Tumor proliferative activity and response to first-line chemotherapy in advanced breast carcinoma

Summary The relationship between tumor proliferative activity and response to first-line chemotherapy and survival was investigated in 76 advanced breast cancer patients. Proliferative activity was determined by means of Ki-67 immunohistologic staining on primary tumors (55 patients) or at the relapse site (21 patients), and was classified as low ( 25% of stained cells) or high (> 25% of stained cells). The usual WHO response criteria were used. The median duration of follow-up was 18 months (range 3–58).Forty-seven patients (62%) had tumors with low, and 29 (38%) had tumors with a high rate of proliferative activity. The two groups were well balanced in terms of important variables such as disease-free survival, performance status, age, menopausal status, and the type of first-line chemotherapy (anthracycline-based regimens versus cyclophosphamide-methotrexate-5-fluorouracil). The estrogen receptor (ER) content, measured by means of immunohistochemical assay, was markedly different in the two groups, with 27/47 tumors with low proliferative activity (57%) and 6/29 with high-proliferative activity (21%) being ER positive ( 45% of stained cells) (p = 0.003). Moreover, a significant difference in the metastatic pattern was also evident, with a higher incidence of bone and a lower incidence of soft tissue metastases in the group of patients with tumors with low proliferative activity (p = 0.004). Overall, 10/47 responses (21%: PR = 7, and CR = 3) were observed in the group with a low rate of proliferative activity, versus 14/29 (48%: PR = 9, and CR = 5) in the group with highly proliferative tumors, the difference being statistically significant (p = 0.03). When a multivariate analy-sis was performed, the only factor that retained independent prognostic significance was the predominant site of disease, particularly soft tissues (p = 0.003). Despite the difference in response rate, when survival analysis was performed according to the Kaplan-Meier method, no significant difference was observed in the two groups, but when the analysis was limited to responsive patients, the median survival observed in those with a low and those with a high rate of proliferation was 35 and 19 months respectively (p = 0.02). The same results were obtained when multivariate survival analysis was carried out using Cox's regression model. These data suggest that there is a link between tumor proliferative activity and response to chemotherapy in advanced breast cancer, and may indicate the need to use more intensive treatments in selected patients with highly proliferative tumors.Presented in part at the Annual Meeting of the American Society of Clinical Oncology, May 14–17, 1994, Dallas, TX, USA     

Caustic ingestion in childhood: current treatment possibilities and their complications

In a review of 15 pediatric patients who had ingested caustic substances, the authors describe the diagnostic and therapeutic procedures to be followed as well as the complications that may occur with their use. The cases reported include 1 esophageal rupture caused by balloon dilatation and 1 recurrent stenosis treated with a silastic tutor.     

Ependymomas of the filum terminale in childhood: report of four cases and review of the literature

Four cases of ependymoma of the filum terminale occurring in childhood are reported. The clinical, therapeutic and prognostic features seen at this age and in adults were compared.     

The triangular vaginal patch sling for stress urinary incontinence and hypermobile urethra

OBJECTIVE: We describe an alternative sling procedure that permits concomitant correction of urethral hypermobility and urinary incontinence through a single surgical exposure. STUDY DESIGN: Fifteen women with severe urinary stress incontinence and urethral hypermobility underwent a sling procedure by creation of a simple triangular patch from the anterior vaginal wall. RESULTS: The mean operative time for the vaginal sling procedure was 38 minutes (range 29 to 65 minutes) in addition to other operations. The mean postoperative hospital stay was 7.7 days (range 5 to 13 days) and all patients were routinely discharged with an indwelling Foley catheter. Spontaneous micturition occurred in 12 patients after a mean period of 25 days (range 13 to 36 days). In three cases long-term catheterization was necessary. By subjective and objective evaluations, all the patients were cured of their stress incontinence. CONCLUSION: The triangular vaginal patch with the single sutures on each side provides an alternative approach for bladder neck stabilization that may permit a more anatomic suspension of a hypermobile urethra.(Am J Obstet Gynecol 1997;177:31)     

