Trastuzumab deruxtecan in human epidermal growth factor receptor 2-positive breast cancer brain metastases: a systematic review and meta-analysis.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) has shown promising results in patients with breast cancer brain metastases (BCBMs). We conducted a systematic review and meta-analysis to evaluate the effectiveness and safety of T-DXd in the human epidermal growth factor receptor 2 (HER2)-positive BCBM population. PATIENTS AND METHODS: We searched PubMed, Embase, and Cochrane Library databases as well as American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and San Antonio Breast Cancer Symposium (SABCS) websites for clinical trials (CTs) and observational studies evaluating T-DXd in patients with HER2-positive BCBM. Heterogeneity was assessed with I2 statistics. Random effects models were used for all statistical analyses, which were carried out using R software (version 4.2.2). RESULTS: Ten studies were included, six CTs (n = 189) and four observational studies (n = 130), with a total of 319 patients. The median progression-free survival was 15 months [95% confidence interval (CI) 13.9-16.1 months]. The objective response rate (ORR) was 61% (95% CI 52% to 70%), and the intracranial (IC)-ORR was 61% (95% CI 54% to 69%). No significant differences in ORR and IC-ORR were observed between CTs and observational studies (P = 0.31 and 0.58, respectively). The clinical benefit rate (CBR) was 80% (95% CI 52% to 94%), and the IC-CBR was 70% (95% CI 54% to 82%). The ORR was 68% (95% CI 57% to 77%) in the subgroup of patients with stable BMs and 60% (95% CI 48%-72%) in patients with active BM, with no significant difference between groups (P = 0.35). CONCLUSIONS: Our systematic review and meta-analysis supports the IC activity of T-DXd in patients with stable BM and active BM. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) under the protocol number CRD42023422589.

Postoperative infections following total knee replacement: an epidemiological study.

From January 1991 to June 1997 217 patients undergoing monolateral or bilateral total knee replacement (TKR) were consecutively enrolled in a prospective study on the incidence of postoperative infections and related risk factors. Regional antimicrobial prophylaxis (teicoplanin 400 mg) was used in 263 (95%) prostheses implanted; in the remaining 14 implants (5%) perioperative antibiotic prophylaxis (teicoplanin 800 mg) was administered as usual by systemic route. None of the patients experienced local or systemic adverse effects. Over the 2-year follow-up period, 8 (2.9%) primary site infectious complications were recorded, i.e. 4 superficial infections, which were cured without involvement of the prostheses, and 4 deep infections, which required prosthesis removal. Six infections occurred in patients who had undergone previous surgery of the same knee joint, and 2 in patients undergoing primary TKR (p= 0.0005); diabetic patients had infections (13%) more frequently than non-diabetic patients (1.9%, p=0.01). Staphylococci were the leading organisms isolated from infections; however 3 strains of Escherichia coli were isolated from patients who had undergone a previous prosthesis implantation at the same knee joint. Regional administration of teicoplanin appears to be a safe and valuable prophylactic technique; however, in patients at risk of infection a prophylactic regimen which is also active against gram-negative bacteria should probably be considered.

Fibrogenesis serum markers in patients with chronic hepatitis C treated with alpha-IFN.

The correlation between therapeutic response and liver fibrogenesis was studied in serum and liver specimens taken from 31 patients treated with alpha-interferon (IFN) (14 sustained responders and 17 non-responders) for chronic hepatitis C. Serum samples, collected before therapy, and at further 6-month intervals over 2 years, were tested for markers of liver neofibrogenesis. Serum N-terminal procollagen III peptide (PIIINP) displayed a significant and persistent decrease (P < 0.05) in sustained responders but not in non-responders; significantly lowered (P < 0.05) mean levels of C-terminal procollagen I peptide (PICP) were transiently observed in both patient groups, apparently as a result of IFN administration. Serum laminin (Lam) levels remained unchanged. One year after the cessation of treatment, liver biopsy re-testing showed an improvement in necro-inflammatory scores only in sustained responders, with the histological fibrosis scores remaining unaltered in both groups. IFN treatment seemed to exert an influence on serum levels of markers of hepatic connective tissue turnover even in patients that did not respond to therapy, while no effect was observed on preexistent liver fibrosis.

Mutagenicity, carcinogenicity, and teratogenicity of acrylonitrile.

