Therapy-related Adverse Effects Research Articles

Cardio-Oncology Awareness: A multidisciplinary survey amongst health care trainees and practicing professionals at academic institutions.

e24023 Background: The awareness of cancer therapy-related adverse cardiac effects is incited by recent literature on cardiotoxicity incidence and detection strategies. Despite availability of guidelines, cardiotoxicity monitoring and treatment are not structurally performed across institutions. Aim: Assessing knowledge of health care professionals’ cardiac complications of cancer treatments, current perspectives on cardio-oncology ultimately to determine an agenda for improvements in practice. Methods: A web-based survey (Google Forms) was adapted from that of Ottawa Hospital Research Institute’s survey, consisting of 45 questions organized into 7 sections, modified according to our local needs and circulated to cardiologists, oncologists (radiation, medical) practicing or training in a multi-disciplinary setup and academic centers. Fortnightly reminders were sent for to receive a maximum response. The survey enquired about implementing respondent’s perception of cardio-oncology, availability of cardio-oncology services at the respondent’s institution, opinions towards current practice. A descriptive statistical analysis was carried out. Results: Fifty-five professionals completed the survey, of which 12 were cardiologists, 31 radiation oncologists, and 12 medical oncologists. Majority, 31 (54.5%) were trainees and only 1.8% had some formal training in cardio-oncology while 20% respondents reported to have a formal cardio-oncology training programme. Nearly 90% understood cardio-oncology as a stream to be able to identify side-effects and refer for treatment to the cardiologists while 84% felt that timely referral would improve outcomes.72% recognized follow-up and 67.3% felt patient education to be important component. Awareness of cardio-oncology guidelines was reported by 38.2% respondents. In the setting of metastatic cancer, there was a difference in risk tolerance for cardiotoxicity with the majority accepting 1-5% risk in curative setting and 56% accepting > 5% risk of cardiotoxicity in the metastatic setting. None of the institutions reported on having a formal training programme. Limited infrastructure (54.5%) and limited interest (47.3%) were cited the most common reasons. Conclusions: This survey identified that professionals recognize cardio-oncology services to be an important component of cancer treatment. Lack of formal training and awareness about guidelines was reported. There is a felt need for collaboration between cardiologists and oncologists to improve cardiovascular outcomes of cancer patients.

Long-term cardiac effects of modern treatment for Hodgkin’s lymphoma

BackgroundHodgkin’s lymphoma (HL) is a hematological malignancy that affects both children and young adults. Traditional treatment is associated with a life-time prevalence of cardiac disease exceeding 50%. In the late 1990s protocols were modified to reduce cancer therapy-related adverse cardiac effects. This study aimed to assess the long-term impact of advances in treatment protocols on the cardiac health of HL survivors (HLS).MethodsHLS (n = 246) treated between 1997 and 2007 with anthracycline-based chemotherapy in three centers in Norway were included. Of these, 132 (53%) had also received mediastinal radiotherapy. HLS were compared to controls (n = 58) recruited from the general population and matched for sex, age, smoking status, and heredity for coronary artery disease. All subjects underwent echocardiography, clinical assessment, and blood sampling.ResultsThe HLS were 46 ± 9 years old and had been treated 17 ± 3 years before inclusion in the study. There was no significant difference between HLS and controls in ejection fraction (EF) (58%±5 vs. 59%±4, p = 0.08) or prevalence of heart failure. HLS treated with both anthracyclines and mediastinal radiotherapy (AC + MRT) had slightly worse left ventricular global longitudinal strain than controls (-19.3 ± 2.5% vs. -20.8 ± 2.0%, p < 0.001), but those treated with only anthracyclines did not. HLS treated with AC + MRT had a higher prevalence of valve disease than those treated only with anthracyclines (12% vs. 4%, p < 0.05).ConclusionsHLS treated with anthracyclines after the late 1990s have similar cardiac function and morphology as age-matched controls, apart from higher rates of valvular disease in those who also underwent mediastinal radiotherapy.

Cisplatin Provokes Peripheral Nociception and Neuronal Features of Therapy-Induced Senescence and Calcium Dysregulation in Rats.

