Trastuzumab deruxtecan in patients with previously treated HER2-low advanced breast cancer and active brain metastases: the DEBBRAH trial.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) is approved for human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). T-DXd has shown encouraging intracranial activity in HER2-positive ABC patients with stable or active brain metastases (BMs); however, its efficacy in patients with HER2-low ABC with BMs is not well established yet. METHODS: DEBBRAH is a single-arm, five-cohort, phase II study evaluating T-DXd in patients with central nervous system involvement from HER2-positive and HER2-low ABC. Here, we report results from patients with heavily pretreated HER2-low ABC and active BMs, enrolled in cohorts 2 (n = 6, asymptomatic untreated BMs) and 4 (n = 6, progressing BMs after local therapy). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was intracranial objective response rate per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) for both cohorts. RESULTS: Intracranial objective response rate per RANO-BM was 50.0% [3/6 patients; 95% confidence interval (CI) 11.8% to 88.2%] and 33.3% [2/6 patients; 95% CI 4.3% to 77.7%; P = 0.033 (one-sided)] in cohorts 2 and 4, respectively. All responders had partial responses. Median time to intracranial response was 2.3 months (range, 1.5-4.0 months) and median duration of intracranial response was 7.2 months (range, 2.8-16.8 months). Median progression-free survival per RECIST v.1.1. was 5.4 months (95% CI 4.1-10.0 months). Treatment-emergent adverse events occurred in all patients included (16.7% grade 3). Three patients (25.0%) had grade 1 interstitial lung disease/pneumonitis. CONCLUSIONS: T-DXd demonstrated promising intracranial activity in pretreated HER2-low ABC patients with active BMs. Further studies are needed to validate these results in larger cohorts. This trial is registered with ClinicalTrials.gov, NCT04420598.

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.

Breast cancer in very young women-a multicenter 10-year experience.

BACKGROUND: Breast cancer (BC) is the most prevalent cancer in adult young women in Europe. Although rare, it is one of the leading causes of death in this age group. The aim of this study is to characterize a cohort of young women regarding tumor stage, biology, treatment and survival. PATIENTS AND METHODS: We present a multicenter retrospective analysis of women <35 years of age, diagnosed with BC between 2008 and 2017. A total of 207 patients from five Portuguese centers were included, from whom 172 were eligible for analysis. Data were analyzed using IBM SPPSS statistics. RESULTS: Median age at diagnosis was 31 years. Fifty-one percent of tumors were hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 20% HR-positive/HER2-positive, 8% HR-negative/HER2-positive and 20% triple-negative BC. Twenty-two percent of patients were diagnosed in stage I, 26% stage II, 45% stage III and 6% had de novo metastatic cancer. Thirty-nine percent of patients were treated with neoadjuvant chemotherapy. Mean follow-up time was 64.9 months and overall survival at 5 years, of the entire cohort and metastatic patients, was 86.5% and 26%, respectively. CONCLUSIONS: In our study we found similar population characteristics to other cohorts <35 years of age. To our knowledge, this is one of the largest cohorts in very young women. BC in young women is an important issue and further studies are needed to provide better care and survivorship to patients.

Characterization of lip prints in a Portuguese twins' population.

Lip print patterns are referred to as unique to each individual, but controversy exists surrounding twins. In this study, the lip prints of 19 pairs of monozygotic and 47 pairs of dizygotic twins were studied. The left lower lip was photographed and the furrows were classified using Renaud's classification. Results showed the same lip pattern was found only in one monozygotic pair (5.3%) and in 4 dizygotic pairs (8.5%), and no significant statistical differences were found between groups (p > 0.05). In monozygotic twins only type C furrows presence displayed statistical significant differences (p=0.034). As for dizygotic twins, there were statistical significant differences in the frequency of type A (p=0.005) and type G furrows (p=0.018). As for the most common types, both groups displayed a higher prevalence of vertical furrows (type B: 97.4% and 96.8%, type A: 86.8% and 87.2%, in monozygotic and dizygotic, respectively). The least frequent furrow type was type I and type E in monozygotic (2.6% and 5.3%, respectively) and types E, F and I, in dizygotic (6.4%, 7.4%. and 7.4%, respectively). Our results seem to point out that lip print patterns should be useful carefully in twins' identification.

