Safety, Pharmacokinetics, and Pharmacodynamics of the New Aldose Reductase Inhibitor Govorestat (AT-007) After a Single and Multiple Doses in Participants in a Phase 1/2 Study.

In classic galactosemia (CG) patients, aldose reductase (AR) converts galactose to galactitol. In a phase 1/2, placebo-controlled study (NCT04117711), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of govorestat were evaluated after single and multiple ascending doses (0.5-40 mg/kg) in healthy adults (n = 81) and CG patients (n = 14).

A meta-analysis of cases of Rosai Dorfman disease reported on the African continent and a description of two cases from a tertiary academic hospital in Johannesburg, South Africa.

Rosai-Dorfman-Destombes disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by the accumulation of activated histiocytes within affected tissues. The original haematopathological description of RDD has links to the late South African born haematopathologist, Ronald Dorfman, with a descriptive account of two cases of the disease treated at Chris Hani Baragwanath Academic Hospital are described herein. Alongside the two case descriptions is a meta-analysis of 149 published cases from the African continent.

Real-World Impact of Prophylactic Growth Factor Use on Timing of Febrile Neutropenia and Infection After High-Risk Chemotherapy.

Background: Prophylactic growth-factor therapy with granulocyte colony-stimulating factor (G-CSF) reduces the risk of febrile neutropenia (FN) in patients with breast cancer initiating myelosuppressive chemotherapy. However, little is known about the protective benefit early in the chemotherapy cycle.

Methods: To assess the relationship between G-CSF prophylaxis and incidence of FN/infection in week 1 versus beyond week 1 of the first chemotherapy cycle, a retrospective study was conducted using Medicare claims from 2005 through 2020 among patients with breast cancer initiating high-risk chemotherapy.

HER2 Equivocal (Score = 2+) Breast Carcinoma Cases Identified by Immunohistochemistry at a South African Hospital. What is the Impact of Fluorescent In Situ Hybridization Testing?

The American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) guidelines are used for human epidermal growth factor receptor 2 (HER2) reporting in breast carcinoma. Cases that demonstrate weak to moderate complete membrane immunohistochemical staining in >10% of the tumor are scored as 2+ (equivocal). This study aimed to determine what proportion of HER2 immunohistochemistry (IHC) score = 2+ breast carcinomas were confirmed to be positive by HER2 fluorescent in situ hybridization (FISH).

Rectal suction biopsies to diagnose Hirschsprung's disease in a low-resource environment - optimising cost-effectiveness.

Background: The diagnosis of Hirschsprung's disease (HD) by rectal suction biopsy (RSB) has cost implications that could be reduced by ascertaining the optimal number of specimens required. The aim was to audit our experience to optimise cost-effectiveness.

Methods: Medical records of all patients who underwent an RSB between January 2018 and December 2021 were reviewed.

Grade 4 Neutropenia Frequency as a Binary Risk Predictor for Adverse Clinical Consequences of Chemotherapy‑Induced Neutropenia: A Meta-analysis.

Neutropenia is the major toxicity of myelosuppressive cancer chemotherapy. Grade 4 neutropenia (Gr4N) is a measure of chemotherapy-induced neutropenia (CIN) severity. We conducted a meta-analysis of CIN data.

Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Docetaxel-Induced Neutropenia in Patients With Solid Tumors: A Randomized Clinical Trial.

Importance: Prevention of chemotherapy-induced neutropenia (CIN) and its clinical consequences is an unmet need for which plinabulin, a selective immunomodulating microtubule-binding agent, is being tested.

Objective: To demonstrate noninferiority between plinabulin and pegfilgrastim for days of severe neutropenia in cycle 1 in patients with solid tumors treated with docetaxel.

Design, Setting, And Participants: The Plinabulin vs Pegfilgrastim for the Prevention of Docetaxel-Induced Neutropenia in Patients With Solid Tumors (PROTECTIVE-1) double-blind phase 3 randomized clinical trial was performed in multiple centers in China, Russia, Ukraine, and the US.

Plinabulin, a Distinct Microtubule-Targeting Chemotherapy, Promotes M1-Like Macrophage Polarization and Anti-tumor Immunity.

