Neoadjuvant-adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial.

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population.

Literature Review of Ascorbic Acid, Cranberry, and D-mannose for Urinary Tract Infection Prophylaxis in Older People.

Background Urinary tract infections (UTIs) are the most prevalent infections in older patients with the potential for morbidity and mortality. Antibiotics are not generally recommended for UTI prophylaxis in this population. There is interest among the public and health providers to try over-the-counter products, such as cranberry, D-mannose, and vitamin C. The objective of this analysis was to review the literature for the efficacy and tolerability of these supplements in older individuals. Methods A literature review was conducted on PubMed using the search terms urinary tract infection or UTI, prevention/prophylaxis, cranberry, D-mannose, vitamin C/ascorbic acid. Few studies were conducted among older people; therefore, the authors included studies of all adults who had recurrent UTIs or were at increased risk of UTIs. Level (quality) of evidence were determined using the ACC/AHA Clinical Practice Guideline Recommendation Classification System. Results A total of 24 studies were included. This review captured all studies in previous reviews as well as recent publications. The authors determined that there were limited data for D-mannose and vitamin C, and randomized data for cranberry as defined by the classification system. Conclusions The three supplements reviewed appear not to be strongly supported by clinical data. For those who are interested in trying these products despite the lack of robust evidence for clinical efficacy, it may be helpful to know that the studies included in this review did not identify any clinically important signs of harm, to the extent that safety data were documented and reported.

Pharmacological Treatment of Disinhibition in Acquired Brain Injury.

PURPOSE/BACKGROUND: Traumatic brain injury is a major universal public health concern and results in chronic neurobehavioral sequelae including disinhibition. Objectives of this study were to review the literature on pharmacological treatment of disinhibition post-acquired brain injury (ABI), describe a snapshot of pharmacotherapy used in ABI at a tertiary neuropsychiatric unit in British Columbia, Canada, and share expert opinion. METHODS/PROCEDURES: A retrospective chart review of 11 patients from October to December 2021 was conducted based on exclusion criteria: age greater than 18 years, primary neurodegenerative conditions, or aphasia. Patient demographics, behavioral and cognitive test results, and disinhibition treatment were recorded. A brief review of the literature was conducted to find the best available evidence of pharmacological interventions to treat disinhibition post-ABI. FINDINGS/RESULTS: In ABI, there was a high utilization of antipsychotics and benzodiazepines, at 91% and 64% respectively, in patients with severe cognitive deficit and disinhibition. Mood stabilizers and nonselective ß-blockers were less prescribed in this population at 73% and 18%. At the point of data collection, all the patients had responded well to treatment and were in the maintenance phase of their pharmacological treatment. IMPLICATIONS/CONCLUSIONS: A limited number of studies with weak methodology suggest that mood stabilizers and ß-blockers should be first line for disinhibition treatment. Our findings are complementary to the literature describing treatment of severe disinhibition. The choice of treatment for disinhibition depends on factors including nature and severity of target symptoms, level of drug evidence, patient-tailored objectives, concurrent psychiatric diagnoses, clinical experience of clinicians, adverse drug reactions, and treatment acuity.

The role of motor proteins in photoreceptor protein transport and visual function.

BACKGROUND: Rods and cones are photoreceptor neurons in the retina that are required for visual sensation in vertebrates, wherein the perception of vision is initiated when these neurons respond to photons in the light stimuli. The photoreceptor cell is structurally studied as outer segments (OS) and inner segments (IS) where proper protein sorting, localization, and compartmentalization are critical for phototransduction, visual function, and survival. In human retinal diseases, improper protein transport to the OS or mislocalization of proteins to the IS and other cellular compartments could lead to impaired visual responses and photoreceptor cell degeneration that ultimately cause loss of visual function. RESULTS: Therefore, studying and identifying mechanisms involved in facilitating and maintaining proper protein transport in photoreceptor cells would help our understanding of pathologies involving retinal cell degeneration in inherited retinal dystrophies, age-related macular degeneration, and Usher Syndrome. CONCLUSIONS: Our mini-review will discuss mechanisms of protein transport within photoreceptors and introduce a novel role for an unconventional motor protein, MYO1C, in actin-based motor transport of the visual chromophore Rhodopsin to the OS, in support of phototransduction and visual function.

