Phase 1b study to assess the safety, tolerability, and clinical activity of pamiparib in combination with temozolomide in patients with locally advanced or metastatic solid tumors.

BACKGROUND: Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. METHODS: Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. RESULTS: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. CONCLUSIONS: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.

Corneal Manifestations in Patients with Hidradenitis Suppurativa.

PURPOSE: To report two cases of bilateral blepharokeratoconjunctivitis associated with hidradenitis suppurativa (HS). METHODS: Case report and literature review. The clinical courses of two patients with HS, including ocular presentation and medical management, are described. RESULTS: Two female patients aged 18 and 23-years-old with severe HS presented with bilateral blepharokeratoconjunctivitis. Shared slit lamp findings included bilateral corneal neovascularization and inferior corneal thinning. Systemic immunosuppression was needed in the first case, which resulted in improvement in the patient's ophthalmic and dermatological findings. CONCLUSION: We report two cases of bilateral blepharokeratoconjunctivitis in two patients with severe HS. To our knowledge, this association has not previously been described in the literature. Clinicians should be aware of this association given its potentially visually devastating manifestations and the need for early therapeutic interventions.

Serotonin modulates excitatory synapse maturation in the developing prefrontal cortex.

Serotonin (5-HT) imbalances in the developing prefrontal cortex (PFC) are linked to long-term behavioral deficits. However, the synaptic mechanisms underlying 5-HT-mediated PFC development are unknown. We found that chemogenetic suppression and enhancement of 5-HT release in the PFC during the first two postnatal weeks decreased and increased the density and strength of excitatory spine synapses, respectively, on prefrontal layer 2/3 pyramidal neurons in mice. 5-HT release on single spines induced structural and functional long-term potentiation (LTP), requiring both 5-HT2A and 5-HT7 receptor signals, in a glutamatergic activity-independent manner. Notably, LTP-inducing 5-HT stimuli increased the long-term survival of newly formed spines ( ≥ 6 h) via 5-HT7 Gαs activation. Chronic treatment of mice with fluoxetine, a selective serotonin-reuptake inhibitor, during the first two weeks, but not the third week of postnatal development, increased the density and strength of excitatory synapses. The effect of fluoxetine on PFC synaptic alterations in vivo was abolished by 5-HT2A and 5-HT7 receptor antagonists. Our data describe a molecular basis of 5-HT-dependent excitatory synaptic plasticity at the level of single spines in the PFC during early postnatal development.

Associations Between Measures of Disability and Quality of Life at Three Months After Stroke.

Background: The modified Rankin Scale (mRS), which measures degree of disability in daily activities, is the most common outcome measure in stroke research. Quality of life (QoL), however, is impacted by factors other than disability. The goal of this study was to assess the correlation between functional dependence and a more patient-centered QoL measure, the European QoL visual analog scale (EQ VAS). Methods: We reviewed prehospital and hospital records from 11 acute care hospitals in Seattle, Washington (USA) from June 2000 to January 2003 for this cohort study. Patients with a final diagnosis of stroke were contacted three to four months after stroke, and mRS and EQ VAS were assessed. Good QoL was defined as EQ VAS ≥65. Results: Of 760 patients with stroke, 346 were available at three to four months. Most (296, 85.5%) had ischemic stroke. Overall, mRS and QoL were negatively correlated (Spearman's ρ -0.53, p < 0.001). Percentage of good QoL decreased as mRS increased from 0 to 5 (88%, 70%, 52%, 50%, 31%, 20%, respectively, p < 0.001). However, 36% (n = 62) of patients with dependent mRS (3-5, n = 174) reported good QoL, and 30% (n = 52) of patients with independent mRS (0-2, n = 172) reported poor QoL. In multivariable analysis, older age, male gender, and absence of dementia, were associated with good QoL despite dependent mRS; atrial fibrillation was associated with poor QoL despite independent mRS. Conclusions: QoL decreases with increasing mRS, but exceptions exist with good QoL despite high mRS. To provide patient-centered care, clinicians and researchers should avoid equating disability with QoL after stroke.

Massage Therapy May be Safe and Reduce Pain in Critically Ill Patients with Acute Neurological Injury: a Case Control Study.

