Response-guided neoadjuvant sacituzumab govitecan for localized triple-negative breast cancer: results from the NeoSTAR trial.

BACKGROUND: Sacituzumab govitecan (SG), a novel antibody-drug conjugate (ADC) targeting TROP2, is approved for pre-treated metastatic triple-negative breast cancer (mTNBC). We conducted an investigator-initiated clinical trial evaluating neoadjuvant (NA) SG (NCT04230109), and report primary results. PATIENTS AND METHODS: Participants with early-stage TNBC received NA SG for four cycles. The primary objective was to assess pathological complete response (pCR) rate in breast and lymph nodes (ypT0/isN0) to SG. Secondary objectives included overall response rate (ORR), safety, event-free survival (EFS), and predictive biomarkers. A response-guided approach was utilized, and subsequent systemic therapy decisions were at the discretion of the treating physician. RESULTS: From July 2020 to August 2021, 50 participants were enrolled (median age = 48.5 years; 13 clinical stage I disease, 26 stage II, 11 stage III). Forty-nine (98%) completed four cycles of SG. Overall, the pCR rate with SG alone was 30% [n = 15, 95% confidence interval (CI) 18% to 45%]. The ORR per RECIST V1.1 after SG alone was 64% (n = 32/50, 95% CI 77% to 98%). Higher Ki-67 and tumor-infiltrating lymphocytes (TILs) were predictive of pCR to SG (P = 0.007 for Ki-67 and 0.002 for TILs), while baseline TROP2 expression was not (P = 0.440). Common adverse events were nausea (82%), fatigue (76%), alopecia (76%), neutropenia (44%), and rash (48%). With a median follow-up time of 18.9 months (95% CI 16.3-21.9 months), the 2-year EFS for all participants was 95%. Among participants with a pCR with SG (n = 15), the 2-year EFS was 100%. CONCLUSIONS: In the first NA trial with an ADC in localized TNBC, SG demonstrated single-agent efficacy and feasibility of response-guided escalation/de-escalation. Further research on optimal duration of SG as well as NA combination strategies, including immunotherapy, are needed.

Mid-term results of Miller-Galante unicompartmental knee replacement for medial compartment knee osteoarthritis.

BACKGROUND: The purpose of this study is to analyse and report the mid-term results of 175 unicompartmental knee replacement (UKR) procedures performed for medial compartment knee arthritis from January 2001 to January 2010. MATERIALS AND METHODS: The cohort participants were selected after stringent inclusion criteria and the average follow-up was 5.6 years (range 2-10 years). The fixed-bearing UKR procedure was carried out on all patients. RESULTS: The pre-operative mean knee range of movement improved from 100° ± 11.3° to 118.3° ± 12° (p value <0.001). The pre-operative mean Knee Society (KS) knee and functional score improved from 47 ± 5.5 and 55.1 ± 4.6 to 91.8 ± 9.2 and 92 ± 10.1 (p value <0.001), respectively. The revision rate of the cohort was 4 % (seven knees) and implant survival rate was 96 % at the end of 10 years; 87 % of the cohort were satisfied with the procedure and had a normal gait pattern. In this study, there was no statistical difference between groups with a body mass index (BMI) ≤30 kg/m(2) and those with a BMI ≥30 kg/m(2), and between groups aged ≤55 years and those aged ≥55 years, in clinical and functional outcome following UKR. CONCLUSION: This study confirms that fixed-bearing UKR gives excellent results in patients with medial compartment knee arthritis who comply with the inclusion criteria. Age and BMI were not considered to influence the clinical and functional outcomes. Level of evidence-III.

Current therapeutic protocols for chronic granulomatous fungal sinusitis.

BACKGROUND: The treatment of chronic granulomatous fungal sinusitis (CGFS), a rare form of invasive fungal sinusitis, is controversial. AIM: To assess the response to postoperative antifungal therapy in patients with CGFS and suggest an effective treatment protocol. METHODOLOGY: Clinical records of patients with CGFS who had undergone excisive surgery followed by antifungal therapy were reviewed to assess current disease status. RESULTS: Fourteen male and 4 female patients were diagnosed with CGFS, based on typical histopathological and fungal smear/ culture results. Aspergillus flavus was isolated from 88.9% cases. Stage 1 patients had resectable sinonasal disease, stage 2 had additional spread to orbit/palate and stage 3 had extensive disease. Follow-up ranged from 6 months to 8 years. Residual disease was seen in all but one patient who received amphotericin B as first line therapy and in none of those who received itraconazole or voriconazole. Even those who received azoles as second line therapy were disease free at last follow-up. CONCLUSION: Surgery followed by itraconazole or voriconazole for Stage 1 and 2 disease and voriconazole for stage 3 disease is recommended for a good outcome. Amphotericin B is not recommended as first line therapy for CGFS.