Otopathologic Abnormalities in CHARGE Syndrome.

OBJECTIVE: To perform an otopathologic analysis of temporal bones (TBs) with CHARGE syndrome. STUDY DESIGN: Otopathologic study of human TB specimens. SETTING: Otopathology laboratories. METHODS: From the otopathology laboratories at the University of Minnesota and Massachusetts Eye and Ear Infirmary, we selected TBs from donors with CHARGE syndrome. These TBs were serially sectioned at a thickness of 20 µm, and every 10th section was stained with hematoxylin and eosin. We performed otopathologic analyses of the external ear, middle ear (middle ear cleft, mucosal lining, ossicles, mastoid, and facial nerve), and inner ear (cochlea, vestibule, internal auditory canal, and cochlear and vestibular nerves). The gathered data were statistically analyzed. RESULTS: Our study included 12 TBs from 6 donors. We found a high prevalence of abnormalities affecting the ears. The most frequent findings were stapes malformation (100%), aberrant course of the facial nerve (100%) with narrow facial recess (50%), sclerotic and hypodeveloped mastoids (50%), cochlear (100%) and vestibular (83.3%) hypoplasia with aplasia of the semicircular canals, hypoplasia and aplasia of the cochlear (66.6%) and vestibular (91.6%) nerves, and narrowing of the bony canal of the cochlear nerve (66.6%). The number of spiral ganglion and Scarpa's ganglion neurons were decreased in all specimens (versus normative data). CONCLUSIONS: In our study, CHARGE syndrome was associated with multiple TB abnormalities that may severely affect audiovestibular function and rehabilitation.

Lung Cancer Screening in the Community Setting: Challenges for Adoption.

Secondary prevention of lung cancer by screening a high-risk population with low-dose CT (LDCT) of the chest has been shown to save lives. Our Institution offered a free screening program in 2013. The program was promoted through flyers, radio programs, face-to-face information sessions, and a multidisciplinary lung symposium. A lung navigator confirmed the eligibility of patients according to National Lung Screening Trial (NLST) criteria. Data were, prospectively, collected over a 12-month period using Lung-RADs (Lung Imaging Reporting and Data System). After one year, an online survey was sent out to all primary care and referring physicians in the network. One hundred and sixty-nine patients were found to be eligible for screening. Sixty-five per cent were black, 44 per cent white, 9 per cent Hispanic, and 6 per cent were Asian. Sixty per cent patients were referred by their physician. Thirty-one were Lung-RADs 1 (18.3%), 116 were Lung-RADs 2 (68.6%), 16 were Lung-RADs 3 (9.5%), and six were Lung-RADs 4 (3.6%). At the end of the study period, the survey showed that 100 per cent of the providers were aware of the screening program but 15 per cent never referred a patient. Time constraints and requirement for precertification were cited as potential barriers to referral. Twenty-six per cent of providers were unaware that LDCT was recommended by the U.S. Preventive Services Task Force on par with colonoscopy and mammography. The NLST showed that screening with LDCT could reduce lung cancer mortality by 20 per cent. Significant concerns exist about the generalizability of these results and the applicability of screening programs in the community.

Thoracic Surgery in Patients with AIDS.

The picture of human immunodeficiency virus (HIV)-infected patients has changed dramatically since the original description in 1981. The introduction of antiretroviral drugs in 1987 and combination antiretroviral therapy has decreased mortality by as much as 80%. We now see patients in their 60s and 70s, having lived decades with HIV and living a normal live. As outlined in the article, despite good viral control, patients with HIV may present with solid organ cancers earlier than noninfected patients and are also prone to other complications of their disease that may require the attention of a thoracic surgeon.

Loss of signal transducer and activator of transduction 4 or 6 signaling contributes to immune cell morbidity and mortality in sepsis.