Therapy-Induced Senescence (TIS) is a form of senescence that is typically described in malignant cells in response to the exposure of cancer chemotherapy or radiation but can also be precipitated in non-malignant cells. TIS has been shown to contribute to the development of several cancer therapy-related adverse effects; however, evidence on its role in mediating chemotherapy-induced neurotoxicity, such as Chemotherapy-induced Peripheral Neuropathy (CIPN), is limited. We hereshow that cisplatin treatment over two cycles (cumulative dose of 23 mg/kg) provoked mechanical allodynia and thermal hyperalgesia in Sprague-Dawley rats. Isolation of dorsal root ganglia (DRG) from the cisplatin-treated rats demonstrated robust SA-β-gal upregulation at both day 8 (after the first cycle) and day 18 (after the second cycle), decreased lmnb1 expression, increased expression of cdkn1a and cdkn2a, and of several factors of the Senescence-associated Secretory Phenotype (SASP) (Il6, Il1b, and mmp9). Moreover, single-cell calcium imaging of cultured DRGs revealed a significant increase in terms of the magnitude of KCl-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats. No significant change was observed in terms of the magnitude of capsaicin-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats but with decreased area under the curve of the responses in cisplatin-treated rats. Further evidence to support the contribution of TIS to therapy adverse effects is required but should encourage the use of senescence-modulating agents (senotherapeutics) as novel palliative approaches to mitigate chemotherapy-induced neurotoxicity.

Abstract PR007: The combination of TRIP13 and Aurora kinase A inhibition caused cell cycle specific DNA damage and death in Rb-deficient cancers

Abstract Many diverse, common, and lethal cancer types have inactivation of the retinoblastoma (RB1, Rb) tumor suppressor pathway including cancers caused by the human papillomavirus (HPV), which causes &amp;gt;5% of all cancers worldwide. Despite therapeutic advances, advanced Rb-deficient cancers are still lethal with therapy-related adverse effects. Moreover, there are no therapies that uniquely target HPV-driven or Rb-deficient cancers. Therefore, biomarker-selected, targeted therapy for Rb-deficient cancers represents both a substantial unmet need and a significant translational knowledge gap. Rb-deficient cancer cells depend on Aurora A kinases to bypass the spindle assembly checkpoint (SAC) and survive due to overexpression of the mitotic checkpoint protein Mad2. Thyroid hormone receptor interactor 13 (TRIP13) catalyzes the ATP-dependent conversion of Mad2 from its active to inactive form, which turns off the SAC. Our lab discovered that the combination of Aurora A inhibition with alisertib plus TRIP13 depletion induced extensive apoptosis selectively in Rb-deficient cancer cells. Moreover, our results demonstrated that the synthetic lethality between Aurora A and TRIP13 reflects mitotic catastrophe. The combination led to highly abnormal mitoses in Rb-deficient cancer cells, evidenced by unaligned, dispersed chromosomes, mitotic spindle defects, and G2/M arrest. Moreover, live cell imaging showed that alisertib treatment increased the duration of first mitoses and induced mitotic cell death, which was even more pronounced in second mitotic events. The combination resulted in both prolonged mitotic arrest and enhanced lethality, indicated by increased mitotic cell death after the first mitoses and interphase cell death following the first mitotic arrest. Furthermore, using degron tagging to rapidly degrade TRIP13, we showed that TRIP13 depletion led to transient mitotic arrest in cells that were in late G2, supporting the role of TRIP13 in regulating the SAC and mitotic progression. Since prolonged mitotic arrest is known to cause DNA damage and both Aurora A and TRIP13 are known to be involved in the DNA damage response, we also tested the effect of the combination treatment on DNA damage. Treating Rb-deficient cancer cells with the combination resulted in robust increases in gamma-H2AX, pTIF1 beta (KAP1, TRIM28), and DNA PKcs. The lethal effects of the combination required mitotic entry as concurrent CDK1 inhibition with RO-3306 prevented apoptosis and DNA damage induced by the combination. The selective effect of the combination in Rb-deficient cancer cells may have a wide therapeutic index resulting in less toxic and more effective therapy. Additionally, targeting mitosis may contribute to a cancer-specific effect due to cancer cells’ high proliferation rate. Our study suggests that targeting TRIP13 and Aurora A led to DNA damage and death specifically during mitosis in Rb-deficient cells. This work has potential to establish a foundation for future clinical trials and may change current clinical practice paradigms. Citation Format: Lacin Yapindi, Soma Ghosh, Tuhina Mazumdar, Faye M. Johnson. The combination of TRIP13 and Aurora kinase A inhibition caused cell cycle specific DNA damage and death in Rb-deficient cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr PR007.

Rapid glucocorticoid tapering regimen in patients with giant cell arteritis: a single centre cohort study

ObjectivesWe evaluated the feasibility of a rapid glucocorticoid tapering regimen to reduce glucocorticoid exposure in patients with giant cell arteritis (GCA) treated with glucocorticoids only.MethodsNewly diagnosed patients with GCA treated...