In vivo neutron dosimetry during high-energy Bremsstrahlung radiotherapy

Purpose: A new technique is presented for in vivo measurements of the dose equivalent from photoneutrons produced by high-energy radiotherapy accelerators.Methods and Materials: The dosimeters used for this purpose are vials of superheated halocarbon droplets suspended in a tissue-equivalent gel. Neutron interactions nucleate the formation of bubbles, which can be recorded through the volume of gel they displace from the detector vials into graduated pipettes. These detectors offer inherent photon discrimination, dose-equivalent response to neutrons, passive operation, and small sensitive size. An in vivo vaginal probe was fabricated containing one of these neutron detector vials and a photon-sensitive diode. Measurements were carried out in patients undergoing high-energy x-ray radiotherapy and were also repeated in-phantom, under similar irradiation geometries.Results and Conclusion: Neutron doses of 0.02 Sv were measured in correspondence to the cervix, 50 cm from the photon beam axis, following a complete treatment course of 46.5 Gy with an upper mantle field of 18-MV x-rays. This fraction of dose from neutrons is measured reliably within an intense photon background, making the technique a valid solution to challenging dosimetry problems such as the determination of fetal exposure in radiotherapy. These measurements can be easily carried out with tissue-equivalent phantoms, as our results indicate an excellent correlation between in vivo and in-phantom dosimetry.     

Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes.

PURPOSE: Nemorubicin (3'-deamino-3'-[2'(S)-methoxy-4'-morpholinyl]doxorubicin; MMDX) is an investigational drug currently in phase II/III clinical testing in hepatocellular carcinoma. A bioactivation product of MMDX, 3'-deamino-3',4'-anhydro-[2'(S)-methoxy-3'(R)-oxy-4'-morpholinyl]doxorubicin (PNU-159682), has been recently identified in an incubate of the drug with NADPH-supplemented rat liver microsomes. The aims of this study were to obtain information about MMDX biotransformation to PNU-159682 in humans, and to explore the antitumor activity of PNU-159682. EXPERIMENTAL DESIGN: Human liver microsomes (HLM) and microsomes from genetically engineered cell lines expressing individual human cytochrome P450s (CYP) were used to study MMDX biotransformation. We also examined the cytotoxicity and antitumor activity of PNU-159682 using a panel of in vitro-cultured human tumor cell lines and tumor-bearing mice, respectively. RESULTS: HLMs converted MMDX to a major metabolite, whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of synthetic PNU-159682. In a bank of HLMs from 10 donors, rates of PNU-159682 formation correlated significantly with three distinct CYP3A-mediated activities. Troleandomycin and ketoconazole, both inhibitors of CYP3A, markedly reduced PNU-159682 formation by HLMs; the reaction was also concentration-dependently inhibited by a monoclonal antibody to CYP3A4/5. Of the 10 cDNA-expressed CYPs examined, only CYP3A4 formed PNU-159682. In addition, PNU-159682 was remarkably more cytotoxic than MMDX and doxorubicin in vitro, and was effective in the two in vivo tumor models tested, i.e., disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts. CONCLUSIONS: CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo.     

The Effect of Ramadan and COVID-19 on the Relationship between Physical Activity and Burnout among Teachers

The objective of this study was to explore the effect of COVID-19 and Ramadan on physical activity (PA) and burnout in teachers and the relationship between them. A total of 57 secondary school teachers from public education centers participated in the present study. They were aged between 29 and 52 years. To determine the effect of Ramadan and COVID-19 on PA and burnout, participants completed the online questionnaires before COVID-19, one week before Ramadan and during the second week of Ramadan. The International Physical Activity Questionnaire-BREF and the Maslach Burnout Inventory-Human Services Survey were used to assess PA intensities and burnout, respectively. The data revealed that total PA (p < 0.001, p < 0.05, respectively) vigorous metabolic equivalent of task (MET) (p < 0.001, p < 0.05, respectively), moderate MET (p < 0.001, p < 0.01, respectively) were higher before COVID-19 and before Ramadan than during Ramadan. Regarding burnout subscales, emotional exhaustion (p < 0.001, p < 0.01, respectively) was higher before Ramadan than before COVID-19 and during Ramadan. A lower personal accomplishment was reported before Ramadan than before COVID-19 and during Ramadan (both p < 0.05). In addition, low to high correlations were observed between PA intensities and burnout subscales, except for the correlation between depersonalization and all PA intensities. In conclusion, Ramadan intermittent fasting along with PA was highly recommended for teachers and the general population to improve positive emotions and general health.     