OBJECTIVE: The role of signal transducer and activator of transduction (STAT) 4 vs. 6 has been assessed thus far only in a model of high mortality strongly driven by proinflammation alone. Their role in a low-mortality (LD25) model of sepsis remains unclear. DESIGN AND SETTING: Prospective controlled animal study in a research laboratory. SUBJECTS: STAT4 and STAT6 knockout mice. INTERVENTIONS: We induced sepsis by cecal ligation and puncture (CLP) or sham CLP in three groups of mice: (a) STAT4-/-, (b) STAT6-/-, (c) BALB/c. Splenic T cells or macrophages were then harvested 24 h after CLP, and their ability to produce cytokines was assessed. RESULTS: Following CLP T-cells from BALB/c mice were suppressed in the ability to release the Th1 cytokines interleukin (IL) 2 and interferon gamma. The release of Th2 cytokine IL-10 was increased. The Th1 response of STAT4-deficient animals was not only markedly lower in shams but was further suppressed by CLP. The Th2 cytokine response was elevated even more than that of the septic BALB/c. This was associated with lower survival than in the BALB/c. STAT6 deficiency resulted in a stronger Th1 response and a suppressed Th2 response to CLP. A similar difference between IL-12 and IL-10 release was seen in macrophages from these mice. Interestingly, while this resulted in improved survival, compared to STAT4-/- mice, the STAT6-/- animals still had a higher mortality than the BALB/c. CONCLUSIONS: These data suggest that contributions from both STAT4 driven processes as well as STAT6 responses are needed in a balanced fashion to maximize the animals' ability to survive septic challenge.

The effect of inhibition of a major cell signaling pathway following trauma hemorrhage on hepatic injury and interleukin 6 levels.

HYPOTHESIS: Recent studies have shown that intracellular signaling pathways, such as the mitogen-activated protein kinases, play a pivotal role in the activation of the inflammatory response. We hypothesized that administration of a specific mitogen-activated protein kinase inhibitor, PD 98059, at the end of resuscitation following severe hemorrhagic shock can reduce the plasma levels of interleukin 6 (IL-6) and hepatocellular damage. DESIGN: Prospective controlled animal study. SETTING: Medical school-affiliated university hospital. INTERVENTIONS: Male Sprague-Dawley (275-325 g) rats underwent laparotomy (ie, soft tissue trauma) and were then bled to a mean arterial pressure of 40 mm Hg for approximately 90 minutes. The animals were then resuscitated with 4 times the bleed-out volume using Ringer lactate solution for 60 minutes. PD 98059, an inhibitor of extracellular signal-regulated kinases (ERKs) 1 and 2 (750 mmol/L), or vehicle (dimethyl sulfoxide and isotonic sodium chloride solution) was administered intravenously as a bolus at the end of resuscitation. MAIN OUTCOME MEASURES: At 24 hours after resuscitation or sham operation, plasma levels of IL-6 and alpha-glutathione S-transferase were determined with enzyme-linked immunosorbent assay and enzyme immunoassay, respectively. Moreover liver sections were stained with monoclonal antibody against the phosphorylated form of ERKs. RESULTS: At 24 hours following trauma hemorrhage and resuscitation, plasma levels of IL-6 and alpha-glutathione S-transferase were markedly elevated. Administration of PD 98059, however, reduced levels to sham values. Moreover, liver expression of phosphorylated ERKs was found in the cytosol and nuclear compartment of hepatocytes only following trauma hemorrhage. CONCLUSION: Administration of PD 98059 (ie, inhibition of intracellular signaling pathways) may represent a feasible approach to blunt the inflammatory response and improve outcome following traumatic injuries and hemorrhagic shock.

Models of causation and the semantics of causal verbs.

This research examines the relationship between the concept of CAUSE as it is characterized in psychological models of causation and the meaning of causal verbs, such as the verb cause itself. According to focal set models of causation (; ), the concept of CAUSE should be more similar to the concepts of ENABLE and PREVENT than either is to each other. According to a model based on theory of force dynamics, the force dynamic model, the concepts of CAUSE, ENABLE, and PREVENT should be roughly equally similar to one another. The relationship between these predictions and the meaning of causal verbs was examined by having participants sort causal verbs and rate them with respect to the dimensions specified by the two models. The results from five experiments indicated that the force dynamic model provides a better account of the meaning of causal verbs than do focal set models of causation. Implications for causal inference and induction are discussed.

Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity.