Reprogramming tumor infiltrating myeloid cells to elicit pro-inflammatory responses is an exciting therapeutic maneouver to improve anti-tumor responses. We recently demonstrated that a distinct microtubule-targeting drug, plinabulin-a clinical-stage novel agent-modulates dendritic cell maturation and enhances anti-tumor immunity. Here, we investigated the effects of plinabulin on macrophage polarization and .

Endometrial sampling at an academic hospital in South Africa: Histological findings, lessons learnt and interesting surprises.

Background: Outpatient sampling is used to investigate endometrial pathology. Little is known about practice habits and local failure rates at Chris Hani Baragwanath Academic Hospital in Johannesburg, South Africa.

Objective: This study assessed the frequency of samples that showed no or limited histological representation of endometrium, and described demographic and pathological features.

Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Chemotherapy-Induced Neutropenia in Adults With Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

Importance: Plinabulin is a novel, non-granulocyte colony-stimulating factor (GCSF) small molecule with both anticancer and neutropenia-prevention effects.

Objective: To assess the efficacy and safety of plinabulin compared with pegfilgrastim for the prevention of chemotherapy-induced neutropenia following docetaxel chemotherapy in patients with non-small lung cancer.

Design, Setting, And Participants: This was a randomized, open-label, phase 2 clinical trial of 4 treatment arms that was conducted in 19 cancer treatment centers in the United States, China, Russia, and Ukraine.

Spectrum of HIV-associated infectious diseases: A case series through the eyes of the histopathologist.

Background: Human immunodeficiency virus (HIV) infection increases the risk of infection by a host of other opportunistic pathogens. The clinical presentations of these co-infections in immunocompromised patients are often atypical; therefore diagnosis is delayed in the absence of investigations such as tissue biopsy. Infection may involve sites that are difficult to access for biopsy and, as a consequence, there is limited diagnostic tissue available for analysis.

Ki67 Immunohistochemistry Quantification in Breast Carcinoma: A Comparison of Visual Estimation, Counting, and ImmunoRatio.

Background: Molecular analysis has shown that breast carcinomas can be classified into several intrinsic subtypes, with implications for management and prognosis. In the majority of pathology laboratories molecular analysis of each case is not possible and immunohistochemistry is used for subtyping. This includes analysis of hormone receptors as well as HER2-neu and Ki67.

Xanthogranulomatous prostatitis: A rare mimicker of prostate adenocarcinoma.

Xanthogranulomatous prostatitis as mimicker of prostate adenocarcinoma can cause a diagnostic dilemma, as presented in this case. Therefore, alongside histopathology analysis, multiparametric magnetic resonance imaging (mpMRI) would be useful in this situation by identifying and characterizing suspicious prostatic lesions before biopsy thereby supporting current recommendations on the use of mpMRI.

Plinabulin ameliorates neutropenia induced by multiple chemotherapies through a mechanism distinct from G-CSF therapies.

Purpose: Chemotherapy-induced neutropenia (CIN) increases the risk of infections and mortality in cancer patients. G-CSF therapies are approved for the treatment of CIN, but non-G-CSF therapies are needed to increase efficacy and minimize side effects. Plinabulin is an inhibitor of tubulin polymerization that ameliorates CIN caused in patients by the microtubule stabilizer docetaxel.

Indirect Evaluation of Bone Saturation with Zoledronic Acid After Long-Term Dosing.

Background: Zoledronic acid (ZA), a potent bisphosphonate used for treatment of bone metastasis, has high bone affinity. This post hoc analysis evaluated the effects of long-term treatment and reduction in dosing frequency of ZA on bone saturation.

Materials And Methods: Pharmacokinetic data from three independent studies, OPTIMIZE-2 (patients receiving ≥9 doses of bisphosphonates) and two phase I studies, CZOL4460503 and CZOL4460506 (patients who were bisphosphonate naïve/bisphosphonate free for ≥1 year after previous dosing), were pooled.

Outcomes of Kasai hepatoportoenterostomy in children with biliary atresia in Johannesburg, South Africa.

Background: Without timely surgical intervention, most children with biliary atresia (BA) are not expected to live beyond 2 years of age. The initial intervention, the Kasai hepatoportoenterostomy (KPE), aims to achieve biliary drainage. Liver transplantation (LT) is performed if jaundice fails to clear or when biliary cirrhosis occurs.

First Report of Renal Cell Carcinoma Metastasizing to the Clivus in a Pediatric Patient.