Abstract 3212: OQL06x, a gut-restricted janus kinase inhibitor to control epidermal growth factor receptor inhibitor-induced diarrhea

Abstract Background: Epidermal growth factor receptor inhibitors (EGFRIs) are widely used; however, therapy-related adverse effects (AEs) are common with diarrhea being the most frequent (e.g., afatinib up to 90% for all grades). Currently, there is no effective treatment or prevention, and severe diarrhea (~30%) results in EGFRi dose reduction or discontinuation. EGFRIs disrupt the gut epithelium and induce an inflammatory response characterized by cytokine release and neutrophil and T-cell infiltration. Janus kinase inhibitors (JAKIs) are immunosuppressive drugs and a candidate treatment for EGFRi-associated inflammation/diarrhea. However, oral JAKIs are associated with serious AEs (e.g., CV events, VTE, cancer, infections) and may lead to EGFR inhibitor resistance. We developed a gut-restricted JAKI with minimal systemic exposure that may reduce AEs and decrease the incidence of EGFRi-induced diarrhea. Methods: Multiple compounds were tested in vitro for their physiochemical properties (e.g., solubility, stability, and enzyme activity) and potential for inhibiting the activation of the JAK pathway and subsequent signal transducers transcription 3 (STAT3) after cytokine IL-6 activation in human peripheral blood mononuclear cells (hPBMC). Selected compounds were tested in vivo with afatinib (40mg/kg) plus OQL06x, tofacitinib, or placebo started on Day 1 and continued for 10 days in a rat EGFRi-induced diarrhea model. Orally administered OQL06x pharmacokinetics (PK) were tested in mice (5-25 mg/kg) and rats (2-5 mg/kg). Oral tofacitinib was used as a control. Results: OQL06x demonstrated favorable pharmaceutical properties and superior JAK enzyme inhibition (e.g., IC50: JAK1: OQL06x 0.06nM vs. tofacitinib 1.4nM). In vitro, hPBMC treated with OQL06x vs. tofacitinib showed greater inhibition of the IL-6, JAK-induced STAT3 activation (IC50: OQL06x 30nM vs. tofacitinib 222nM). OQL06x and tofacitinib showed a significant decrease in diarrhea compared with placebo control (both reduced diarrhea grade by 1.4 units vs. control, p &amp;lt; 0.01, two-way ANOVA). OQL06x was gut-specific vs. tofacitinib, with a significantly higher gut:blood ratio of up to 2000:1 vs. tofacitinib up to 20:1, p &amp;lt; 0.001, two-way ANOVA). Importantly, low bioavailability of OQL06x was found in both mouse (1.50%) and rat (0.23%) models demonstrating OQL06x’s limited systemic exposure. Moreover, no CYP inhibition was found (IC50 &amp;gt; 50µM), which favors a low drug-drug interaction potential. Conclusion: Our research demonstrated that an orally administered, gut-restricted JAK inhibitor, OQL06x, can reduce EGFR inhibitor-induced diarrhea severity. Additionally, OQL06x’s gut restriction and low systemic exposure may reduce the risk of serious AEs observed with other oral JAK inhibitors and limit the potential for interference with EGFR inhibition anti-cancer efficacy. Citation Format: Chengguang Wu, Kun Fang, Wenqin Zeng, Wenxi Li, Shilan Liu, Qing You, Robert Claude Tyler, Jie Luo, Shiyi Zhang, Hong Tang. OQL06x, a gut-restricted janus kinase inhibitor to control epidermal growth factor receptor inhibitor-induced diarrhea [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3212.

Abstract 3186: Anti-tumor effects and immunological responses by aGalCer loaded antigen presenting cell infusion in the patients with malignant tumor