Signaling through the Fas/Fas ligand (FasL) pathway plays a central role in immune-cell response and function; however, under certain pathological conditions such as sepsis, it may contribute to the animal's or patient's morbidity and mortality. To determine the contribution of FasL to mortality, we conducted survival studies by blocking Fas/FasL with Fas receptor fusion protein (FasFP) in vivo. C3H/HeN mice received FasFP or the saline vehicle (veh) immediately (0 h) or delayed (12 h), after sepsis induced by cecal ligation and puncture (CLP). Subsequently, we examined the effect of FasFP treatment (12 h post-CLP) on macrophage apoptosis and functional capacities. Peritoneal and splenic macrophages and Kupffer cells from sham-veh-, CLP-veh-, sham-FasFP-, or CLP-FasFP-treated mice were harvested 24 h after CLP and stimulated with lipopolysaccharide (LPS) for 24 h. The results indicate that only delayed (12 h) but not 0 h administration of FasFP demonstrated a significant increase in survival. The ability of all macrophage populations to release interleukin (IL)-6 was significantly depressed, and IL-10 release was augmented after CLP. FasFP treatment attenuated the increased IL-10 release in Kupffer cells. However, althogh enhanced susceptibility to LPS-induced apoptosis could be suppressed in CLP mouse Kupffer cells by FasFP, FasFP did not change the peritoneal or splenic macrophage response. Furthermore, FasFP attenuated the elevated plasma levels of liver enzymes after sepsis. These data indicate that in vivo inhibition of Fas/FasL signaling has tissue-specific effects on the induction of macrophage apoptosis, functional changes, and liver damage, which may contribute to the host's ability to ward off a septic challenge.

Mechanisms of immune resolution.

Initially after injury, the innate/proinflammatory and some aspects of the acquired immune response are up-regulated to maintain a defense against foreign pathogens, clear tissue debris present at the wound site, and orchestrate aspects of tissue remodeling, cell proliferation and angiogenic process, associated with the wound response. However, for proper wound healing to progress, this initial inflammatory response has to be regulated or shut down so as to allow for the reestablishment of matrix, recellularization, and tissue remodeling. Inability to properly resolve the extent of innate/acquired response at a site of injury can lead to poor wound healing, immune suppression, and recurrent infectious episodes. This review attempts to summarize information on regulatory mechanisms that are thought to be involved in controlling/resolving innate or acquired immune responses so as to provide a framework for use in thinking about the impact these processes and their manipulation may have on wound healing and its potential management.

Shock-induced neutrophil mediated priming for acute lung injury in mice: divergent effects of TLR-4 and TLR-4/FasL deficiency.

Acute lung injury (ALI) leading to respiratory distress is a common sequela of shock/trauma, however, modeling this process in mice with a single shock or septic event is inconsistent. One explanation is that hemorrhage is often just a "priming insult," thus, secondary stimuli may be required to "trigger" ALI. To test this we carried out studies in which we assessed the capacity of hemorrhage alone or hemorrhage followed by septic challenge (CLP) to induce ALI. Lung edema, bronchoalveolar lavage interleukin (IL)-6, alveolar congestion, as well as lung IL-6, macrophage inflammatory protein (MIP)-2, and myeloperoxidase (MPO) activity were all increased in mice subjected to CLP at 24 but not 72 hours following hemorrhage. This was associated with a marked increase in the susceptibility of these mice to septic mortality. Peripheral blood neutrophils derived from 24 hours post-hemorrhage, but not Sham animals, exhibited an ex vivo decrease in apoptotic frequency and an increase in respiratory burst capacity, consistent with in vivo "priming." Subsequently, we observed that adoptive transfer of neutrophils from hemorrhaged but not sham-hemorrhage animals to neutropenic recipients reproduce ALI when subsequently septically challenged, implying that this priming was mediated by neutrophils. We also found marked general increases in lung IL-6, MIP-2, and MPO in mice deficient for toll-like receptor (TLR-4) or the combined lack of TLR-4/FasL. However, the TLR-4 defect markedly attenuated neutrophil influx into the lung while not altering the change in local cytokine/chemokine expression. Alternatively, the combined loss of FasL and TLR-4 did not inhibit the increase in MPO and exacerbated lung IL-6/MIP-2 levels even further.

NF-kappaB activation has tissue-specific effects on immune cell apoptosis during polymicrobial sepsis.