Plants utilized as medicines by residents of Quilombo da Fazenda, Núcleo Picinguaba, Ubatuba, São Paulo, Brazil: A participatory survey.

ETHNOPHARMACOLOGICAL RELEVANCE: Participatory research can help to broaden the understanding of medical systems and beliefs of traditional communities. An ethnopharmacological survey in collaboration with local people focused on plants used in quilombos located in Southeast Region in Brazil identified cultural factors that influence plant and recipe choice. AIM OF THE STUDY: To investigate the factors related to the therapeutic efficiency of medicinal plants from the perspective of Quilombo da Fazenda residents. MATERIALS AND METHODS: University researchers collaborated with community residents for both aims and methods of the study. The local partners were trained in the gathering of ethnopharmacological data and then selected and interviewed the residents considered experts on the use of medicinal plants. Data on the use of each species were supported by voucher specimens collected by the local partners and university researchers. Participant observations and field diaries by the university researchers supplemented the data. RESULTS: Eight interviewees mentioned 92 medicinal species with 60 therapeutic uses, applied in 208 recipes or remedies. Asteraceae (13 species), Lamiaceae (5) and Urticaceae (5) contributed most medicinal plant species. Of the 12 etic categories of use, the circulatory system category had the highest number of plants mentioned. Decoction was the most commonly used preparation method (66.8%), and most remedies were administered orally (76.4%). Eighty-six recipes included more than one plant species and/or the addition of other components, such as sugar, salt or animal products. Several cultural factors influence medicinal plant use. Popular beliefs on the quality of blood or the humoral properties of plants and illnesses, characteristics of the plants and other factors determine which plant is used and why. CONCLUSIONS: The participatory method identified a large number of factors that influence medicinal plant use: the patient's blood type; the condition of the plant and the disease (hot-cold system); the route of administration and dosage; the preventive uses of the plants; and the influence of other factors, such as the sun, the moon and dew. The participatory approach is useful for gaining insight on the decision processes of medicinal plant use in traditional societies, and also for those communities wanting to document their knowledge with or without the participation of the academy.

Hemogasometria arterial pré e pós-rinoplastia em cães braquicefálicos portadores de estenose de narina / Arterial hemogasometry pre and post rhinoplasty in brachyphalic dogs with nostril stenosis

Vinte e seis cães braquicefálicos portadores de estenose de narina, 22 machos e quatro fêmeas, foram submetidos à rinoplastia bilateral. Dezesseis cães eram Buldogues Franceses; dois, Buldogues Ingleses; seis, Pugs; e dois, Shih Tzus, com idade variando de seis meses a seis anos. Foram efetuadas coletas de sangue arterial para análises hemogasométricas no pré-operatório e 30 dias após a cirurgia. Para cada avaliação, foi obtida uma amostra de 0,5mL de sangue coletado da artéria femoral, em seringa plástica heparinizada. Em seguida, procedeu-se à avaliação hemogasométrica em analisador de gases sanguíneos (I-stat-Abbot®). Os resultados da hemogasometria pré e pós-rinoplastia mostraram uma redução nos valores médios de pCO2, TCO2 , HCO3- e BEecf, hematócrito e hemoglobina, e aumento de pH, pO2 e SO2, indicando melhora na condição ventilatória dos animais após a correção cirúrgica da estenose de narina. Isso posto, conclui-se que a hemogasometria arterial é um exame importante no diagnóstico da síndrome respiratória dos cães braquicefálicos, e extremamente útil no acompanhamento da resposta do paciente ao tratamento. A rinoplastia mostrou-se eficaz no tratamento da síndrome respiratória, promovendo melhora nos parâmetros hemogasométricos que indicam acidose respiratória secundária à obstrução das vias aéreas, comum nas raças braquicefálicas.(AU)