Acrylonitrile (AN) is an important intermediary for the synthesis of a variety of organic products, such as artificial fibres, household articles and resins. Although acute effects are the primary concern for an exposure to AN, potential genotoxic, carcinogenic and teratogenic risks of AN have to be taken seriously in view of the large number of workers employed in such industries and the world-wide population using products containing and possibly liberating AN. An understanding of the effect of acrylonitrile must be based on a characterization of its metabolism as well as of the resulting products and their genotoxic properties. Tests for mutagenicity in bacteria have in general been positive, those in plants and on unscheduled DNA synthesis doubtful, and those on chromosome aberrations in vivo negative. Wherever positive results had been obtained, metabolic activation of AN appeared to be a prerequisite. The extent to which such mutagenic effects are significant in man depends, however, also on the conditions of exposure. It appears from the limited data that the ultimate mutagenic factor(s), such as 2-cyanoethylene oxide, may have little opportunity to act under conditions where people are exposed because it is formed only in small amounts and is rapidly degraded. The carcinogenic action of AN has been evaluated by various agencies and ranged from 'reasonably be anticipated to be a human carcinogen' to 'cannot be excluded', the most recent evaluation being 'possibly carcinogenic to humans'. Animal data that confirm the carcinogenic potential of AN have certain limitations with respect to the choice of species, type of tumors and length of follow up. Epidemiological studies which sometimes, but not always, yielded positive results, encounter the usual difficulties of confounding factors in chemical industries. Exposure of workers to AN should continue to be carefully monitored, but AN would not have to be considered a cancer risk to the population provided limitations on releases from consumer products and guidelines on AN in water and air are enforced. AN is teratogenic in laboratory animals (rat, hamster) at high doses when foetal/embryonic (and maternal) toxicity already is manifest. Pregnant workers should not be exposed to AN. In view of the small concentrations generally encountered outside plants, women not professionally exposed would appear not to be at risk of teratogenic effects due to AN. Future research should concentrate on the elucidation of the different degradation pathways in man and on epidemiological studies in workers including pregnant women, assessing also, if possible, individual exposure by bio-monitoring.

HGV/GBV-C in liver tissue and in sera from patients with chronic hepatitis C.

Forty-eight persons (M = 45, F = 3; age range = 20-53, mean = 32.2) affected with chronic hepatitis C were tested for HGV/GBV-C RNA and HCV-RNA by nested PCR and DEIA in serum and in liver specimens to evaluate the prevalence and the impact of HGV/GBV-C coinfection in patients with chronic HCV-related hepatitis. Sera were also assayed for antibodies to HGV/GBV-C E2 protein. Serum HGV/GBV-RNA could be detected in nine (19%) patients, and anti-E2 antibodies in 22 (46%) patients. The presence of HGV/GBV-C RNA or anti-E2 antibodies was mutually exclusive. The cumulative prevalence of HGV/GBV-C infection was 65% (31/48); the majority of these patients (26/31, 84%) were intravenous drug users (IVDUs). In eight of nine patients viraemic for HGV/GBV-C, RNA positivity could be revealed even in liver specimens; these eight patients were also positive for HCV-RNA both in serum and the liver and did not exhibit any specific association with HCV genotype. HGV/GBV-C RNA negative strand RT-PCR testing was negative in all of the eight liver specimens, providing little support to the hypothesis that liver represents the primary site of HGV/GBV-C replication. Moreover, patients with HGV/GBV-C and HCV coinfection were comparable to those with HCV infection alone in terms of biochemistry and liver histology.

Adaptive response to DNA-damaging agents: a review of potential mechanisms.

The study of the adaptive response, i.e. a reduced effect from a higher challenging dose of a stressor when a smaller inducing dose had been applied a few hours earlier, has opened many new vistas into the mechanisms by which cells can adapt to hazardous environments. Although the entire chain from the initial event, supposedly the presence of DNA damage, to the end effect, presumably improved DNA repair, has not been fully elucidated, many individual links have been postulated. Initial elements--following the still unknown signal for the presence of radiation damage--are various kinases (protein kinase C and stress-activated protein kinases), which, in turn, induce early response genes whose products initiate a cascade of protein-DNA interactions that regulate gene transcription and ultimately result in specific biological responses. These responses include the activation of later genes that can promote production of growth factors and cytokines, trigger DNA repair, and regulate progress through the cell cycle. Indeed, there appears to be a relation between the induction of the adaptive response and the effects of radiation and cytostatic agents on the cell cycle, although these effects, especially the G1 delay, occur at much higher doses than the adaptive response, and one may not indiscriminately extrapolate mechanisms responsible for cell cycle changes observed at high doses, e.g. for radiation in the order of grays, to those involved in the adaptive responses at much lower doses, i.e. some tens of milligrays.