Abstract Natural Killer T (NKT) cells are unique lymphocyte lineage that present both NK and T cell phenotype. NKT cells hold strong direct cytotoxic ability toward tumor cells through glycolipid/CD1d complex on tumor cells, NKT cells secrete large amounts of IFNγ and stimulate CD8 and NK cells as indirect cytotoxic effects. To elicit NKT cells responses in cancer patients, adoptive transfer of α-galactosyl ceramide (αGalCer) loaded APCs was exploited in a decade. I summarized anti-tumor effects and immune reaction treated with this therapy in recent 3 years. Methods: For αGalCer loaded APCs, CD14-monocyte (MO) or mature dendritic cells (DC) was used. Monocytes isolated by leukapheresis were purified ether plastic adherence or CD14-positive selection. Plastic adherent monocytes were cultured for 6 days for differentiation into DC, then for an additional day for maturation with αGalCer loading. CD14-Mo was cultured for 2 days with GM-CSF and αGalCer. After cultivation, all cells were frozen and stored in liquid nitrogen until use. For tumor treatment, patients were injected αGalCer-DC at least 4 times via SC with 2 weeks interval or injected at least twice with αGalCer-CD14-Mo intravenously with 3-4 weeks interval. We evaluated safety and efficacy of αGalCer-APCs immunotherapy by CTCAE, tumor maker, RECIST and immunological analysis. Fifty patients were enrolled in this immunotherapy between 2020-2022. Results: In all cases, we could not observe any therapy-related adverse effects above CTCAE Grade 2. Several anti-tumor effects such as tumor marker reduction and/or tumor regression including CR were observed in 60.6% of evaluated cases. In the cases with iv injection of αGalCer-CD14-Mo, CD3+CD56+ circulating NKT (cNKT) cells were significantly increased after the therapy. In the cases with subcutaneous injection of αGalCer-DC, NK number was significantly increased. Also, cNKT cells and CD8 cells were increased with tendency of significance after the therapy. We obtained CR case in chemotherapy naïve DLBCL patient by αGalCer-DC therapy. After 6 injections, multiple LN swelling was disappeared completely. In another cases, breast cancer with axillary LN metastasis, we obtained rapid tumor regression with αGalCer-DC SC injection. In the case combined αGalCer-APCs with some cytotoxic chemotherapy or conventional radiation immune responses were abolished. In the cases combined αGalCer-APCs with taxane, platinum, gemcitabine-based chemotherapy, immune responses were clearly observed. Conclusion: αGalCer-APCs infusion efficiently promote cNKT response. cNKT response was clearly related with immune responses such as CD8/NK upregulation and anti-tumor effects. Immune responses induced by the therapy seemed to be abolished by combined conventional radiotherapy or several cytotoxic chemotherapies. αGalCer-APCs infusion might be promising for cancer therapy. Citation Format: Yoshinori Ito. Anti-tumor effects and immunological responses by aGalCer loaded antigen presenting cell infusion in the patients with malignant tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3186.

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

Cystic fibrosis (CF) is a potentially fatal monogenic disease that causes a progressive multisystemic pathology. Over the last decade, the introduction of CF transmembrane conductance regulator (CFTR) modulator drugs into clinical practice has profoundly modified the lives of many people with CF (PwCF) by targeting the fundamental cause of the disease. These drugs consist of the potentiator ivacaftor (VX-770) and the correctors lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). In particular, the triple combination of CFTR modulators composed of elexacaftor, tezacaftor, and ivacaftor (ETI) represents a life-changing therapy for the majority of PwCF worldwide. A growing number of clinical studies have demonstrated the safety and efficacy of ETI therapy in both short- and long-term (up to two years of follow-up to date) and its ability to significantly reduce pulmonary and gastrointestinal manifestations, sweat chloride concentration, exocrine pancreatic dysfunction, and infertility/subfertility, among other disease signs and symptoms. Nevertheless, ETI therapy-related adverse effects have also been reported, and close monitoring by a multidisciplinary healthcare team remains vital. This review aims to address and discuss the major therapeutic benefits and adverse effects reported by the clinical use of ETI therapy for PwCF.

Differences in concomitant medication prescribing before and after novel hormonal therapy (NHT) in men with prostate cancer: A population-based study.

138 Background: Prostate cancer (PCa) is the most common non-skin cancer affecting American men. Two common NHTs used to treat PCa are enzalutamide and abiraterone. Due to the different mechanisms of these two NHTs, we hypothesized that the concomitant medications prescribed might be related to therapy-related adverse effects. The purpose of this study was to examine whether changes in concomitant medications depended on the NHT prescribed. Methods: Medicare patients with a prescription of either enzalutamide or abiraterone in the Surveillance, Epidemiology, and End Results (SEER)–Medicare database diagnosed with prostate cancer from January 01, 2004 to December 31, 2015 were included. Medications were classified by Lexicomp’s pharmacologic category. Only oral prescriptions were included. McNemar’s test was used to compare the drug use prevalence of each category prior to and after initiation of NHT. Generalized logistic regression was used to evaluate whether changes in prescription drug class during the 6 months post-NHT initiation periods depended on the type of NHT. Results: Among the 1067 patients included, 354 were prescribed enzalutamide and 713 were prescribed abiraterone. We found statistically significant interactions between NHT (enzalutamide vs. abiraterone) and period (post vs. preinitiation NHT). Patients prescribed enzalutamide were more likely to discontinue prescriptions for steroids (p&lt;0.01) as expected. The odds of fluoroquinolones, non-steroidal anti-inflammatory drugs (NSAIDs), and loop diuretics prescriptions were similar pre-NHT initiation for both enzalutamide and abiraterone patients; however, patients treated with enzalutamide were significantly less likely than abiraterone patients to have post-NHT initiation prescriptions for fluoroquinolones (Odds ratio (OR) 0.69 p=0.01) or loop diuretics (OR: 0.57 p&lt;0.01). Conclusions: To our knowledge, this is the first population-based study to describe concurrent medication prescribing before and after NHT. Further studies are warranted to better understand the underlying reasons for the observed patterns.