Background: The clivus is a rare site of tumor occurrence in general, and metastases to this site are especially rare. Renal cell carcinoma is an uncommon entity in the pediatric population. Although not infrequent in adults, when it does occur, metastases to the clivus are extremely uncommon, only having been reported 3 times in the literature.

Continued Treatment Effect of Zoledronic Acid Dosing Every 12 vs 4 Weeks in Women With Breast Cancer Metastatic to Bone: The OPTIMIZE-2 Randomized Clinical Trial.

Importance: Zoledronic acid, a potent bisphosphonate, is commonly administered to patients with bone metastases to reduce the risk of skeletal-related events (SREs). However, there have been concerns regarding its long-term monthly administration.

Objective: To examine whether zoledronic acid every 12 weeks was noninferior to zoledronic acid every 4 weeks in patients with metastatic breast cancer that involved the bone who had previously received a standard dosing regimen of zoledronic acid and/or pamidronate disodium.

Long-Term Safety Follow-Up of Subjects Previously Treated with Non-Replicating Retroviral Vector-Based Gene Therapies.

Objective: Our objective was to evaluate the life-long safety profile of gene therapy using retroviral (non-replicating) vectors (nRCR), or cell products in 127 subjects with hemophilia, human immunodeficiency virus (HIV), or cancer, previously treated with such gene therapy.

Methods: We assessed the occurrence of serious adverse events (SAEs), deaths and presence of replication competent retrovirus (RCR).

Results: A total of 23 subjects remained until the data cut-off date of 31 July 2013 and provided safety information of up to 18 years.

Do Not Forget the Glycophorin A: An Unusual Case of Myeloid Sarcoma.

Acute erythroid leukemia is rare, with isolated reports on presentation as an extramedullary tumor mass (myeloid sarcoma). We describe a case of pure erythroid leukemia presenting as an orbital mass in a 1-year, 9-month-old girl. This is only the second case described in a child.

Kaposi's sarcoma, a South African perspective: Demographic and pathological features.

Background: The incidence of Kaposi's sarcoma (KS) has increased dramatically since the onset of the AIDS epidemic. Of the estimated 66 200 cases of KS worldwide, 58 800 are considered to have occurred in sub-Saharan Africa.

Objectives: To describe the epidemiology and pathological characteristics of KS at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.

Variability of HHV8 LNA-1 Immunohistochemical Staining Across the 3 Histologic Stages of HIV-Associated Mucocutaneous Kaposi Sarcoma: Is There a Relationship to Patients' CD4 Counts?

The histologic diagnosis of Kaposi sarcoma (KS) can be confirmed with human herpes virus 8 (HHV8) latency-associated nuclear antigen (LNA)-1 immunohistochemistry, which may show variability in distribution and intensity. This retrospective study was aimed at addressing the factors that may contribute to this variability. All cases of mucocutaneous KS diagnosed in a 5-year period at the histopathology department at a tertiary hospital in South Africa with available patients' CD4 counts and HHV8 LNA-1 immunohistochemically stained slides were reviewed, and the biopsy stages of KS (patch/plaque/nodular), CD4 counts, immunohistochemistry staining method (manual vs.

c-Jun N-terminal kinases mediate reactivation of Akt and cardiomyocyte survival after hypoxic injury in vitro and in vivo.

Akt is a central regulator of cardiomyocyte survival after ischemic injury in vitro and in vivo, but the mechanisms regulating Akt activity in the postischemic cardiomyocyte are not known. Furthermore, although much is known about the detrimental role that the c-Jun N-terminal kinases (JNKs) play in promoting death of cells exposed to various stresses, little is known of the molecular mechanisms by which JNK activation can be protective. We report that JNKs are necessary for the reactivation of Akt after ischemic injury.

Effect of selective inhibition of the p38 MAP kinase pathway on platelet aggregation.

Systemic inflammation has been shown to be a contributing factor to the instability of atherosclerotic plaques in patients with acute coronary syndromes (ACS). VX-702, a novel p38 mitogen-activated protein kinase (MAPK) inhibitor, is currently under investigation in ACS patients with unstable angina to evaluate its safety and efficacy during percutaneous coronary intervention (PCI). The role of p38 MAPK in platelet aggregation of normal individuals was examined using the selective second generation p38 MAPK inhibitor VX-702.