Relative etiological importance of adenoid hypertrophy versus sinusitis in children with persistent rhinorrhoea.

Persistent rhinorrhoea is a common, yet often neglected, problem among Indian children. This study was designed to evaluate the relative etiological importance of adenoid hypertrophy versus sinusitis in children with persistent rhinorrhea. Additionally, the association between S. pneumoniae colonization and adenoid hypertrophy was studied. Children aged 1-14 years with persistent rhinorrhea underwent clinical evaluation, rigid nasal endoscopy and xrays of the nasopharynx and paranasal sinuses to ascertain the presence of adenoid hypertrophy and sinusitis using standard criteria. Nasopharyngeal swabbing to ascertain the presence of nasopharyngeal colonization with S. pneumoniae was also performed. Adenoid hypertrophy was more consistently associated with persistent rhinorrhea than sinusitis (p < 0.0001). Coincident adenoid hypertrophy and sinusitis occurred in 57 %. S. pneumoniae was cultured in only 29 % of children. Up to 47 % of patients had features of nasal allergy. There was no association between S. pneumoniae colonization and adenoid hypertrophy (p = 0.1). Adenoid hypertrophy is an important cause of persistent rhinorrhea in children. Measures to evaluate for and treat adenoid hypertrophy should be instituted early to alleviate the problem of persistent rhinorrhoea in children. S. pneumoniae colonization of the nasopharynx is not a major etiological factor for persistent rhinorrhoea in these children. Nasal allergy may be a cause of adenoid hypertrophy in roughly half the children.

Draft Genome Sequences of Two Pasteurella multocida Strains Isolated from Buffaloes in India with Hemorrhagic Septicemia Disease.

Pasteurella multocida serotype B:2 is the causative agent of hemorrhagic septicemia in cattle and buffaloes in Asia. It is an acute fatal disease and is considered one of the most economically important diseases in this region of the world. We present here the draft genome sequences of strains 2213 and 3213 of P. multocida.

Topical (intra-articular) tranexamic acid reduces blood loss and transfusion rates following total knee replacement: a randomized controlled trial (TRANX-K).

BACKGROUND: Approximately one-third of patients undergoing total knee replacement require one to three units of blood postoperatively. Tranexamic acid (TXA) is a synthetic antifibrinolytic agent that has been successfully used intravenously to stop bleeding after total knee replacement. A topical application is easy to administer, provides a maximum concentration of tranexamic acid at the bleeding site, and is associated with little or no systemic absorption of the tranexamic acid. METHODS: A double-blind, randomized controlled trial of 157 patients undergoing unilateral primary cemented total knee replacement investigated the effect of topical (intra-articular) application of tranexamic acid on blood loss. The primary outcome was the blood transfusion rate. Secondary outcomes included the drain blood loss, hemoglobin concentration drop, generic quality of life (EuroQol), Oxford Knee Score, length of stay, a cost analysis, and complications as per the protocol definitions. RESULTS: Tranexamic acid reduced the absolute risk of blood transfusion by 15.4% (95% confidence interval [CI], 7.5% to 25.4%; p = 0.001), from 16.7% to 1.3%, and reduced blood loss by 168 mL (95% CI, 80 to 256 mL; p = 0.0003), the length of stay by 1.2 days (95% CI, 0.05 to 2.43 days; p = 0.041), and the cost per episode by £333 (95% CI, £37 to £630; p = 0.028). (In 2008, £1 = 1.6 U.S. dollars.) Oxford Knee Scores and EuroQol EQ-5D scores were similar at three months. CONCLUSIONS: Topically applied tranexamic acid was effective in reducing the need for blood transfusion following total knee replacement without important additional adverse effects. LEVEL OF EVIDENCE: Therapeutic level I. See Instructions for Authors for a complete description of levels of evidence.

Novel multidrug therapy for disseminated rhinosporidiosis, refractory to dapsone ­ case report.