A Randomized Controlled Trial Comparing Remission Induction with Modified Multitarget Therapy with Intravenous Cyclophosphamide in Proliferative Lupus Nephritis.

Therapy of proliferative lupus nephritis (PLN) is yet to be optimized. Standard of care for induction consists of intravenous (IV) cyclophosphamide (CYC) and steroids, which shows an improved outcome, but end-stage renal disease (ESRD) progression, increased mortality, and therapy-related adverse effects remain a major concern. The other treatment reported to induce early remission was the multitarget therapy comprising tacrolimus, mycophenolate, and steroid, but infections were high in the multitarget therapy. Considering azathioprine as a potentially safer and effective alternative anti-B-cell therapy, modified multitarget therapy (MMTT) was planned replacing mycophenolate with azathioprine. A single-center, 24-week, open-label, randomized controlled trial comprising adults of age 18-65 years with biopsy-proven PLN was carried out. The intervention groups were 1) MMTT: tacrolimus 0.075 mg/kg/day and azathioprine 2 mg/kg/day and 2) IV CYC group with a starting dose of 0.75 (adjusted to 0.5-1.0) g/m2 every 4 weeks for 6 months. Both groups received 3 days of pulse methylprednisolone followed by a tapering course of oral prednisone therapy. Among 100 randomized patients, 48 were in MMTT arm and 52 were in IV CYC arm. At the end of 24 weeks, overall remission (complete and partial) was comparable in both the arms: MMTT (86.36%) and IV CYC (87.75%). There was comparable proteinuria reduction and systemic lupus erythematosus disease activity index (SLEDAI) score improvement with recovery of complement level C3 in both groups. Major adverse events were numerically more in the IV CYC group, including one death from pneumonia. The MMTT arm is as effective as IV CYC in improving short-term outcome in PLN, with a comparable safety profile.

LB1002 Melanocyte depletion in vitiligo and canities is associated with M2 macrophage deficiency and responds to modulation by M2-secreted soluble mediator maresin 1 in vitro and in vivo

Melanocyte depletion occurs in vitiligo and aging associated hair greying (canities). Currently available therapies are unsatisfactory due to limited efficacy or therapy-related adverse effects. The purpose of our study is to uncover previously unknown pathogenic pathways for vitiligo and canities and develop therapies that can block these pathways. Transcriptome sequencing-based immune cellular profiling was performed on skin biopsies from healthy volunteers (N=9) and patients with vitiligo (N=36) and chronic dermatitis (N=15), revealing a 3-fold reduction of M2 macrophages in vitiligo skin lesions (p=0.037).

Antagonistic Pharmacological Interaction between Sirtuin Inhibitor Cambinol and Paclitaxel in Triple-Negative Breast Cancer Cell Lines: An Isobolographic Analysis.

Breast cancer (BC) is a heterogeneous disease with different intrinsic subtypes. The most aggressive subtype of BC–triple-negative breast cancer (TNBC) is characterized by high heterogeneity and metastasis rate, poor prognosis and lack of therapeutic targets due to the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Targeted therapies have been approved for many other cancers and even other subtypes of BC, but treatment options for TNBC are still mainly limited to chemotherapy. Therefore, new, more effective treatment regimens are needed. Combined chemotherapy with two or more active agents is considered a promising anti-neoplasm tool in order to achieve better therapeutic response and reduce therapy-related adverse effects. The study demonstrated an antagonistic effect commonly used in TNBC therapy cytostatic drug-paclitaxel (PAX) and sirtuin inhibitor: cambinol (CAM) in BT-549, MDA-MB-468 and HCC1937 TNBC cell lines. The type of pharmacological interaction was determined by a precise and rigorous pharmacodynamic method-isobolographic analysis. The cytotoxic and anti-proliferative effects of CAM used alone or combined with PAX were determined utilizing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2′-deoxyuridine (BrdU) assays, respectively. Induction of apoptosis in TNBC cell lines after PAX and CAM treatment applied individually or in combination was determined by flow cytometry (FACS) as a number of cells with active caspase-3. It has been observed that both agents used separately inhibit cell proliferation and induce apoptosis; however, applying them in combination ameliorated antiproliferative and pro-apoptotic effects in all analyzed TNBC cell lines. Our results demonstrate that CAM and PAX used in combination act antagonistically, limiting anti-cancer efficacy and showing the importance of preclinical testing.

Combining Telbivudine with Tenofovir in hepatitis B virus related acute on chronic liver failure reduce the risk of renal impairment.