Twenty-six brachycephalic dogs with nostril stenosis, 22 males and four females, underwent bilateral rhinoplasty. Sixteen dogs were French Bulldogs; two, English Bulldogs; Six, Pugs; and two, Shih tzus, ranging in age from six months to six years. Blood samples were collected for hemogasometric analysis in the preoperative period and 30 days after surgery. For each evaluation, a 0.5ml sample of blood collected from the femoral artery was obtained in a heparinized plastic syringe. Hemogasometric evaluation was then performed on a blood gas analyzer (I-stat-Abbot®). The results of hemogasometry before and after rhinoplasty showed a reduction in the mean values of pCO2, TCO2, HCO3- and BEecf, hematocrit and hemoglobin, and an increase in pH, pO2 and SO2, indicating an improvement in the ventilatory condition of the animals after surgical correction of Nostril stenosis. Therefore, it is concluded that arterial hemogasometry is an important diagnostic tool for the diagnosis of brachycephalic respiratory syndrome and is extremely useful in monitoring the patient's response to treatment. Rhinoplasty was effective in the treatment of respiratory syndrome, promoting improvement in hemogasometric parameters that indicate respiratory acidosis secondary to airway obstruction, common in the brachycephalic races.(AU)

Risk factors and seroprevalence of hepatitis E evaluated in frozen-serum samples (2002-2003) of pregnant women compared with female blood donors in a Southern region of Brazil.

Hepatitis E has always been related to morbidity in pregnant women. Its epidemiology is not well understood in Brazil. Therefore, we tested sera from 209 pregnant women and 199 female blood donors, collected at a single center in Curitiba, Brazil. The Wantai assay was used for testing the anti-hepatitis E virus (anti-HEV), immunoglobulin G (IgG), and an in-house polymerase chain reaction process for testing HEV RNA. Anti-HEV was detected in 22.5% of the total group, 19% in the pregnant women group, and 26% in the blood donor group (P = 0.11), a much higher prevalence when compared with other studies in Brazil. Demographical analysis showed that 92.4% were born in the South Region of Brazil, 4.9% in the Southeast, and 2.7% were distributed over other regions of the country. With respect to their origin, 99% were from the South, 0.7% from the Southeast, and 0.2% from the Central-West regions. Income, education, race, number of pregnancies, and abortion did differ significantly when comparing both the groups (P < 0.001). Age >30 (P = 0.012) and the number (>3) of pregnancies (P = 0.008) were related to anti-HEV positivity. All anti-HEV IgG-positive females were HEV RNA negative. In conclusion, HEV positivity was found in one out of five young women, which showed an urgent need for further epidemiological studies in Brazil.

Circulating endothelial cell count: a reliable marker of endothelial damage in patients undergoing hematopoietic stem cell transplantation.

The physio-pathologic interrelationships between endothelium and GvHD have been better elucidated and have led to definition of the entity 'endothelial GvHD' as an essential early phase prior to the clinical presentation of acute GvHD. Using the CellSearch system, we analyzed circulating endothelial cells (CEC) in 90 allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients at the following time-points: T1 (pre-conditioning), T2 (pre-transplant), T3 (engraftment), T4 (onset of GvHD) and T5 (1 week after steroid treatment). Although CEC changes in allo-HSCT represent a dynamic phenomenon influenced by many variables (that is, conditioning, immunosuppressive treatments, engraftment syndrome and infections), we showed that CEC peaks were constantly seen at onset of acute GvHD and invariably returned to pre-transplant values after treatment response. Since we showed that CEC changes during allo-HSCT has rapid kinetics that may be easily missed if blood samples are drawn at pre-fixed time-points, we rather suggest an 'on demand' evaluation of CEC counts right at onset of GvHD clinical symptoms to possibly help differentiate GvHD from other non-endothelial complications. We confirm that CEC changes are a suitable biomarker to monitor endothelial damage in patients undergoing allo-transplantation and hold the potential to become a useful tool to support GvHD diagnosis (ClinicalTrials.gov NCT02064972).

Ru(II)-based antimicrobials: looking beyond organic drugs.