Rhinosporidiosis is a chronic granulomatous disorder, caused by Rhinosporidium seeberi endemic in India and Sri Lanka. The most common sites are the nasal mucosa and the nasopharynx and cutaneous lesions usually occur as a part of disseminated rhinosporidiosis. Dapsone has been frequently used in treating disseminated disease in immunocompetent individuals. Here we report a case of disseminated rhinosporidiosis in an immunocompromised individual on antiretroviral drugs, non-responsive to Dapsone and therefore treated with a multidrug therapy of Cycloserine, Dapsone and Ketoconazole with good response.

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib.

The B-cell translocation gene-2 (BTG2), a p53-inducible gene, is suppressed in mammary epithelial cells during gestation and lactation. In human breast cancer, decreased BTG2 expression correlates with high tumor grade and size, p53 status, blood and lymph vessel invasion, local and metastatic recurrence and decrease in overall survival, suggesting that suppression of BTG2 has a critical role in disease progression. To analyze the role of BTG2 in breast cancer progression, BTG2 expression was knocked down in mammary epithelial cells. Suppression of BTG2 enhances the motility of cells in vitro and tumor growth and metastasis in vivo. The effects of BTG2 knockdown are mediated through stabilization of the human epidermal growth factor receptor (HER) ligands neuregulin and epiregulin and activation of the HER2 and HER3 receptors, leading to elevated AKT phosphorylation. Suppression of HER activation using the tyrosine kinase inhibitor lapatinib abrogates the effects of BTG2 knockdown, including the increased cell migration observed in vitro and the enhancement of tumorigenesis and metastasis in vivo. These results link BTG2-dependent effects on tumor progression to ErbB receptor signaling, and raise the possibility that targeted inhibition of this pathway may be relevant in the treatment of breast cancers that have reduced BTG2 expression.

Application of the 4-trifluoromethylbenzenepropargyl ether group as an unhindered, electron deficient protecting group for stereoselective glycosylation.

4-Trifluoromethylbenzenepropargyl ethers are stable and sterically minimal alcohol protecting groups that are readily cleaved in a single step by exposure to lithium naphthalenide. In conjunction with the 4,6-O-benzylidene protecting group, glycosylation reactions of 2-O-(4-trifluoromethylbenzenepropargyl)-protected mannosyl donors are extremely beta-selective.

Human CD18 is the functional receptor for Aggregatibacter actinomycetemcomitans leukotoxin.

Aggregatibacter (Actinobacillus) actinomycetemcomitans is the causative organism of localized aggressive periodontitis, a rapidly progressing degenerative disease of the gingival and periodontal ligaments, and is also implicated in causing subacute infective endocarditis in humans. The bacterium produces a variety of virulence factors, including an exotoxic leukotoxin (LtxA) that is a member of the repeats-in-toxin (RTX) family of bacterial cytolysins. LtxA exhibits a unique specificity to macrophages and polymorphonuclear cells of humans and other primates. Human lymphocyte function-associated antigen 1 (LFA-1) has been implicated as the putative receptor for LtxA. Human LFA-1 comprises the CD11a and CD18 subunits. It is not clear, however, which of its subunits serves as the functional receptor that confers species-specific susceptibility to LtxA. Here we demonstrate that the human CD18 is the receptor for LtxA based on experiments performed with chimeric beta2-integrins recombinantly expressed in a cell line that is resistant to LtxA effects. In addition, we show that the cysteine-rich tandem repeats encompassing integrin-epidermal growth factor-like domains 2, 3, and 4 of the extracellular region of human CD18 are critical for conferring susceptibility to LtxA-induced biological effects.

A concise total synthesis of DL-histrionicotoxin.

The synthesis of (+/-)-histrionicotoxin has been achieved in just nine steps using a two-directional synthesis strategy. Key reactions include a two-directional cross-metathesis, a tandem oxime formation/Michael addition/1,4-prototopic shift/[3 + 2]-cycloaddition cascade, a selective Z,Z-bisenyne formation, and a one-pot N-O and bischloroacetylene reduction.

Mapping of the binding site for Mannheimia haemolytica leukotoxin within bovine CD18.

To map the site involved in Mannheimia haemolytica leukotoxin (LktA) binding and biological activity within bovine CD18, bovine x human CD18 chimeric constructs were generated and coexpressed with bovine CD11a in K562 cells. Studies with the chimeric leukocyte function-associated antigen 1 transductants demonstrate that the site required for LktA binding and biological effects resides within amino acid residues 500 and 600 of the extracellular region of bovine CD18.