Connecting aging biology and inflammation in the omics era

Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging — and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities.

Aging has been conceptualized as a continuous duel between damage accumulation — due to a combination of environmental and endogenous processes — and resilience mechanisms that cope with such stressors and resolve damage (1). With aging, resilience mechanisms become less effective at repairing or removing damage and preventing its deleterious effects on health (2). Persistent molecular and cellular damage due to exhausted resilience is ultimately expressed as phenotypes of aging, including inflammaging, susceptibility to chronic diseases, physical and cognitive impairments, and, ultimately, frailty and death.Atop the hierarchy of resilience is the immune system, the aggregate of cells, mediators, and signaling pathways that continuously patrol for pathogens or structural perturbations revealed as “unusual” molecular motifs. The immune system reacts to a variety of threats, such as symbiotic commensal and pathogenic microorganisms, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs) from endogenous and exogenous sources, and orchestrates defense responses aimed at eliminating the specific threat while minimizing damage to the host. While inflammation is important for tissue repair and regeneration, when abnormally intense or persistent, it can drive degeneration and chronic diseases.The immune system undergoes numerous and profound changes with aging, which are extensively reviewed elsewhere (3–5). Hallmarks of immune aging are (a) a state of proinflammatory activation characterized by high circulating levels of proinflammatory cytokines — such as IL-6 and TNF-α — and localized tissue inflammation, and (b) an aberrant response to antigens and pathogens that could either be blunted, such as in flu vaccination, or excessive, such as in response to SARS-CoV-2 (6).Considerable research in both animal models and humans has examined the causes and consequences of inflammaging (4). Although increased levels of inflammatory mediators (mostly IL-1, IL-6, TNF-α, and its receptors) are detected in all elderly individuals, higher levels of these biomarkers are associated with increased risk for many chronic conditions, including dementia, disability, and physical frailty. Inflammation’s causal role in cardiovascular disease was established by the CANTOS trial (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), which demonstrated that IL-1β inhibition reduced the risk of cardiovascular events versus the placebo, particularly in participants whose IL-6 levels were initially elevated (7).Mechanisms identified as hallmarks of aging biology and immune cell dysfunction have all been hypothesized as causes of inflammation (8). Aging researchers now recognize that measuring a few cytokines in circulation fails to capture the complexity and potential ramifications of inflammaging. Immune cells in tissues, particularly lymphocytes and resident macrophages, show tissue-specific age-related changes likely connected to specific pathological processes (9). By measuring hundreds or thousands of molecules in a few drops of blood, scientists are attempting to identify (a) signatures of accelerated aging that are both informative of the complexity and diversity of the response and predictive of health outcomes and (b) key molecules and molecular mechanisms that can be targeted for intervention (10).Given the extreme complexity of inflammaging, we focus herein on a few topics that have attracted considerable attention and controversy in the field. First, we discuss cellular senescence as a source of local and systemic inflammation. We highlight evidence that mitochondrial dysfunction is a nexus that binds impaired mitophagy with DNA damage and cellular senescence to ultimately foster a chronic inflammatory state. We then summarize efforts to identify circulating signatures of inflammation through “omics.” Finally, we review emerging data indicating that inflammation is involved in brain aging and dementia. Our intent is to discuss the causes and consequences of inflammaging and to enrich the research agenda toward the development of new therapeutic strategies.