Studies indicate that critically ill patients who succumb to sequela of sepsis/multiorgan failure, as well as septic animals, exhibit an apparently pathological increase in apoptosis (Ao) in the immune system. However, the mechanisms regulating these changes are unclear. Studies also indicate that, dependent on the cell population and the nature and/or duration of the stimuli, activation of the nuclear factor (NF)-kappaB can either suppress or enhance Ao. Thus, the aim of this study was to determine the contribution of NF-kappaB activation to the onset of Ao seen in divergent immune cell populations during sepsis, as produced by cecal ligation and puncture (CLP). To assess this, C3H/HeN mice were pretreated (for 1 h) subcutaneously with either 100 mg/kg body weight of pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor, or with saline vehicle, prior to subjecting them to CLP or Sham-CLP (Sham). Thymocytes, phagocytes, and Peyers Patch cells were harvested 24 h later, and the extent of Ao was determined by flow cytometry. The results indicate that PDTC pretreatment had no marked effect on the increase in thymocyte or phagocyte Ao seen following CLP, but there was a significant decline in the extent of Ao observed in septic mouse Peyer's patch B cells. To the extent that this was a result of NF-kappaB inhibition, we demonstrate by Western analysis, electrophoretic mobility shift assay (EMSA) and transfactor assay that the translocation of c-Rel to septic mouse Peyer's patch B cell nuclei is attenuated by PDTC. PDTC pretreatment also markedly reduced the number of Peyer's patch B cells that were producing IgA as well as attenuated the increase of proinflammatory cytokines in the blood. Interestingly, PDTC pretreatment did not restore peritoneal macrophage function or improve animal survival. Taken together, the inability of PDTC pretreatment to alter the Ao response of thymocytes or phagocytes, while inhibiting the increase in Peyer's patch B cell Ao in septic mice, implies not only that the activation of NF-kappaB has highly tissue/cell-specific effects that must be discerned when trying to clarify the pathophysiological role of NF-kappaB in sepsis, but that the activation of NF-kappaB may contribute to the early adaptive responses required by the host to fend off septic challenge.

Mechanism of immune dysfunction in sepsis: inducible nitric oxide-meditated alterations in p38 MAPK activation.

BACKGROUND: After the onset of sepsis, there is a marked dysfunction in cell-mediated immunity that contributes to the morbidity and mortality seen in this condition. Although both nitric oxide (NO) from inducible NO synthase (iNOS) and the activation of p38 mitogen-activated protein kinase (p38 MAPK) appear to contribute to this immune dysfunction, the extent to which NO regulates p38 MAPK activity in sepsis remains unknown. METHODS: To examine this, we induced sepsis by cecal ligation and puncture (CLP) in iNOS knockout (iNOS -/-) or C57BL/6 control mice. Twenty-four hours after CLP or sham operation, splenic T cells and macrophages were isolated and then stimulated with monoclonal antibody against the T-cell marker CD3 (anti-CD3) or lipopolysaccharide. At 4 or 24 hours after stimulation, cytokine release was determined by enzyme-linked immunosorbent assay, and p38 MAPK phosphorylation (activation) was determined by immunoblotting with antibody specific to phosphorylated p38 MAPK. RESULTS: Splenic T-cell p38 MAPK activation and interleukin (IL)-10 release was increased by CLP, whereas Th1 cytokine (IL-2, interferon-gamma) release was depressed. iNOS gene deficiency inhibited p38 MAPK activation in splenic T cells taken from septic mice, and also suppressed IL-10 release in both sham and septic mice. Interestingly, although deficiency of iNOS restored IL-2 release after CLP, both sham and CLP T cells remained depressed in their ability to release interferon-gamma. Septic insult markedly suppressed C57BL/6 splenic macrophage release of proinflammatory agents tumor necrosis factor, IL-12, and IL-1, while augmenting the release of IL-10. However, although deficiency of iNOS concomitantly restored the ability to produce tumor necrosis factor while suppressing the rise in IL-10 release and p38 MAPK activation, it only partially restored IL-1 release and had no effect on IL-12 production seen after CLP. CONCLUSION: These data suggest that NO release from iNOS regulates aspects of sepsis-induced immune dysfunction by the activation of p38 MAPK.