Treatment Considerations for Patients with Locoregionally Advanced Head and Neck Cancer with a Contraindication to Cisplatin.

OPINION STATEMENT: Significant advancements have been made in the treatment of locally advanced head and neck cancer, predominantly driven by the integration of concurrent chemotherapy with radiation therapy as a standard of care for many patients. The most heavily investigated chemotherapeutic is cisplatin, yet many patients are ineligible for cisplatin due to the presence of pre-existing medical comorbidities. Moreover, given the toxicity profile of cisplatin, identifying which patients stand to benefit from cisplatin is challenging, which is particularly evident in older patients. Efforts to better risk-stratify patients based on age, performance status, and the degree of pre-existing comorbidities are ongoing and have been increasingly utilized in national clinical trials. In parallel, exploration into alternative systemic agents, including novel targeted therapies and immunotherapies, in cisplatin-ineligible patients are rapidly expanding. Cumulatively, identifying appropriate treatment paradigms in patients who harbor contraindications to cisplatin can not only improve clinical outcomes but also critically mitigate detrimental adverse effects.

Quantitative prediction of aspiration risk in head and neck cancer patients treated with radiation therapy.

OBJECTIVE: To determine characteristics most strongly associated with risk for aspiration events among head and neck cancer (HNC) patients undergoing curative intent treatment. MATERIALS AND METHODS: This was a retrospective, cross-sectional study of 106 patients with previously untreated HNC who received definitive or postoperative radiation therapy (RT) +/- systemic therapy with curative intent. Patients who received post-treatment videofluoroscopic swallow study (VFSS) between 2018-2021 were included. Using ordinal multivariable logistic regression, we modeled the effects of age (>60 years vs. ≤60 years), sex, body mass index (BMI) (>20 kg/m2 vs. ≤20 kg/m2), American Joint Committee on Cancer 8th edition stage (I-II vs. III-IVB), treatment with cisplatin (vs. other or no systemic therapy), post-operative status, primary site (oral cavity vs. P16+ oropharynx vs. P16- Mucosal Site vs. other), and quantitative VFSS measures on Penetration-Aspiration Scale (PAS) score. RESULTS AND CONCLUSION: On ordinal multivariable logistic regression, age >60 years (odds ratio (OR): 3.91, 95% confidence interval (CI): 1.29, 11.9), advanced stage (stage III-IVB) (OR: 3.13, 95% CI: 1.23, 7.79), pharyngeal constriction ratio (PCR) >0.25 (OR: 3.65, 95% CI: 1.14, 11.7), and bolus clearance ratio (BCR) > 0.10 (OR: 3.42, 95% CI: 1.20, 9.75) were found to be significant risk factors for higher PAS scores. Patients with ≥ 2 pre-treatment risk factors had statistically significant increased risk for post-treatment aspiration (OR 2.52, 95% CI: 1.31, 4.86) on ordinal logistic regression. This model could be useful to direct high-risk patients toward interventions designed to reduce risk of aspiration events.

Interactive CLV3, CLE16 and CLE17 signaling mediates stem cell homeostasis in the Arabidopsis shoot apical meristem.

The ability of plants to grow and form organs throughout their lifetime is dependent on their sustained stem cell activity. These stem cell populations are maintained by intricate networks of intercellular signaling pathways. In Arabidopsis thaliana, the small secreted peptide CLAVATA3 (CLV3) controls shoot apical meristem (SAM) maintenance by activating a signal transduction pathway that modulates the expression of the homeodomain transcription factor WUSCHEL (WUS). Here, we demonstrate that two CLV3-related peptides, CLE16 and CLE17, restrict stem cell accumulation in the absence of CLV3. CLE16 and CLE17 contribute independently to SAM maintenance and organ production in clv3 plants at all stages of development. We show that CLE16 and CLE17 signal through a subset of CLV3 receptors, the BARELY ANY MERISTEM (BAM) receptor kinases, and act upstream of WUS. Our study reveals that CLE16 and CLE17 function in a mechanism that partially compensates for CLV3 to maintain stem cell homeostasis and plant resiliency, and expands the potential targets for enhancing yield traits in crop species.

Improved Prognosis of Treatment Failure in Cervical Cancer with Nontumor PET/CT Radiomics.