Introduction: Chronic hepatitis B virus (HBV) infection is a major health problem because of its worldwide distribution and its potential adverse sequel, including acute-on-chronic liver failure (ACLF), liver cirrhosis and hepatocellular carcinoma. Short term prognosis of patients with spontaneous severe acute exacerbation of CHB leading to ACLF- like presentation is extremely poor, with mortality ranging from 30% to 70%. Therefore, early and rapid reduction of HBV DNA is the essence of therapy in ACLF-B. Methods: Patients with spontaneous reactivation of HBV [(ALT &gt;5 × upper limit of normal or &gt;2 × baseline) and HBV DNA &gt;20,000 IU/ml] were randomized to Tenofovir mono therapy (300 mg/day) or Tenofovir plus Telbivudine (600 mg/day) dual therapy along with standard medical treatment. Clinical and biochemical parameters were evaluated at baseline, 1 week, 4 weeks and at 3 months. Virological evaluation was done at baseline and at 3 months. Primary end point was reduction of HBV DNA. Secondary end point was reduction of liver related complication, therapy related adverse effects and survival at 3 months. Results: 27 patients were enrolled and 15 of them received mono therapy with Tenofovir and 12 patients received dual therapy (Tenofovir plus Telbivudine). Baseline parameters in two groups had no significant difference. Both groups significantly improve s. bilirubin, ALT, INR, CTP score and MELD score. Only MELD score showed significant improvement in patient with dual therapy at 3 months in comparison of mono therapy. 11 patient on Tenofovir mono therapy (n=15) showed undetected HBV DNA (91.7%) at 3 month and one patient had detectable HBV DNA (&lt;2,000 IU/ml). 10 patients on dual therapy (n=12) had undetectable HBV DNA (100%). Patients receiving dual therapy showed significant improvement in AKI on follow up compared to those on Tenofovir mono therapy. Among 5 deaths, 3 had received mono therapy with Tenofovir and 2 had received dual therapy. Predictors of mortality were high S. bilirubin (25.8±7.8), HBV DNA (5.18±1.17 log10 IU/ml), MELD score (33.0±4.2) and CTP score (12.2±0.8). Conclusion: In spontaneous reactivation of hepatitis B presenting as acute on chronic liver failure, combination of Telbivudine plus Tenofovir is potentially safer with less risk of Tenofovir related nephrotoxicity and hence improved outcomes. Bangladesh Crit Care J March 2022; 10 (1): 48-51

Long-Term Real-World Outcomes of First-Line Pembrolizumab Monotherapy for Metastatic Non-Small Cell Lung Cancer With ≥50% Expression of Programmed Cell Death-Ligand 1.

ObjectivesImmune checkpoint inhibitors (ICIs) of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) have been rapidly adopted in US clinical practice for first-line therapy of metastatic non-small cell lung cancer (NSCLC) since regulatory approval in October 2016, and a better understanding is needed of long-term outcomes of ICI therapy administered in real-world settings outside of clinical trials. Our aim was to describe long-term outcomes of first-line pembrolizumab monotherapy at US oncology practices for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status.MethodsThis retrospective two-cohort study used technology-enabled abstraction of deidentified electronic health records (EHR cohort) plus enhanced manual chart review (spotlight cohort) to study adult patients with stage IV NSCLC, PD-L1 expression ≥50%, no documented EGFR/ALK/ROS1 genomic aberration, and ECOG performance status 0–1 who initiated first-line pembrolizumab monotherapy from 1-November-2016 to 31-March-2020 (EHR cohort, with data cutoff 31-March-2021) or from 1-December-2016 to 30-November-2017 (spotlight cohort, with data cutoff 31-August-2020). Kaplan-Meier analysis was used to determine overall survival (OS; both cohorts) and, for the spotlight cohort, real-world progression-free survival (rwPFS) and real-world tumor response (rwTR).ResultsThe EHR cohort included 566 patients (298 [53%] men); the spotlight cohort included 228 (105 [46%] men); median age in both cohorts was 71. Median follow-up from pembrolizumab initiation to data cutoff was 35.1 months (range, 12.0–52.7) and 38.4 months (range, 33.1–44.9) in EHR and spotlight cohorts, respectively. Median OS was 19.6 months (95% CI, 16.6–24.3) and 21.1 months (95% CI, 16.2–28.9), respectively; 3-year OS rates were 36.2% and 38.2% in EHR and spotlight cohorts, respectively. In the spotlight cohort, median rwPFS was 7.3 months (95% CI, 5.7–9.2); 88 patients (38.6%; 95% CI, 32.2–45.2) experienced rwTR of complete or partial response. For 151/228 patients (66%) who discontinued pembrolizumab, the most common reasons were disease progression (70 [46%]) and therapy-related adverse effects (35 [23%]).ConclusionsReal-world outcomes remain consistent with outcomes observed in clinical trials, supporting long-term benefits of first-line pembrolizumab monotherapy for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status.

