A Phase II Trial of Pevonedistat and Docetaxel in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer.

BACKGROUND: Postimmunotherapy (IO) treatment options for stage IV non-small-cell lung cancer (NSCLC) remain limited. Docetaxel alone or in combination with ramucirumab remains a standard of care, but response rates and survival benefit are suboptimal. Cullin-RING ligases (CRL) catalyze degradation of tumor suppressor proteins and are overactivated in NSCLC. Neddylation, which is catalyzed by the NEDD8 activating enzyme (NAE), is required for the activation of CRLs. Pevonedistat, a first-in-class small molecule NAE inhibitor, exerted antitumor activity when combined with docetaxel in preclinical studies. METHODS: We conducted a phase II, single-arm, investigator-initiated study evaluating the efficacy of pevonedistat plus docetaxel in patients with relapsed/refractory stage IV NSCLC. Patients received docetaxel 75 mg/m2 on day 1 and pevonedistat 25 mg/m2 on days 1, 3 and 5 of a 21-day cycle. The primary endpoint was objective response rate (ORR). RESULTS: From March 5, 2018 to January 26, 2021, we enrolled 31 patients. The ORR was 22% (1 CR, 5 PR), median PFS was 4.1 months, and median OS was 13.2 months. The incidence of Grade ≥3 adverse events (AE) was 53% in patients (n = 30) who received at least 1 dose of both drugs, with the most frequent being neutropenia and AST/ALT elevation. One patient was taken off study for a Grade 4 transaminase elevation. There were no Grade 5 toxicities. CONCLUSION: Our data suggest that the combination of docetaxel and pevonedistat is safe and exerts activity in patients with relapsed NSCLC. These encouraging results suggest that the neddylation pathway is an antitumor pathway that should be further studied.

Treatment of Non-Small Cell Lung Cancer with Atypical EGFR Mutations.

OPINION STATEMENT: EGFR tyrosine kinase inhibitors (TKI) should always be considered when treating advanced/metastatic non-small cell lung cancer (NSCLC) with atypical EGFR mutations. The first choice of TKI depends on the specific mutation(s) present and its effect on structure and function of the EGFR protein. Afatinib is the only EGFR TKI currently FDA approved for atypical EGFR mutations and has the strongest data to support its use in PACC mutations, a subgroup of atypical EGFR mutations which includes G719X and S7681. Dacomitinib may also be an option for these mutations given similar efficacy to afatinib. In contrast, for classical-like mutations such as L861Q, osimertinib should be considered the first choice given that their behavior mimics that of the classical mutations exon 19 deletion and L858R. Osimertinib should also be utilized in the setting of a concurrent T790M mutation. Superior CNS penetrance and well managed toxicity profile may also be reasons to consider osimertinib. Given that the choice of TKI may depend on the specific mutation, it is crucial that every patient diagnosed with NSCLC undergo comprehensive sequencing to identify these mutations.

Identifying Fibroblast Growth Factor Receptor 3 as a Mediator of Periosteal Osteochondral Differentiation through the Construction of microRNA-Based Interaction Networks.

Human periosteum-derived progenitor cells (hPDCs) have the ability to differentiate towards both the chondrogenic and osteogenic lineages. This coordinated and complex osteochondrogenic differentiation process permits endochondral ossification and is essential in bone development and repair. We have previously shown that humanised cultures of hPDCs enhance their osteochondrogenic potentials in vitro and in vivo; however, the underlying mechanisms are largely unknown. This study aimed to identify novel regulators of hPDC osteochondrogenic differentiation through the construction of miRNA-mRNA regulatory networks derived from hPDCs cultured in human serum or foetal bovine serum as an alternative in silico strategy to serum characterisation. Sixteen differentially expressed miRNAs (DEMis) were identified in the humanised culture. In silico analysis of the DEMis with TargetScan allowed for the identification of 1503 potential miRNA target genes. Upon comparison with a paired RNAseq dataset, a 4.5% overlap was observed (122 genes). A protein-protein interaction network created with STRING interestingly identified FGFR3 as a key network node, which was further predicted using multiple pathway analyses. Functional analysis revealed that hPDCs with the activating mutation FGFR3N540K displayed increased expressions of chondrogenic gene markers when cultured under chondrogenic conditions in vitro and displayed enhanced endochondral bone formation in vivo. A further histological analysis uncovered known downstream mediators involved in FGFR3 signalling and endochondral ossification to be upregulated in hPDC FGFR3N540K-seeded implants. This combinational approach of miRNA-mRNA-protein network analysis with in vitro and in vivo characterisation has permitted the identification of FGFR3 as a novel mediator of hPDC biology. Furthermore, this miRNA-based workflow may also allow for the identification of drug targets, which may be of relevance in instances of delayed fracture repair.