Radiomics has been applied to predict recurrence in several disease sites, but current approaches are typically restricted to analyzing tumor features, neglecting nontumor information in the rest of the body. The purpose of this work was to develop and validate a model incorporating nontumor radiomics, including whole-body features, to predict treatment outcomes in patients with previously untreated locoregionally advanced cervical cancer. Methods: We analyzed 127 cervical cancer patients treated definitively with chemoradiotherapy and intracavitary brachytherapy. All patients underwent pretreatment whole-body 18F-FDG PET/CT. To quantify effects due to the tumor itself, the gross tumor volume (GTV) was directly contoured on the PET/CT image. Meanwhile, to quantify effects arising from the rest of the body, the planning target volume (PTV) was deformably registered from each planning CT to the PET/CT scan, and a semiautomated approach combining seed-growing and manual contour review generated whole-body muscle, bone, and fat segmentations on each PET/CT image. A total of 965 radiomic features were extracted for GTV, PTV, muscle, bone, and fat. Ninety-five patients were used to train a Cox model of disease recurrence including both radiomic and clinical features (age, stage, tumor grade, histology, and baseline complete blood cell counts), using bagging and split-sample-validation for feature reduction and model selection. To further avoid overfitting, the resulting models were tested for generalization on the remaining 32 patients, by calculating a risk score based on Cox regression and evaluating the c-index (c-index > 0.5 indicates predictive power). Results: Optimal performance was seen in a Cox model including 1 clinical biomarker (whether or not a tumor was stage III-IVA), 2 GTV radiomic biomarkers (PET gray-level size-zone matrix small area low gray level emphasis and zone entropy), 1 PTV radiomic biomarker (major axis length), and 1 whole-body radiomic biomarker (CT bone root mean square). In particular, stratification into high- and low-risk groups, based on the linear risk score from this Cox model, resulted in a hazard ratio of 0.019 (95% CI, 0.004, 0.082), an improvement over stratification based on clinical stage alone, which had a hazard ratio of 0.36 (95% CI, 0.16, 0.83). Conclusion: Incorporating nontumor radiomic biomarkers can improve the performance of prognostic models compared with using only clinical and tumor radiomic biomarkers. Future work should look to further test these models in larger, multiinstitutional cohorts.

4-Coumaroyl-CoA ligases in the biosynthesis of the anti-diabetic metabolite montbretin A.

BACKGROUND: Montbretins are rare specialized metabolites found in montbretia (Crocosmia x crocosmiiflora) corms. Montbretin A (MbA) is of particular interest as a novel therapeutic for type-2 diabetes and obesity. There is no scalable production system for this complex acylated flavonol glycoside. MbA biosynthesis has been reconstructed in Nicotiana benthamiana using montbretia genes for the assembly of MbA from its various different building blocks. However, in addition to smaller amounts of MbA, the therapeutically inactive montbretin B (MbB) was the major product of this metabolic engineering effort. MbA and MbB differ in a single hydroxyl group of their acyl side chains, which are derived from caffeoyl-CoA and coumaroyl-CoA, respectively. Biosynthesis of both MbA and MbB also require coumaroyl-CoA for the formation of the myricetin core. Caffeoyl-CoA and coumaroyl-CoA are formed in the central phenylpropanoid pathway by acyl activating enzymes (AAEs) known as 4-coumaroyl-CoA ligases (4CLs). Here we investigated a small family of montbretia AAEs and 4CLs, and their possible contribution to montbretin biosynthesis. RESULTS: Transcriptome analysis for gene expression patterns related to montbretin biosynthesis identified eight different montbretia AAEs belonging to four different clades. Enzyme characterization identified 4CL activity for two clade IV members, Cc4CL1 and Cc4CL2, converting different hydroxycinnamic acids into the corresponding CoA thioesters. Both enzymes preferred coumaric acid over caffeic acid as a substrate in vitro. While expression of montbretia AAEs did not enhance MbA biosynthesis in N. benthamiana, we demonstrated that both Cc4CLs can be used to activate coumaric and caffeic acid towards flavanone biosynthesis in yeast (Saccharomyces cerevisiae). CONCLUSIONS: Montbretia expresses two functional 4CLs, but neither of them is specific for the formation of caffeoyl-CoA. Based on differential expression analysis and phylogeny Cc4CL1 is most likely involved in MbA biosynthesis, while Cc4CL2 may contribute to lignin biosynthesis. Both Cc4CLs can be used for flavanone production to support metabolic engineering of MbA in yeast.

MMiRNA-Viewer2, a bioinformatics tool for visualizing functional annotation for MiRNA and MRNA pairs in a network.