Patellar clunk syndrome in patellofemoral arthroplasty--a case report.

Patellar clunk syndrome is characterised by the formation of a fibrous nodule at the articular side of junction of superior pole of patella and the quadriceps tendon. Until now, it is only described in posterior cruciate substituting total knee replacements. We report the patellar clunk syndrome in a lady with patellofemoral joint replacement.

Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model.

Mullerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro. To extend the use of MIS to treat breast cancer, it is essential to test the responsiveness of mammary tumor growth to MIS in vivo. Mammary tumors arising in the C3(1) T antigen mouse model expressed the MIS type II receptor, and MIS in vitro inhibited the growth of cells derived from tumors. Administration of MIS to mice was associated with a lower number of palpable mammary tumors compared with vehicle-treated mice (P=0.048), and the mean mammary tumor weight in the MIS-treated group was significantly lower compared with the control group (P=0.029). Analysis of proliferating cell nuclear antigen (PCNA) expression and caspase-3 cleavage in tumors revealed that exposure to MIS was associated with decreased proliferation and increased apoptosis, respectively, and was not caused by a decline in T antigen expression. The effect of MIS on tumor growth was also evaluated on xenografted human breast cancer cell line MDA-MB-468, which is estrogen receptor- and retinoblastoma-negative and expresses mutant p53, and thus complements the C3(1)Tag mouse mammary tumors that do not express estrogen receptor and have functional inactivation of retinoblastoma and p53. In agreement with results observed in the transgenic mice, MIS decreased the rate of MDA-MB-468 tumor growth and the gain in mean tumor volume in severe combined immunodeficient mice compared with vehicle-treated controls (P=0.004). These results suggest that MIS can suppress the growth of mammary tumors in vivo.

3,3,3-trichloropropyl-1-triphenylphosphorane: a reagent for the synthesis of (Z)-1,3-enynes, (Z,Z)-1-chloro-1,3-dienes, and 1,3-diynes.

3,3,3-Trichloropropyl-1-triphenylphosphonium chloride is conveniently prepared from 2-chloroethanol, triphenylphosphine, and trichloroacetic acid. Deprotonation of this reagent generates 3,3,3-trichloropropyl-1-triphenylphosphorane, which reacts with aldehydes to give trichloromethylated (Z)-olefins, which are useful for the synthesis of (Z)-1,3-enynes, (Z,Z)-1-chloro-1,3-dienes, and 1,3-diynes in high yields and stereospecificities.

Protective effect of dexamethasone in experimental bovine pneumonic mannheimiosis.

Clinical and experimental studies provide unequivocal evidence that neutrophils participate in the pathogenesis of lung injury in bovine pneumonic mannheimiosis (BPM). Since the inflammatory cytokines tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 play a central role in the recruitment and activation of neutrophils, we hypothesize that pharmacological inhibition of their expression may prevent or reduce the inflammatory lung injury that is characteristic of the disease. The purpose of this study was to determine whether systemic therapy with dexamethasone sodium phosphate (DEX), a potent inhibitor of inflammatory cytokine synthesis, ameliorates disease development in an in vivo experimental model of BPM. Four experimental calves were treated intravenously with DEX (2 mg/kg 6 h prior to infection, 2 mg/kg immediately prior to infection, and 1 mg/kg every 12 h thereafter), while two placebo-treated control calves received dose-matched volumes of sterile saline. Disease was induced in the left lungs of the six calves by endobronchial administration of Mannheimia haemolytica. Clinical disease was characterized using a non-parametric scoring system, and the extent of gross pulmonary pathology affecting the left lung 48 h post-infection (PI) was determined using morphometric methods. Disease scores for DEX-treated calves were significantly lower than those for placebo-treated controls at all time points beyond 2 h PI (P<0.05) and the percent volume of the left lung exhibiting gross pneumonic lesions was significantly lower in DEX-treated calves (6.0+/-1.1%) as compared to controls (68.9+/-13.3%), P<0.05. In addition, histopathological lesions were less severe and extensive in DEX-treated calves. These findings indicate that pharmacological modulation of pulmonary inflammation may represent an alternative approach to control this disease. Successful implementation of this strategy will require additional research to identify drug agents that target the expression of cytokines and other inflammatory mediators without compromising host immune responses.

Transforming Growth Factor-beta superfamily: evaluation as breast cancer biomarkers and preventive agents.