Purpose: Massage therapy is an important adjunctive treatment for physiologic and psychologic symptoms and has been shown to benefit patients among a wide variety of patient populations. Setting: Few studies have investigated the utility of massage therapy in the general ICU setting, and even fewer have done so in the neurological ICU (NeuroICU). Research Design: If massage therapy was determined to improve objective outcomes-or even subjective outcomes in the absence of harm-massage may be more readily employed as a complementary therapy, particularly in the ICU setting or in patients with acute neurological injury. Intervention: This pilot study aimed to assess the safety of massage in the neurocritical care unit and its impact on patient vital signs, subjective pain assessment, and other clinical outcomes. Participants: Twenty-one patients who received massage therapy during admission to the neurocritical care service were compared to matched controls in a retrospective case control study design. Results: We found a statistically significant reduction in pain scores among patients with acute neurological injury who received massage therapy. There was no statistical difference in hospital length of stay, discharge destination, in-hospital mortality, adverse events, or incidence/duration of delirium between patients who received massage therapy and those who did not. No adverse events were ascribed to the massage therapy when evaluated by blinded neurocritical care specialists. Conclusion: This study found that massage therapy may be safe for many patients in the NeuroICU and may offer additional subjective benefits.

Neural circuits controlling choice behavior in opioid addiction.

As the opioid epidemic presents an ever-expanding public health threat, there is a growing need to identify effective new treatments for opioid use disorder (OUD). OUD is characterized by a behavioral misallocation in choice behavior between opioids and other rewards, as opioid use leads to negative consequences, such as job loss, family neglect, and potential overdose. Preclinical models of addiction that incorporate choice behavior, as opposed to self-administration of a single drug reward, are needed to understand the neural circuits governing opioid choice. These choice models recapitulate scenarios that humans suffering from OUD encounter in their daily lives. Indeed, patients with substance use disorders (SUDs) exhibit a propensity to choose drug under certain conditions. While most preclinical addiction models have focused on relapse as the outcome measure, our data suggest that choice is an independent metric of addiction severity, perhaps relating to loss of cognitive control over choice, as opposed to excessive motivational drive to seek drugs during relapse. In this review, we examine both preclinical and clinical literature on choice behavior for drugs, with a focus on opioids, and the neural circuits that mediate drug choice versus relapse. We argue that preclinical models of opioid choice are needed to identify promising new avenues for OUD therapy that are translationally relevant. Both forward and reverse translation will be necessary to identify novel treatment interventions. This article is part of the Special Issue on "Opioid-induced changes in addiction and pain circuits".

Clinical Diagnosis and Histopathologic Features of a Synthetic Fiber Granuloma.

The authors report a case of a synthetic fiber granuloma to demonstrate the challenges in diagnosing these lesions and to highlight their histopathologic features. This is the first report in the literature to use histopatho-logic and immunofluorescence studies to characterize the subtype and distribution of macrophages in synthetic fiber granuloma. [J Pediatr Ophthalmol Strabismus. 2020;57:e92-e95.].

Photophysical and Chiroptical Properties of the Enantiomers of N,N'-Bis(1-phenylpropyl)-2,6-pyridinecarboxamide and their Chiral 9-Coordinate Ln3+ Complexes.

The R,R and S,S enantiomers of N,N'-bis(1-phenylpropyl)-2,6-pyridinedicarboxamide, L(Et), react with Ln3+ ions (Ln = La, Eu, Gd, and Tb) to give stable [Ln((R,R)- and (S,S)-L(Et))3]3+ in anhydrous acetonitrile solution, as evidenced by various spectroscopic measurements, including NMR and luminescence titrations. In addition to the characteristic Eu3+ and Tb3+ luminescence bands, the steady-state and time-resolved luminescence spectra of the aforementioned complexes show the residual ligand-centered emission of the 1ππ* to 3ππ* states, indicating an incomplete intersystem crossing (ISC) transfer from the 1ππ* to 3ππ* and ligand-to-Ln3+ energy transfer, respectively. The high circularly polarized luminescence (CPL) activity of [Eu(L(Et))3]3+ confirms that using a single enantiomer of L(Et) induces the preferential formation of one chiral [Eu(L(Et))3]3+ complex, consistent with the [EuL 3]3+ complexes formed with other ligands derived from a 2,6-pyridine dicarboxamide moiety. Furthermore, the CPL sign patterns of complexes with (R,R) or (S,S) enantiomer of L(Et) are consistent with the CPL sign pattern of related [LnL 3]3+ complexes with the (R,R) or (S,S) enantiomer of the respective ligands in this family.

Dinuclear Rhenium Complexes with a Bridging Helicene-bis-bipyridine Ligand: Synthesis, Structure, and Photophysical and Chiroptical Properties.

