Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.

BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

The National Research Council's assessment of research doctorate programs can be used to strengthen doctoral programs in nutrition.

The National Research Council (NRC) is for the first time including the field of nutrition in its Assessment of Research Doctorate Programs in 2006. This assessment will rate doctoral programs, in terms of research impact and graduate student support and outcomes, through the use of questionnaires and standardized national databases (such as research funding, publications, and citations of publications) rather than through name recognition as was used in past NRC surveys of graduate programs. Nutritionists can make this survey more valuable to the field by making sure all eligible faculty involved in training of graduate students in nutrition are included in the survey, by encouraging all eligible faculty members to complete the faculty questionnaire, and by being prepared to use and discuss the data and reports when they are released in 2007. The nutrition community should use the data from this national survey to strengthen doctoral programs and research in nutrition.

The effect of interleukin-6 on hepatitis B virus replication in peripheral blood mononuclear cells in vitro.

Although the major target organ for hepatitis B virus (HBV) is the liver, the possibility of infection of peripheral blood mononuclear cells (PBMCs) with HBV has also been reported. This study was performed to analyze the course of HBV infection of PBMCs and to investigate the influence of interleukin-6 (IL-6) on the efficiency of infection of PBMCs with HBV in vitro. PBMCs isolated from a healthy donor were infected by exposing to a HBsAg-, HBeAg-positive serum in the presence or absence of exogenous IL-6. The efficiency of infection was estimated by HBV DNA determination in the cells and medium in the course of infection. The results of this study show that the presence of IL-6 during the PBMCs infection with HBV increased the efficiency of this infection.

Characterization of a naphthalene derivative inhibitor of retroviral integrases.

The retroviral integrase protein (IN) is essential for virus replication and, therefore, an attractive target for the development of inhibitors to treat human immunodeficiency virus (HIV) infection. Diverse classes of compounds that are active against this protein have been discovered using in vitro assays. Here we describe the synthesis of a novel compound, 3,8-dibromo-7-amino-4-hydroxy-2-naphthalenesulfonic acid (2BrNSA), which inhibits the in vitro activities of the full-length HIV-1 and avian sarcoma virus (ASV) integrases, and the isolated catalytic core fragment of the ASV protein (residues 52-207). The compound also inhibits retroviral reverse transcriptase in vitro, but the IC(50) for the HIV-1 enzyme is almost two orders of magnitude higher than for HIV-1 integrase. The inhibitor was found to be active in cell culture, preventing reporter gene transduction of HeLa cells by both ASV and HIV-1 vectors. Neither viral attachment nor uptake into cells appeared to be affected in these transfections, whereas accumulation of vector DNA and its joining to host DNA were both drastically reduced in the presence of the inhibitor. Propagation of two different strains of replication-competent HIV-1 in human peripheral blood mononuclear cells (PBMCs) was also reduced by the inhibitor, allowing survival of a substantial number of cells in the treated cultures. Based on these and other results we speculate that binding of 2BrNSA to integrase in infected cells interferes not only with its catalytic activity but also with critical interactions that are required for the formation or function of the reverse transcriptase complex. Its activity in cell culture suggests that this inhibitor may provide a valuable new lead for further development of drugs that target early steps in the HIV life cycle.

Activity of type IV collagenases (MMP-2 and MMP-9) in primary pulmonary carcinomas: a quantitative analysis.

PURPOSE: Matrix metalloproteinases MMP-2 and MMP-9 are implicated in invasion and metastasis of malignant tumors. We investigated the expression and activation of MMP-2 and MMP-9 in lung cancer compared with normal lung parenchyma, and looked for a potential marker of malignancy. METHODS: Thirty-six pulmonary carcinomas and paired normal lung specimens were analyzed by gelatin zymography and computer-assisted image analysis for the expression of MMP-2 and MMP-9. RESULTS: We showed that expression of both type IV collagenases was remarkably higher in carcinoma samples than in lung parenchyma. The MMP-9 levels in lung cancer were over twofold higher than in normal lung tissues. The levels of latent and active forms of MMP-2 in lung cancer samples were, correspondingly, 3.8- and 17-fold higher than in lung parenchyma. The tumor/normal (T/N) ratios of MMP-2 were negatively correlated with the hemoglobin levels and erythrocytes number. CONCLUSIONS: A high level of the active form of MMP-2 in almost all of the carcinomas and the near lack of its activation in normal lung parenchyma shows that MMP-2 activation is associated with the malignant phenotype and may serve as a good marker of malignancy. The correlation between low hemoglobin level and T/N ratio of MMP-2 may indicate significance of MMP-2 for angiogenesis.