Amphotericin B as primary therapy for cryptococcosis in patients with AIDS: reliability of relatively high doses administered over a relatively short period.

Thirty-one consecutive AIDS patients with cryptococcal disease were enrolled in a study of the efficacy and safety of short-course primary treatment with a relatively high dose of amphotericin B (1 mg/[kg.d] for 14 days); 26 patients also received flucytosine (100-150 mg/[kg.d], given either intravenously or orally). Twenty-five patients had cryptococcal meningitis confirmed by culture, three had presumed cryptococcal meningitis, and three had disseminated extrameningeal cryptococcosis. After successful primary treatment, all patients were given oral itraconazole or fluconazole as suppressive therapy, and their lifelong clinical and mycologic follow-up was planned. Successful primary therapy was defined as the resolution of symptoms and the documentation of negative cultures of cerebrospinal fluid and/or blood 2 months after the initial diagnosis. Therapy was successful in 29 (93.5%) of all 31 cases and in 26 (92.8%) of the 28 cases of culture-proven or presumed cryptococcal meningitis. Nephrotoxicity developed as a result of amphotericin B administration in seven cases; this adverse reaction required a reduction of the dose in two cases and the discontinuation of therapy in five. No deaths due to cryptococcosis were documented during primary therapy. Treatment failed in two cases. During a mean observation period of 10.7 months, three relapses of the underlying infection occurred. Our results indicate that an aggressive approach to the primary treatment of cryptococcosis in AIDS patients, with the administration of a relatively high dose of amphotericin B for a relatively short period, is effective and well tolerated.

Regional and systemic prophylaxis with teicoplanin in monolateral and bilateral total knee replacement procedures: study of pharmacokinetics and tissue penetration.

Twenty-four patients undergoing monolateral or bilateral total knee replacement (TKR) procedures were randomized to receive teicoplanin (T) either systemically or regionally. Subjects scheduled for systemic prophylaxis and undergoing monolateral (six patients) or bilateral (five patients) TKR received a single 800-mg dose of T in 100 ml of saline as a 5-min infusion into a forearm vein 2.5 h before surgery. For regional prophylaxis, patients undergoing monolateral surgery (eight subjects) received 400 mg of T in 100 ml of saline as a 5-min infusion into a foot vein of the leg to be operated on immediately after the tourniquet was inflated. For the five patients scheduled for bilateral operation and regional prophylaxis, the administration of T was also repeated for the second knee operation. The tourniquet, as the standard TKR surgical technique, was inflated to 400 mm Hg (c. 50 kPa) in all 24 patients immediately before the beginning of surgery and kept in place for the duration of the operation. Samples of serum, bone, skin, synovia, and subcutaneous tissue were collected at timed intervals during surgery. They were microbiologically assayed for T by using Bacillus subtilis as the test organism. Overall, the mean T concentrations obtained with regional route prophylaxis were found to be 2 to 10 times higher than those achieved following systemic prophylaxis. Moreover, peak levels in different tissues after regional prophylaxis were significantly higher (P < 0.05). None of the patients experienced adverse effects due to regional or systemic T administration; no prosthetic or wound infections were observed in the follow-up period (from 12 to 26 months).

Metabolic activation by a supernatant from human hepatoma cells: a possible alternative in mutagenic tests.

The supernatant from human Hep G2 hepatoma cells was examined for typical enzymatic activities involved in the metabolism of xenobiotics. Neither cytochrome P-450 nor b5 was detectable, but associated enzymatic activities were found especially after induction with hydrocortisone (HC) and benzanthracene (BA) suggesting that this Hep G2 supernatant contains cyt P-450 IA1 and IA2. Other critical enzymes are also present, but, as expected, at lower activities than in Aroclor 1254 rat liver S9, except for NADH and NADPH cytochrome c reductase. Results of the Ames test indicate that the induced Hep G2 supernatant is a suitable activator for the evaluation of genotoxicity of indirect mutagens.

Mutagenicity of some heterocyclic amines in Salmonella typhimurium with metabolic activation by human red blood cell cytosol.

Purified human red blood cell cytosol was used to activate the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) into mutagenic intermediate(s) in the Salmonella test. The liquid preincubation method in the presence of strain TA98 was utilized. In order to understand the mechanism involved in this metabolic activation, some modulators were incorporated in the medium. The results suggest that an oxygenated hemoprotein, probably oxyhemoglobin, is involved in the activation into genotoxic intermediate(s).