By attaching pyridine groups to a diaza[6]helicene, a helical, bis-ditopic, bis-N N-coordinating ligand can be accessed. Dinuclear rhenium complexes featuring this bridging ligand, of the form [{Re(CO)3 Cl}2 (N N-N N)], have been prepared and resolved to give enantiopure complexes. These complexes are phosphorescent in solution at room temperature under one- and two-photon excitation. Their experimental chiroptical properties (optical rotation, electronic circular dichroism and circularly polarized emission) have been measured. They show, for instance, emission dissymmetry factors of c.a. ±3x10-3 . Quantum-chemical calculations indicate the importance of stereochemistry on the optical activity, pointing towards further design improvements in such types of complexes.

Routine preoperative endoscopy in patients undergoing bariatric surgery.

BACKGROUND: The role of routine preoperative endoscopy before primary weight loss surgery remains controversial. OBJECTIVE: We reviewed our experience to determine the frequency of abnormal findings in patients undergoing routine preoperative endoscopy before bariatric surgery. SETTING: A tertiary level, academic-affiliated bariatric surgery practice. METHODS: A retrospective chart review was performed between July 2014 and June 2016 of patients undergoing routine preoperative endoscopy before primary bariatric surgery. Variables evaluated included preendoscopy symptoms, planned bariatric surgical procedure, abnormal findings on endoscopy, and changes in planned bariatric surgical procedure after endoscopy. RESULTS: A total of 631 patients met inclusion criteria. Of patients, 72% (457) were female. The median age was 44 (interquartile range 36-55). The median body mass index was 46 (interquartile range 42-51). Most patients had no preendoscopy clinical symptoms (61.3%). The most frequent abnormal findings included esophagitis (26.5%), hiatal hernia (27.1%), gastric ulcer (4.9%), and biopsy-proven Barrett's esophagus (4.6%). Although patients with preoperative symptoms were more likely to have abnormal findings on endoscopy, there were no significant differences in rates of Barrett's esophagus in patients with (5.3%) or without (4.1%) symptoms. Of the total cohort, 18.4% had a change in their planned operation after endoscopy results. CONCLUSION: The findings in our large series suggest selective screening in symptomatic patients only may lead to failure of discovery of foregut pathology that should prompt consideration for changes in the planned bariatric surgical procedure. Further study is necessary to see if our findings have broad applicability.

Impact of Sleep Deprivation in the Neurological Intensive Care Unit: A Narrative Review.

Sleep is fundamental for everyday functioning, yet it is often negatively impacted in critically ill patients by the intensive care setting. With a focus on the neurological intensive care unit (NeuroICU), this narrative review summarizes methods of measuring sleep and addresses common causes of sleep disturbance in the hospital including environmental, pharmacological, and patient-related factors. The effects of sleep deprivation on the cardiovascular, pulmonary, immune, endocrine, and neuropsychological systems are discussed, with a focus on short-term deprivation in critically ill populations. Where evidence is lacking in the literature, long-term sleep deprivation studies and the effects of sleep deprivation in healthy individuals are also referenced. Lastly, strategies for the promotion of sleep in the NeuroICU are presented.

Phosphahelicenes: From Chiroptical and Photophysical Properties to OLED Applications.

Herein, the experimental physicochemical and chiroptical properties of a series of phosphahelicenes are reported, focusing on their UV/Vis absorption, luminescence, electronic circular dichroism, optical rotations, and circularly polarized luminescence. Furthermore, detailed analysis of absorption and ECD spectra performed with the help of quantum-chemical calculations allowed us to highlight general features of these helicenic phosphines. Finally, due to well-suited electrochemical properties and thermal stability, the systems were successfully used as emitters in organic light-emitting diodes.

Endophthalmitis following cataract surgery and intracameral antibiotic: Moxifloxacin resistant Staphylococcus epidermidis.