Reduction of operating and recovery room times and overnight hospital stays with interscalene blocks as sole anesthetic technique for rotator cuff surgery.

BACKGROUND: The effort to decrease hospital stays and to increase operating room efficacy has become an important consideration in the practice of anesthesia. METHODS: Fifty-three patients who underwent shoulder rotator cuff repair in the sitting position were divided into four groups according to the anesthesia technique used: Group 1 (general anesthesia), Group 2 (interscalene block), Group 3 (interscalene combined with general anesthesia) and Group 4 (general anesthesia combined with local injection of local anesthetics). Interscalene blocks were performed preoperatively, using a nerve stimulator. After appropriately locating the brachial plexus, a mixture of 40 ml of 2% lidocaine and 0.5% bupivacaine (v/v) was injected. RESULTS: As compared to general anesthesia, the use of an interscalene block alone reduced the following operating room times: 1) from the patient's arrival in the operating room to the beginning of surgery and 2) from the end of surgery to the patient's departure from the operating room. Use of the interscalene block also resulted in a reduction of recovery time when compared to Groups 1, 3 and 4 by 40, 56 and 66%, respectively. Compared to Group 1, this anesthesia technique was furthermore associated with a 64% decrease in the number of patients hospitalized overnight. CONCLUSIONS: This study confirms that the interscalene block as sole anesthesia technique is safe and effective and can contribute to shorten the hospital length of stay of patients undergoing shoulder rotator cuff surgery.

Continuous femoral blocks improve recovery and outcome of patients undergoing total knee arthroplasty.

This study was designed to determine the effects of continuous femoral infusion (CFI) on total knee arthroplasty recovery. A total of 92 patients were distributed in 3 groups: Patients in group 1 received general anesthesia followed by patient-controlled analgesia (PCA) with morphine (n = 33), patients in group 2 received 3-in-1 and sciatic blocks followed by CFI (n = 29), and patients in group 3 received epidural analgesia (n = 30). Blocks reduced postoperative morphine requirement by 74% (vs group 1; P<.05) and 35% (vs group 3; P<.05). Blocks provided better recovery than PCA with morphine or an epidural. The use of CFI was associated with a reduction of postoperative bleeding by 72% (vs group 1; P<.05) and allowed better performance on continuous passive motion. CFI was associated with a 90% decrease in serious complications and a 20% decrease in the length of hospitalization. CFI represents a better alternative than PCA or epidural analgesia for postoperative pain management and immediate rehabilitation after total knee arthroplasty.

Dietary supplement use: consumer characteristics and interests.

Four major issues should be considered in a discussion of what consumers need to know about supplements and herbal treatments. 1) Usage of supplements is changing as consumers are taking charge of their health and seeking alternative forms of medicine (Eisenberg et al. 1998, Gilbert 1999 ). 2) The characteristics of supplement users have been profiled in numerous academic and industrial surveys. However, even the best models based on consumers' characteristics can predict < 30% of diet-related behavior (Baranowski et al. 1999 ). 3) Experts in traditional medicine and nutrition lack information on supplements and herbals. The Practice and Policy Guidelines Panel of the National Institute of Health Office of Alternative Medicine (1997) stated that practices used in complementary and alternative medicine were "unsuitable for the development of evidence-based practice guidelines." Well-designed basic and clinical research is needed on the efficacy, bioavailability and safety of supplements and herbal medications. 4) It is debatable which agencies and professionals are the best gatekeepers of information on supplements and herbals. Significant numbers of consumers do not seem to rely on their physicians for information on alternative forms of medicine (Eisenberg 1997 ). Despite the obstacles, the traditional medical community (including nutritionists) should focus more research efforts on diet supplements and herbal treatments and increase training on these topics for students majoring in health care fields. Then health care professionals can mount high quality, targeted education programs for consumers.

Differentiated reactivity of whole blood neonatal platelets to various agonists.