Challenges of repurposing tetracyclines for the treatment of Alzheimer's and Parkinson's disease.

The novel antibiotic-exploiting strategy in the treatment of Alzheimer's (AD) and Parkinson's (PD) disease has emerged as a potential breakthrough in the field. The research in animal AD/PD models provided evidence on the antiamyloidogenic, anti-inflammatory, antioxidant and antiapoptotic activity of tetracyclines, associated with cognitive improvement. The neuroprotective effects of minocycline and doxycycline in animals initiated investigation of their clinical efficacy in AD and PD patients which led to inconclusive results and additionally to insufficient safety data on a long-standing doxycycline and minocycline therapy in these patient populations. The safety issues should be considered in two levels; in AD/PD patients (particularly antibiotic-induced alteration of gut microbiota and its consequences), and as a world-wide threat of development of bacterial resistance to these antibiotics posed by a fact that AD and PD are widespread incurable diseases which require daily administered long-lasting antibiotic therapy. Recently proposed subantimicrobial doxycycline doses should be thoroughly explored for their effectiveness and long-term safety especially in AD/PD populations. Keeping in mind the antibacterial activity-related far-reaching undesirable effects both for the patients and globally, further work on repurposing these drugs for a long-standing therapy of AD/PD should consider the chemically modified tetracycline compounds tailored to lack antimicrobial but retain (or introduce) other activities effective against the AD/PD pathology. This strategy might reduce the risk of long-term therapy-related adverse effects (particularly gut-related ones) and development of bacterial resistance toward the tetracycline antibiotic agents but the therapeutic potential and desirable safety profile of such compounds in AD/PD patients need to be confirmed.

Randomised clinical trial: comparison of efficacy and adverse effects of a standard triple clarithromycin-containing regimen with high-dose amoxicillin and bismuth therapy in Helicobacter pylori eradication

The clarithromycin-based triple therapy is the most prescribed Helicobacter pylori eradication regimen in Europe; it causes adverse effects in a significant proportion of subjects, leading to discontinuation. Alternative therapies are required because of increasing clarithromycin resistance or to decrease the adverse effects. We compared the efficacy and spectrum of adverse effects of clarithromycin-based triple therapy with the high-dose amoxicillin/bismuth regimen. A randomised clinical trial enrolled healthy individuals aged 40-64 years. H. pylori was assessed with a 13C-urea breath test. In total 579 H. pylori-positive subjects were randomly allocated in two groups: group 1: clarithromycin 500 mg, amoxicillin 1000 mg, esomeprazole 40 mg, all twice daily; group 2: bismuth subcitrate 240 mg twice daily, amoxicillin 1000 mg three times daily, esomeprazole 40 mg twice daily. Regimens were administered for 14 days.Information on treatment completion and adverse effects were collected via a telephone interview at 21-28 days after medication delivery. The efficacy was assessed by UBT 6 months after the treatment. We analysed 483 subjects for adverse effects (248 vs. 235 respectively). Furthermore, 316 subjects were analysed for efficacy. In per-protocol analysis, a higher efficacy was seen in group 1 (88.4 vs. 77.0%; P < 0.001); no difference was observed in compliance (90.3 and 91.2%). Therapy-related adverse effects were more common in group 1 (56.9 vs. 40.0%; P < 0.01). In intention-to-treat analysis no statistical difference in efficacy was revealed. Bismuth-based high-dose amoxicillin therapy showed a lower efficacy but was less frequently associated with adverse effects. Further research is required to examine the high-dose amoxicillin and bismuth-containing regimens in various populations to maximise eradication efficacy.

Apatinib with doxorubicin and ifosfamide as neoadjuvant therapy for high-risk soft tissue sarcomas: a retrospective cohort study

SummaryBackgroundThere is a need to establish an effective neoadjuvant therapy for soft tissue sarcomas (STSs). We previously showed that apatinib, administered in combination with doxorubicin-based chemotherapy, improves the efficacy of treatment. This study aimed to clarify the effectiveness and safety of apatinib combined with doxorubicin and ifosfamide (AI) neoadjuvant chemotherapy for STSs.MethodsThis retrospective study included patients with STS who received neoadjuvant therapy and surgery between January 2016 and January 2019. The patients were divided into two treatment groups: AI + apatinib group and AI group (doxorubicin + ifosfamide).ResultsThe study included 74 patients (AI + apatinib: 26, AI: 48) with STS. There were significant between-group differences in objective response rates (53.85% vs. 29.17%, p = 0.047) and the average change in target lesion size from baseline (-40.46 ± 40.30 vs. -16.31 ± 34.32, p = 0.008). The R0 rate (84.62% vs. 68.75%; p = 0.170) and 2-year disease-free survival (73.08% vs. 62.50%, p = 0.343) were similar across groups. Finally, the rates of neoadjuvant therapy-related adverse effects and postoperative complications were similar in both groups (p > 0.05).ConclusionApatinib plus doxorubicin and ifosfamide regimen is safe and effective as neoadjuvant therapy for patients with STS. However, the significantly improved preoperative ORR observed after neoadjuvant therapy did not translate into a significantly improved R0 rate and 2-year DFS. Prospective, well-powered studies are warranted to determine the long-term efficacy and optimal application of these protocols.