This review deals with the bactericidal, anti-fungal and even anti-parasitary properties of ruthenium complexes, both inorganic and organometallic, establishing comparisons between these and the available commercial drugs. The description is mostly composed of results found in the literature of the past two decades, complemented with relevant results from our group's research on antimicrobial ruthenium complexes. The complexes are divided into five groups according to the kind of ligands, geometry and chemical nature. The first group comprises ruthenium octahedral complexes with Schiff bases, the most well explored kind of ruthenium antimicrobials. The second group comprises complexes with planar ligands and an overall more flattened geometry, designed for DNA intercalation. In the following two groups, ruthenium complexes feature a particular functionality, which is, in one case, the presence of the PTA ligand for higher solubility in water, and, in the second, the mimicry of an active organic drug. Finally, a small section presents the most recent results on supramolecular antimicrobials comprising ruthenium, in particular a polymer and a cyclodextrin adduct.

Effect of the inoculation level of Lactobacillus acidophilus in probiotic cheese on the physicochemical features and sensory performance compared with commercial cheeses.

The complex metabolism of probiotic bacteria requires several technological options to guarantee the functionally of probiotic dairy foods during the shelf life. This research aimed to evaluate the effect of the supplementation of increasing amounts of Lactobacillus acidophilus (0, 0.4, or 0.8 g/L of milk) on the physicochemical parameters and sensory acceptance of Minas fresh cheese. In addition, the sensory acceptance of probiotic cheeses was assessed using a consumer test and compared with commercial cheeses (conventional and probiotic). High counts (9.11 to 9.42 log cfu/g) of L. acidophilus were observed throughout the shelf life, which contributed to the maintenance of its probiotic status and resulted in lower pH values and greater production of organic acids. The probiotic cheeses presented lower scores for appearance, aroma, and texture compared with conventional cheeses. Internal preference mapping explained almost 60% of the total variation of the data and showed a large number of consumers concentrated near the conventional cheeses, demonstrating greater preference for these samples. The findings indicated that some negative sensory effects could occur when high level of supplementation with L. acidophilus is used in probiotic cheese processing.

Acute ischemia of the lower limb after injury by gunshot: case report and review of literature.

INTRODUCTION: Civilian and military vascular trauma has evolved dramatically. It is estimated that 80% of all cases of vascular injuries are due to peripheral vascular trauma, most involving the lower extremities. Arterial below-knee injuries by gunshot still remain a challenge, with an associated rate of amputation of 20-54%. MATERIAL AND METHODS: This case reports a 48 year-old male patient who sustained a gunshot below his left knee. At hospital admission, loss of substance and hemorrhage at the medial and lateral faces of the upper third of his left leg were present with signs of distal ischemia. Arteriography revealed infra-popliteal arterial lesions of the three arterial axes. Two reversed great saphenous vein interposition grafts were performed into the anterior and posterior tibial arteries with immediate revascularization of the left leg and foot. Later, soft tissue reconstruction was accomplished by a split-thickness skin graft. RESULTS: At the fifth month of follow-up, the left leg and foot were viable with good healing, without limitations and with controlled pain. Posterior tibial and dorsalis pedis pulses were palpable. CONCLUSION: This case report shows the importance of an adequate team approach for treatment of a gunshot extremity injury with vascular lesion. The authors want to highlight the scientific background evidence and the value of comparing worldwide civilian trauma center outcomes, mostly reported previously from the military field.

Thrombosed popliteal aneurysm - first manifestation of bilateral popliteal entrapment syndrome.

Popliteal artery entrapment syndrome is a rare and underdiagnosed cause of claudication in the young adult. One of its rare and potentially limb threatening complications is aneurysmal degeneration. We present a case of a fifty years old man with a bilateral popliteal entrapment syndrome admitted with an acutely thrombosed aneurysm at the right inferior limb. An urgent bypass was required. The contralateral limb presented with a type III entrapment and an elective section of a musculotendinous structure was performed. This case suggests that an early diagnosis is mandatory to avoid a dramatic clinical outcome and to limit the surgical treatment to a myotomy.

Components of arterial systolic pressure and RR-interval oscillation spectra in a case of baroreflex failure, a human open-loop model of vascular control.