Neonatal platelets have been occasionally reported to show a reduced response to various agonists. The molecular mechanism(s) of such a depressed reactivity remains unclear. To further address this problem we studied neonatal platelet activation with thrombin, TRAP (thrombin receptor activating peptide, Ser-Phe-Leu-Leu-Arg-Asn-Pro-Asn-Asp-Lys-Tyr-Glu-Pro-Phe) and ADP in 42 healthy 1-2 day old neonates using a whole peripheral blood flow cytometry. The neonates did not show an increased fraction of P-selectin-positive circulating platelets, whereas the expression of GPIb (glycoprotein Ib) in resting neonatal platelets was significantly lower compared to adults. Neonatal platelets were significantly less reactive than adult platelets to thrombin and TRAP, especially at lower agonist concentrations, but not to ADP or when incubated for 1 h at room temperature. Activation of neonatal platelets with agonists resulted in a marked alterations in the expression of P-selectin, whereas the internalization of GPIb was not affected. The reduced neonatal platelet sensitivity to thrombin and TRAP was accompanied by significantly reduced ATIII (antithrombin III) and increased prothrombin fragment F(1+2) in neonatal plasma. We conclude that various receptor systems potentially able to bind thrombin are relatively insensitive in neonatal platelets. The novelty of our work is that neonatal platelet hyposensitivity is not a generalized phenomenon, but concerns only selected agonists and selected receptor systems.

Regional anesthesia for outpatient orthopedic surgery.

The constant search for increased efficiency and reduction of hospital length of stay has led to an increase number of major orthopedic procedures performed as outpatients and the increase in the associated intensity and duration of acute postoperative pain. Although, it is well established that single peripheral blocks provide adequate anesthesia and excellent immediate postoperative analgesia in patients undergoing minor ambulatory orthopedic surgery, the postoperative acute pain benefit is limited to less than 24 hours. However, many patients required over 24 hours of intensive postoperative analgesia. Furthermore the need for immediate postoperative physical therapy in orthopedics dictates that local anesthetics be chosen on the basis of their safety and ability to produce preferential sensory blocks. As early as 1946, Ansbro proposed the use of continuous nerve blocks to prolong the duration of analgesia of nerve block technique during anesthesia. Continuous nerve blocks have also been used for the acute postoperative pain control of patients undergoing major orthopedic surgery as in-patients. This technique has been proven to be safe and effective in controlling acute postoperative pain and improve functional outcome. The recent introduction of safer local anesthetics producing preferential sensory blocks along with the development of ambulatory pumps has allow to extend the use of these continuous block techniques to ambulatory patients. Recent development also included the use of cox2 inhibitors along with cold maximize postoperative analgesia. This multimodal approach has been proven to be safe and efficacious as much for resting pain than pain associated with exercise.

Nutrition versus toxicology of manganese in humans: evaluation of potential biomarkers.

Manganese intake can vary greatly with food choices, water composition, and supplement use. Thus, individuals consuming Western diets consume from < 1 to > 10 mg Mn/d. The levels of manganese intake associated with adverse effects (both deficient and toxic) are debatable. Moreover, many of the symptoms of manganese deficiency (growth retardation, changes in circulating HDL cholesterol and glucose levels, reproductive failure) and manganese toxicity (growth depression, anemia) are non-specific. The bone deformities observed in manganese-deficient animals and neurological symptoms of individuals who have inhaled excess manganese are permanent and illustrate the need to identify sensitive biomarkers of manganese status that appear before these symptoms. Manganese balance and excretion data are not useful biomarkers of manganese exposure but demonstrate that the body is protected against manganese toxicity primarily by low absorption and/or rapid presystemic elimination of manganese by the liver. Serum manganese concentrations in combination with lymphocyte manganese-dependent superoxide dismutase (MnSOD) activity and perhaps blood arginase activity, appear to be the best ways to monitor ingestion of insufficient manganese. Serum manganese concentrations in combination with brain MRI (magnetic resonance imaging) scans, and perhaps a battery of neurofunctional tests, appear to be the best ways to monitor excessive exposure to manganese.

Nondigestible carbohydrates and mineral bioavailability.

Generally, fiber and compounds associated with fiber in cereal products (e.g., phytates) have been found to reduce the apparent absorption of minerals (such as calcium, magnesium, zinc and manganese) in humans, livestock and animal models. The effects of "soluble" forms of fiber (specifically pectins, gums, resistant starches, lactulose, oligofructose and inulin) on mineral absorption are more difficult to characterize. The addition of these soluble forms of fiber has been found in various studies to add viscosity to the gut contents, promote fermentation and the production of volatile fatty acids in the cecum, have a trophic effect on the ceca of animals and increase serum enteroglucagon concentrations. Thus it is not surprising that the addition of soluble forms of fiber to diets often has been found to improve absorption of minerals. This may reflect absorption of electrolytes from the large intestine. Future work should address the mechanisms by which ingestion of nondigestible carbohydrates improves mineral absorption in humans.