Quality of Life and Psychological Distress of Lung Cancer Patients Undergoing Chemotherapy.

BackgroundPatients with lung cancer often experience multiple symptoms associated with both the disease itself and the treatment. The disease and therapy-related adverse effects may lead to poor quality of life (QoL) and increased psychological distress. The aim of this study was to investigate the QoL and psychological distress of patients with lung cancer. The relationship between these two aspects was also an area of focus.MethodsThis was a quantitative descriptive study. Data collection was done using a self-complementary tool. The data were collected between February and March 2020. The sample consisted of 135 patients with lung cancer who were undergoing chemotherapy in 1-day clinic in Athens (a sample of convenience).ResultsRegarding the QoL of our sample, we observed that the mean score of the physical health component of SF-12 was 38.17 ± 9.94 and of the mental health component was 45.63 ± 11.80. As regards the psychological distress of our sample, we observed that the mean score for depression was 4.55 ± 5.04, for anxiety was 3.84 ± 4.17 and for stress was 5.21 ± 5.01.ConclusionAs is clear from the results, lung cancer patients reported poor QoL and increased rates of psychological distress.

Observational study on the response of tenofovir monotherapy versus tenofovir plus telbivudine dual therapy in patients with hepatitis B virus related acute on chronic liver failure.

Introduction:HBV is major health problem globally due to complications, including ACLF, cirrhosis and hepa¬tocellular carcinoma. ACLF due to exacerbation of CHB is associate with 30%-70% mortality. Reduction of HBV-DNA is therefore a target of therapy in ACLF-B.Methods:Patients with spontaneous reactivation of HBV [(ALT >5×ULN or >2× baseline) and HBV-DNA >20,000 IU/ml] were randomized to Tenofovir mono therapy (300 mg/day) or Tenofovir plus Telbivudine (600 mg/day) dual therapy with standard care. Clinical and biochemical parameters were evaluated at baseline, 1 week, 4 weeks and at 3 months. Virological evaluation was done at baseline and at 3 months. Primary end points were reduction of HBV-DNA and resolution of ascites, as applied. Secondary end point was reduction of liver related complications, therapy related adverse effects and survival at 3 months.Results:27 patients were enrolled. 15 received mono therapy with Tenofovir and 12 received dual therapy (Tenofovir plus Telbivudine). Baseline parameters in 2 groups had no significant difference. In both groups there was significant improvement of S. bilirubin, ALT, INR, CTP score and MELD score. Only MELD score showed significant improvement in patient with dual therapy at 3 months in comparison to mono therapy. 11 patients on Tenofovir mono therapy (n=15) showed undetected HBV-DNA (91.7%) at 3 months and one patient had detectable HBV-DNA (<2,000 IU/ml). 10 patients on dual therapy (n=12) had undetectable HBV-DNA (100%). Ascites resolved in 3 patients in both groups. Patients receiving dual therapy showed significant improvement in AKI on follow up compared to those on Tenofovir mono therapy. Among 5 deaths, 3 received mono therapy with Tenofovir and 2 dual therapy. Predictors of mortality had high S. bilirubin, HBV-DNA, MELD score and CTP score.Conclusion:In spontaneous reactivation of HBV presenting as ACLF, combination of Telbivudine plus Tenofovir is safer with less nephrotoxicity and better outcomes.

Challenges and Opportunities for Childhood Cancer Drug Development.

Cancer in children is rare with approximately 15,700 new cases diagnosed in the United States annually. Through use of multimodality therapy (surgery, radiation therapy, and aggressive chemotherapy), 70% of patients will be "cured" of their disease, and 5-year event-free survival exceeds 80%. However, for patients surviving their malignancy, therapy-related long-term adverse effects are severe, with an estimated 50% having chronic life-threatening toxicities related to therapy in their fourth or fifth decade of life. While overall intensive therapy with cytotoxic agents continues to reduce cancer-related mortality, new understanding of the molecular etiology of many childhood cancers offers an opportunity to redirect efforts to develop effective, less genotoxic therapeutic options, including agents that target oncogenic drivers directly, and the potential for use of agents that target the tumor microenvironment and immune-directed therapies. However, for many high-risk cancers, significant challenges remain.