PURPOSE: To describe an immunosuppressed patient who developed acute-onset postoperative endophthalmitis caused by a moxifloxacin-resistant strain of Staphylococcus epidermidis after cataract surgery despite the use of intracameral moxifloxacin. OBSERVATIONS: A 76-year old woman with a history of birdshot chorioretinopathy controlled on systemic immunosuppression underwent uneventful cataract surgery in her right eye. Compounded intracameral moxifloxacin 0.2 cc of 1mg/0.1mL (Edge Pharmacy, Syracuse, NY) was injected intraoperatively as prophylaxis, and the patient was placed on a standard regimen of trimethoprim-polymyxin b (10000-0.1unit/mL) and prednisolone acetate 1% postoperatively. Four days later, the patient experienced a sudden decrease in vision in the right eye. Anterior chamber inflammation, vitritis, and vasculitis were seen in the operated eye. The patient underwent a vitreous tap and intravitreal injections of vancomycin (1mg/0.1mL), ceftazidime (2.25mg/0.1mL), and dexamethasone (0.4mg/0.1mL). Cultures grew Staphylococcus epidermidis, resistant to moxifloxacin (MIC ≥8mg/L). The inflammation resolved over two months. Eight months later, the patient underwent uncomplicated cataract surgery in the left eye. Intracameral antibiotics were not used, however her systemic immunosuppressive therapy was held for several weeks perioperatively. One year after the initial surgeries, the patient had an uncorrected visual acuity of 20/20 in each eye. CONCLUSIONS AND IMPORTANCE: S. epidermidis, the most common cause of postoperative endophthalmitis, is increasingly resistant to fluoroquinolones. Adequate concentrations of intracameral antibiotics need to be achieved in order to exceed minimal inhibitory concentration values of the targeted pathogen. Although intracameral moxifloxacin has been reported to decrease the rate of endophthalmitis after cataract surgery, it does not eliminate the risk.

Isolated Anisocoria as a Presenting Stroke Code Symptom is Unlikely to Result in Alteplase Administration.

BACKGROUND: Acute stroke codes may be activated for anisocoria, but how often these codes lead to a final stroke diagnosis or alteplase treatment is unknown. The purpose of this study was to assess the frequency of anisocoria in stroke codes that ultimately resulted in alteplase administration. METHODS: We retrospectively assessed consecutive alteplase-treated patients from a prospectively-collected stroke registry between February 2015 and July 2018. Based on the stroke code exam, patients were categorized as having isolated anisocoria [A+(only)], anisocoria with other findings [A+(other)], or no anisocoria [A-]. Baseline demographics, stroke severity, alteplase time metrics, and outcomes were also collected. RESULTS: Ninety-six patients received alteplase during the study period. Of the 94 who met inclusion criteria, there were 0 cases of A+(only). There were 9 cases of A+(other) (9.6%). A+(other) exhibited higher baseline National Institutes of Health (NIH) Stroke Scale scores compared to A- (17 versus 7; P = .0003), and no additional differences in demographics or alteplase time metrics. Final stroke diagnosis and other outcome measures were no different between A+(other) and A-. Of the A+ patients without pre-existing anisocoria, 5 of 6 (83%) had posterior circulation events or diffuse subarachnoid hemorrhage. CONCLUSIONS: In this exploratory analysis, zero patients with isolated anisocoria received alteplase treatment. Anisocoria as a part of the neurologic presentation occurred in 10% of alteplase patients, and was strongly associated with a posterior circulation event. Therefore, we conclude that anisocoria has a higher likelihood of leading to alteplase treatment when identified in the presence of other neurologic deficits.

Infliximab for treatment-refractory transverse myelitis following immune therapy and radiation.

BACKGROUND: Neurologic toxicities with immune therapy are rare, but can cause devastating and often permanent injury when they occur. Although there is increasing interest in the potential synergism between immune therapy and radiation, it is possible that such combinations may lead to a greater number or increased severity of immune-related adverse events. We present here a case of extensive and progressive transverse myelitis following combined therapy, which did not improve until treatment with infliximab. This case highlights the unmet need for treatment of adverse events that are refractory to consensus recommendations, and may ultimately require further study and incorporation into future published guidelines. CASE PRESENTATION: We report a case of a 68-year-old with metastatic melanoma, who developed transverse myelitis in the setting of immune checkpoint blockade and spinal irradiation for vertebral metastases. Despite management according to published consensus guidelines: cessation of immune therapy, high-dose steroids, and plasmapheresis, he continued to deteriorate neurologically, and imaging revealed a progressive and ascending transverse myelitis. The patient was then treated with infliximab, and demonstrated dramatic imaging and modest clinical improvement following the first treatment cycle. CONCLUSIONS: This is the first report describing the successful use of infliximab in immune therapy and radiation-related transverse myelitis that was not responding to recommended therapy. Evaluation of additional treatment options such as infliximab for high-grade immune-related neurologic toxicities is warranted, and may be needed earlier in the disease process to prevent significant morbidity. The adverse effects of immune therapy when used in combination with radiation also require further investigation.