The Transforming Growth Factor-beta (TGFbeta) superfamily of cytokines is comprised of a number of structurally-related, secreted polypeptides that regulate a multitude of cellular processes including proliferation, differentiation and neoplastic transformation. These growth regulatory molecules induce ligand-mediated hetero-oligomerization of distinct type II and type I serine/threonine kinase receptors that transmit signals predominantly through receptor-activated Smad proteins but also induce Smad-independent pathways. Ligands, receptors and intracellular mediators of signaling initiated by members of the TGFbeta family are expressed in the mammary gland and disruption of these pathways may contribute to the development and progression of human breast cancer. Since many facets of TGFbeta and breast cancer have been recently reviewed in several articles, except for discussion of recent developments on some aspects of TGFbeta, the major focus of this review will be on the role of activins, inhibins, BMPs, nodal and MIS-signaling in breast cancer with emphasis on their utility as potential diagnostic, prognostic and therapeutic targets.

Pharmacological inhibition of Mannheimia haemolytica lipopolysaccharide and leukotoxin-induced cytokine expression in bovine alveolar macrophages.

The inflammatory cytokines tumor necrosis factor-alpha (TNFalpha), interleukin-1 beta (IL-1beta), and interleukin-8 (IL-8) are believed to contribute to the pathogenesis of lung injury in bovine pneumonic mannheimiosis (BPM) caused by Mannheimia (Pasteurella) haemolytica. Inflammatory cytokines may, therefore, represent therapeutic targets to be modulated for the purpose of treating or preventing this important disease of cattle. The purpose of this study was to evaluate the ability of six pharmacological agents to suppress the expression of TNFalpha, IL-1beta, and IL-8 genes and proteins in bovine alveolar macrophages (AM) exposed to M. haemolytica lipopolysaccharide (LPS) and leukotoxin (LktA) in vitro. The compounds tested included dexamethasone (DEX), tetrahydropapaveroline (THP), pentoxifylline (PTX), rolipram (ROL), SB203580 (SB), and thalidomide (THL). Cytokine expression was induced by the addition of purified M. haemolytica LPS and LktA to AM cell cultures following pretreatment with inhibitor compounds. Secretion of TNFalpha, IL-1beta, and IL-8 proteins into the cell culture supernatant was measured using enzyme-linked immunosorbent assays, and steady-state accumulation of cytokine-specific mRNA was measured by northern blot analysis. Dose-dependent inhibition of cytokine secretion occurred in response to pretreatment of AM with DEX (TNFalpha, IL-1beta, IL-8), THP (TNFalpha, IL-1beta, IL-8), PTX (TNFalpha, IL-1beta, IL-8), ROL (TNFalpha, IL-1beta), and SB (TNFalpha, IL-8). Significant dose-dependent inhibition of cytokine mRNA expression occurred in response to pretreatment with DEX (TNFalpha, IL-1beta, IL-8), THP (TNFalpha, IL-1beta, IL-8), and PTX (TNFalpha). DEX was the most effective inhibitor by far; pretreatment with this compound yielded greater than 95% inhibition of cytokine gene and protein expression over a broad range of concentrations. These findings demonstrate that DEX, THP, PTX, ROL, and SB are capable of suppressing inflammatory cytokine secretion by bovine AM in vitro. If pulmonary cytokine secretion may be similarly inhibited in vivo, anti-cytokine therapy may represent a novel strategy for the management of BPM.

Synthesis, spectra, dioxygen affinity and antifungal activity of Ru(III) Schiff base complexes.

The reaction of ruthenium(III) complexes, [RuX(3)(EPh(3))(3)] (E=As, X=Cl or Br; E=P, X=Cl) and [RuBr(3)(PPh(3))(2)(CH(3)OH)] with bidendate Schiff base ligands derived by condensing salicylaldehyde with methylamine (Hsalmet), cyclohexylamine (Hsalchx), 2-aminopyridine (Hsalampy) have been carried out. The complexes were characterized by analytical and spectral studies (IR, electronic and EPR) and are formulated as [RuX(EPh(3))(LL')(2)] (where LL'=monobasic bidentate Schiff base ligand; E=P or As, X=Cl or Br). An octahedral geometry has been tentatively proposed for the new complexes. Dioxygen affinity of some of the Ru(III) Schiff base complexes was studied by cyclic voltammetry. The representative Schiff bases and their complexes were tested in vitro to evaluate their activity against fungi, namely, Aspergillus flavus (A. flavus) and Fusarium species.