Novel insights on the effect of sclerostin on bone and other organs.

As a key regulator of bone homeostasis, sclerostin has garnered a lot of interest over the last two decades. Although sclerostin is primarily expressed by osteocytes and is well known for its role in bone formation and remodelling, it is also expressed by a number of other cells and potentially plays a role in other organs. Herein, we aim to bring together recent sclerostin research and discuss the effect of sclerostin on bone, cartilage, muscle, liver, kidney and the cardiovascular and immune systems. Particular focus is placed on its role in diseases, such as osteoporosis and myeloma bone disease, and the novel development of sclerostin as a therapeutic target. Anti-sclerostin antibodies have recently been approved for the treatment of osteoporosis. However, a cardiovascular signal was observed, prompting extensive research into the role of sclerostin in vascular and bone tissue crosstalk. The study of sclerostin expression in chronic kidney disease was followed by the investigation of its role in liver-lipid-bone interactions, and the recent discovery of sclerostin as a myokine prompted new research into sclerostin within the bone-muscle relationship. Potentially, the effects of sclerostin reach beyond that of bone alone. We further summarise recent developments in the use of sclerostin as a potential therapeutic for osteoarthritis, osteosarcoma and sclerosteosis. Overall, these new treatments and discoveries illustrate progress within the field, however, also highlight remaining gaps in our knowledge.

Household Dietary Diversity among Households with and without Children with Disabilities in Three Low-Income Communities in Lusaka, Zambia.

The purpose of this manuscript is to describe household dietary diversity (HDDS) in Lusaka, Zambia between households with and without a child with a disability living in the same communities. Cross-sectional data were collected in three low-income compounds in September 2021. Participants included households with a child with a disability enrolled in Kusamala+, a community-based program, (n = 444) and a convenience sample of adults living in the same area without a child with a disability (n = 1027). The HDDS tool asked about food groups consumed in the past 24 h by people in the household. The responses were summed (yes = 1, no = 0), range 0-12. Individual dietary diversity scores (IDDSs) were calculated for children (0-8 items). Analysis included descriptive statistics and linear regression. Mean HDDS for the households with a child with a disability was 4.8 (SD 2.1) vs. 6.1 (SD = 2.2) among households without a child with a disability (p < 0.001). The individual score for children (IDDS) for households with children with disabilities was 2.6 (SD = 1.4) vs. 3.7 (SD = 1.6) for households without a child with a disability. Households with a child with a disability had a significantly lower HDDS and IDDS in unadjusted and adjusted models (p < 0.001). National policy must assure the most vulnerable populations, and often hidden, receive focused financial and food support.

Treatment of Metastatic Disease with Immune Checkpoint Inhibitors Nivolumab and Pembrolizumab: Effect of Performance Status on Clinical Outcomes.

Introduction: Although guidelines exist for appropriate use of chemotherapy in the metastatic setting based on performance status, such recommendations are less readily available for immune checkpoint inhibitors (ICIs). We sought to determine whether there is a relationship between Eastern Cooperative Oncology Group (ECOG) performance status and outcomes of immunotherapy in patients treated for metastatic disease at our community-based oncology practice. Methods: Patients (n = 253) were identified as receiving nivolumab or pembrolizumab for stage IV malignancy at Cancer Centers of Colorado, St. Joseph Hospital/SCL Health between June 2018 and November 2020. Patients who initiated therapy after May 2020 were excluded from analysis due to less than 6 months follow-up time. The remaining 183 patients were included in a retrospective cohort study comparing patients with ECOG 0, 1, and 2-4. Sex, age, type of cancer, line of therapy, time on therapy and best response to therapy were determined. These baseline factors and outcomes were compared using analysis of variance (ANOVA) for numeric variables and χ2 tests of association for categorical variables. Time from initiation of ICI to death or hospice was also compared using a log-rank test as well as a multivariate Cox proportional hazards model. Results: Of the 183 patients included, 31.7% had an ECOG of 0, 48.6% an ECOG of 1, and 19.7% an ECOG of 2-4. Non-small cell lung cancer and melanoma represented the majority of patients in each group. Sex and line of therapy did not differ between groups. There was a significant difference in age, with mean age of 62, 66, and 70 in ECOG 0, 1, and 2-4, respectively. Patients (54.6%) remained on therapy for at least 6 months, with no significant difference between groups in ability to complete 6 months of therapy. For ECOG 0, 1, and 2-4, disease control was achieved in 67.2%, 59.6%, and 41.7%, respectively. Analysis of time to death or hospice with a log-rank test showed a significant difference between groups. A multivariate Cox proportional hazards model revealed that patients with ECOG 0 had significantly longer time to death or hospice compared with patients in both other groups after controlling for age, sex, and line of therapy. Conclusion: In this single institution retrospective study of patients receiving nivolumab or pembrolizumab for metastatic cancer, ECOG 0 was associated with disease control and increased time before death or transition to hospice.