The baroreflex control of circulation is always operating and modulates blood pressure and heart rate oscillations. Thus, the study of cardiovascular variability in humans is performed in a closed-loop model and the physiology of post-sinoaortic denervation is completely unknown in humans. We dissected for the first time the different components of systolic arterial pressure (SAP) and RR-interval spectra in a patient with 'baroreflex failure' (due to mixed cranial nerve neuroma) who represents a human model to investigate the cardiovascular regulation in an open-loop condition. Interactions among cardiovascular variability signals and respiratory influences were described using the multivariate parametric ARXAR model with the following findings: (1) rhythms unrelated to respiration were detected only at frequencies lower than classical low frequency (LF; Slow-LF, around 0.02 Hz) both in SAP an RR spectra, (2) small high-frequency (HF) modulation is present and related with respiration at rest and in tilt (but for SAP only) and (3) the Slow-LF fluctuations detected both in SAP and RR oscillate independently as the multivariate model shows no relationships between SAP and RR, and these oscillations are not phase related. Thus, we showed that in a patient with impaired baroreflex arc integrity the Slow-LF rhythms for RR have a central origin that dictates fluctuations on RR at the same rhythm but unrelated to the oscillation of SAP (which may be related with both peripheral activity and central rhythms). The synchronization in LF band is a hallmark of integrity of baroreflex arc whose impairment unmasks lower frequency rhythms in SAP and RR whose fluctuations oscillate independently.

Rotational dynamics and polymerization of C60 in C60-cubane crystals: a molecular dynamics study.

We report classical and tight-binding molecular dynamics simulations of the C(60) fullerene and cubane molecular crystal in order to investigate the intermolecular dynamics and polymerization processes. Our results show that, for 200 and 400 K, cubane molecules remain basically fixed, presenting only thermal vibrations, while C(60) fullerenes show rotational motions. Fullerenes perform "free" rotational motions at short times (approximately < 1 ps), small amplitude hindered rotational motions (librations) at intermediate times, and rotational diffusive dynamics at long times (approximately > 10 ps). The mechanisms underlying these dynamics are presented. Random copolymerizations among cubanes and fullerenes were observed when temperature is increased, leading to the formation of a disordered structure. Changes in the radial distribution function and electronic density of states indicate the coexistence of amorphous and crystalline phases. The different conformational phases that cubanes and fullerenes undergo during the copolymerization process are discussed.

Molecular dynamics simulation of single wall carbon nanotubes polymerization under compression.

Single wall carbon nanotubes (SWCNTs) often aggregate into bundles of hundreds of weakly interacting tubes. Their cross-polymerization opens new possibilities for the creation of new super-hard materials. New mechanical and electronic properties are expected from these condensed structures, as well as novel potential applications. Previous theoretical results presented geometric modifications involving changes in the radial section of the compressed tubes as the explanation to the experimental measurements of structural changes during tube compression. We report here results from molecular dynamics simulations of the SWCNTs polymerization for small diameter arm chair tubes under compression. Hydrostatic and piston-type compression of SWCNTs have been simulated for different temperatures and rates of compression. Our results indicate that large diameter tubes (10,10) are unlike to polymerize while small diameter ones (around 5 A) polymerize even at room temperature. Other interesting results are the observation of the appearance of spontaneous scroll-like structures and also the so-called tubulane motifs, which were predicted in the literature more than a decade ago.

Current management of ovarian carcinosarcoma.

Ovarian carcinosarcomas (OCS), also known as malignant mixed müllerian tumors, are uncommon malignancies that carry a poor prognosis. The presentation of OCS is usually indistinguishable from that of epithelial ovarian cancer. Due to its low frequency, prospective trials have been difficult to perform, but there is evidence that OCS are sensitive to platinum-based chemotherapy. Recent studies have shown encouraging results with platinum-ifosfamide and platinum-taxane schedules, which are usually considered the treatment of choice. However, poor performance status at presentation is also a common problem, so that many patients may be unsuitable for combination chemotherapy but may still benefit from single-agent platinum or ifosfamide or, occasionally, from nonplatinum schedules such as ifosfamide plus paclitaxel. Aggressive cytoreductive surgery appears to have a positive impact on outcome and should probably be offered to most patients. However, this procedure has been associated with higher rates of complication in OCS and should only be attempted by experienced (gynecological) surgeons in centers with expertise in the management of gynecological malignancies.