti-CLL1 CAR linked to an anti- CD33 CAR via a self-cleaving P2A peptide and expressing both functional CAR molecules on the surface of a T-cell cell. We tested the anti-leukemic activities of CLL1-CD33 cCAR using multiple AML cell lines, primary human AML samples, human leukemia cell line (REH cells) expressing either CLL1 or CD33, and multiple mouse models. An alemtuzumab safety switch has also been established to ensure the elimination of CAR T cells following tumor eradication. Children and adults with relapsed/refractory AML were enrolled in our phase 1 dose escalation trial with primary objective to evaluate the safety of cCAR and secondary objective to assess the efficacy of cCAR anti-tumor activity.ResultsCo-culture assays results showed that cCAR displayed profound tumor killing effects in AML cell lines, primary patient samples and multiple mouse model systems. Our preclinical findings suggest that cCAR, targeting two discrete AML antigens: CLL1 and CD33, is an effective two-pronged approach in treating bulk AML disease and eradicating leukemia stem cells. Patients enrolled in the phase 1 dose escalation trial have shown remarkable response to cCAR treatment. Noticeably, a 6-yr-old female patient diagnosed with a complex karyotype AML including FLT3-ITD mutation had achieved complete remission. The patient was diagnosed with Fanconi anemia, which had progressed to juvenile myelomonocytic leukemia and eventually transformed into AML. The patient had been resistant to multiple lines of treatments, including 5 cycles of chemotherapy with FLT3 inhibitor prior to receiving cCAR. Before the treatment, patient's leukemia blasts comprised 73% of the peripheral blood mononuclear cells and 81% of the bone marrow. Patient underwent lymphodepletion therapy (Fludarabine and Cyclophosphamide) prior to cCAR infusion. Two split doses, each consisting of 1x106/kg CAR T cells, were infused on day 1 and day 2 respectively. On day 12, while leukemia blast still counting up to 98% of the bone marrow (Fig. 1A), robust CAR T cell expansion was detected in both peripheral blood and bone marrow. On day 19, patient achieved MRD- complete remission with bone marrow aspirates revealing complete ablation of myeloid cells (Fig. 1B). Flow cytometry confirmed the absence of leukemia blasts and showed that CAR T cells comprised 36% of the PBMC and 60% of the bone marrow. The patient later underwent non-myeloablative hematopoietic cell transplantation with less toxicities compared to conventional total body radiation and high dose chemotherapies. Updated results on other patients enrolled in this clinical trial including adverse events will be presented.ConclusionOur first-in-human clinical trial demonstrates promising efficacy of cCAR therapy in treating patients with relapsed/ refractory AML. cCAR is able to eradicate leukemia blasts and leukemia stem cells, exerting a profound tumor killing effect that is superior to single target CAR T cell therapies. cCAR is also shown to induce total myeloid ablation in bone marrow, suggesting that it may act as a safer alternative to avoid the severe toxicities caused by standard bone marrow ablation regimens without sacrificing the anti-tumor efficacy. This strategy will likely benefit patients who are unable to tolerate total body radiation or high dose chemotherapies. In addition to AML, cCAR also has the potential to treat blast crisis developed from myelodysplastic syndrome, chronic myeloid leukemia, and chronic myeloproliferative neoplasm. DisclosuresPinz:iCell Gene Therapeutics LLC: Employment. Ma:iCAR Bio Therapeutics Ltd: Employment. Wada:iCell Gene Therapeutics LLC: Employment. Chen:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC, iCAR Bio Therapeutics Ltd: Consultancy, Equity Ownership, Research Funding.

The effect of continuous high versus low dose oral isotretinoin regimens on dermcidin expression in patients with moderate to severe acne vulgaris

The continuous low dose (LD) isotretinoin is frequently used in the treatment regimen for acne vulgaris. However, data about its antimicrobial are lacking. The present study aimed to investigate dermcidin expression and the effects of low and conventional dose isotretinoin on its expression in acne vulgaris patients. Skin dermcidin expression was investigated in 30 patients with moderate-severe acne vulgaris and 15 healthy control subjects using ELISA. 15 patients were given continuous low-dose isotretinoin (20 mg/day) and the other 15 given the conventional high dose (0.5 mg/kg/day). Skin biopsies were taken at the start of the study and 6 months later. Dermcidin was significantly lower in acne vulgaris patients (p < .001). Both isotretinoin regimens significantly raised dermcidin levels compared to pre-treatment values (p < .001). Relapse after 12 months was not statistically different among the two isotretinoin regimens (p = .464). Pretreatment global acne grading system score of 28.6 ± 6.4 was reduced to 6 ± 6.1 following isotretinoin treatment (p < .001). Relapse was significantly related to posttreatment dermcidin levels (p = .017). Dermcidin expression is reduced in acne vulgaris. Conventional and LD isotretinoin regimens are associated with increased dermcidin expression.