What's eating you? oriental rat flea (Xenopsylla cheopis).

The oriental rat flea (Xenopsylla cheopis) is an ectoparasite of small mammals and a vector of many diseases for which humans are incidental hosts. This species of flea is most widely known for carrying Yersinia pestis and Rickettsia typhi, the causative agents of the plague and murine typhus, respectively. Public health issues related to X cheopis may increase in the future as global warming expands the geographic area in which the fleas can survive. A bioterrorist attack of plague also remains a threat. Extensive research is ongoing regarding X cheopis and its interaction with the bacteria it transmits to find better ways of reducing related morbidity and mortality. Traditional control measures include extermination of small mammal hosts, insecticide use to eliminate the flea itself, and use of antibiotics to control the associated diseases. The future may include targeted insecticide usage to prevent the continued development of resistance as well as new methods of reducing transmission of flea-borne diseases that could eliminate the need for chemical insecticides all together.

Rate of conversion to an open procedure is reduced in patients undergoing robotic colorectal surgery: A single-institution experience.

BACKGROUND: Robotic-assisted surgery is becoming increasingly used in colorectal operations. It has many advantages over laparoscopic surgery including three-dimensional viewing, motion scaling, improved dexterity and ergonomics as well as increased precision. However, there are also disadvantages to robotic surgery such as lack of tactile feedback, cost as well as limitations on multi-quadrant surgeries. The purpose of this study was to compare the rate of conversion to an open surgery in patients undergoing robotic-assisted colorectal surgery and traditional laparoscopic surgery. METHODS: Patients undergoing minimally invasive colorectal surgery for neoplastic and dysplastic disease from 2009 to 2016 were identified and examined retrospectively. The statistical software SAS, manufactured by SAS Institute, Cary, North Carolina. Continuous variables were analysed using analysis of variance test. Chi-square test was used to analyse categorical variables. P <0.05 was considered statistically significant. RESULTS: Two hundred and thirty-five patients were identified that underwent minimally invasive colorectal surgery. One hundred and sixty-four underwent laparoscopic resection and 71 underwent robotic-assisted resection. There was no statistical difference in gender or race between the two groups (both P > 0.05). Patients that underwent robotic-assisted resection were slightly younger than patients that underwent laparoscopic resection (61.6 years vs. 65.6 years; P= 0.02). When examining conversion to an open procedure, patients that underwent robotic-assisted resection had a significantly lower chance of conversion than did the patients undergoing a laparoscopic approach (11.27% vs. 29.78%; P= 0.0018). CONCLUSION: Conversion rates from a minimally invasive procedure to an open procedure appear to be lower with robotic-assisted surgery compared to laparoscopic surgery.

Use of secukinumab in a pediatric patient leads to significant improvement in nail psoriasis and psoriatic arthritis.

Many pediatric psoriasis patients suffer from nail involvement and psoriatic arthritis. In adults, biologic agents have demonstrated success in treating refractory nail psoriasis and arthritis, but studies are limited in children. In this report, we present a pediatric patient with severe, recalcitrant nail and joint psoriasis, successfully treated with secukinumab.

Delayed Diagnosis of Vulvar Crohn's Disease in a Patient with No Gastrointestinal Symptoms.

Though Crohn's disease primarily affects the gastrointestinal tract, cutaneous Crohn's disease of the vulva can occur in the absence of gastrointestinal symptoms, complicating the diagnosis. Once clinicians suspect cutaneous Crohn's disease, antibiotics and traditional immunosuppressants comprise initial treatment. Unfortunately, sometimes these therapies are not effective, or they provide only short-lived symptomatic improvement. A few case reports have found tumor necrosis factor-α inhibitors to be helpful in such refractory cases. We describe a patient with long-standing, painful vulvar Crohn's lesions with no gastrointestinal manifestations of the disease. Her diagnosis was delayed for years, and initial therapy with antibiotics and steroids was unsuccessful. Finally, the patient experienced effective and long-lasting symptom improvement with infliximab (RemicadeTM).