BACKGROUND: Although there are many studies on the characteristics of miRNA-mRNA interactions using miRNA and mRNA sequencing data, the complexity of the change of the correlation coefficients and expression values of the miRNA-mRNA pairs between tumor and normal samples is still not resolved, and this hinders the potential clinical applications. There is an urgent need to develop innovative methodologies and tools that can characterize and visualize functional consequences of cancer risk gene and miRNA pairs while analyzing the tumor and normal samples simultaneously. RESULTS: We developed an innovative bioinformatics tool for visualizing functional annotation of miRNA-mRNA pairs in a network, known as MMiRNA-Viewer2. The tool takes mRNA and miRNA interaction pairs and visualizes mRNA and miRNA regulation network. Moreover, our MMiRNA-Viewer2 web server integrates and displays the mRNA and miRNA gene annotation information, signaling cascade pathways and direct cancer association between miRNAs and mRNAs. Functional annotation and gene regulatory information can be directly retrieved from our web server, which can help users quickly identify significant interaction sub-network and report possible disease or cancer association. The tool can identify pivotal miRNAs or mRNAs that contribute to the complexity of cancer, while engaging modern next-generation sequencing technology to analyze the tumor and normal samples concurrently. We compared our tools with other visualization tools. CONCLUSION: Our MMiRNA-Viewer2 serves as a multitasking platform in which users can identify significant interaction clusters and retrieve functional and cancer-associated information for miRNA-mRNA pairs between tumor and normal samples. Our tool is applicable across a range of diseases and cancers and has advantages over existing tools.

Identifying Interaction Clusters for MiRNA and MRNA Pairs in TCGA Network.

Existing methods often fail to recognize the conversions for the biological roles of the pairs of genes and microRNAs (miRNAs) between the tumor and normal samples. We have developed a novel cluster scoring method to identify messenger RNA (mRNA) and miRNA interaction pairs and clusters while considering tumor and normal samples jointly. Our method has identified 54 significant clusters for 15 cancer types selected from The Cancer Genome Atlas project. We also determined the shared clusters across tumor types and/or subtypes. In addition, we compared gene and miRNA overlap between lists identified in our liver hepatocellular carcinoma (LIHC) study and regulatory relationships reported from human and rat nonalcoholic fatty liver disease studies (NAFLD). Finally, we analyzed biological functions for the single significant cluster in LIHC and uncovered a significantly enriched pathway (phospholipase D signaling pathway) with six genes represented in the cluster, symbols: DGKQ, LPAR2, PDGFRB, PIK3R3, PTGFR and RAPGEF3.

The Price We Pay for Radical Curative Pelvic Exenterations: Prevalence and Management of Pain.

BACKGROUND: Pelvic exenterations are extensive surgical procedures for locally advanced or recurrent malignancies of the pelvis. However, this is often at the cost of significant morbidity due to perioperative pain, which has been poorly studied. OBJECTIVE: This study aims to review perioperative pain management in patients undergoing pelvic exenteration. DESIGN: This is a retrospective review of patients undergoing pelvic exenteration between January 2013 and December 2014. Data were gathered from medical records and a prospectively maintained database. SETTING: This study was conducted at a single quaternary referral center for pelvic exenteration. PATIENTS: Consecutive patients underwent pelvic exenteration at a single center. INTERVENTIONS: Pelvic exenteration was performed in consecutive patients. MAIN OUTCOMES MEASURES: Primary outcomes were the prevalence of preoperative pain, preoperative opiate use (type, dosage), and postoperative pain (verbal numerical rating scale). Secondary outcomes included the number of pain consultations and correlations between preoperative opiate use, length of stay, and extent of resection (en bloc sacrectomy and nerve excision). RESULTS: Ninety-nine patients underwent pelvic exenteration. Sixty-one patients (61.6%) underwent major nerve resection and/or sacrectomy. Thirty patients (30%) required opiates preoperatively, with a mean daily morphine equivalent of 72.9 mg (SD 65.0 mg). Patients on preoperative opiates were more likely to have worse pain postoperatively and to require higher opiate doses and more pain consultations (9.3 vs 4.8; p < 0.001). Major nerve excision and sacrectomy were not associated with worse postoperative pain. By discharge, 60% still required opiate analgesia. LIMITATIONS: Retrospective study design, the subjective nature of pain assessment because of a lack of valid methods to objectively quantify pain, and the lack of long-term follow-up were limitations of this study. CONCLUSIONS: Perioperative pain is a significant issue among patients undergoing pelvic exenteration. One in three patients require high-dose opiates preoperatively that is associated with worse pain outcomes. Potential areas to improve pain outcomes in these complex patients could include increased use of regional anesthesia, antineuropathic agents, and opiate-sparing techniques. See Video Abstract at http://links.lww.com/DCR/A572.

Perianal Lesions in Children: An Updated Review.

Perianal lesions in children are common reasons for dermatology clinic visits and a well-defined approach to diagnosis and management is helpful to the practicing clinician. In this article, we review and update various etiologies of perianal lesions in the pediatric population, including infectious, papulosquamous, vascular, and neoplastic. We provide a standard initial approach to diagnosis and updates on current management. Infectious etiologies of perianal lesions discussed in this article include fungal, bacterial, parasitic, and viral. Perianal papulosquamous lesions often encountered in children, and discussed in this article, include acrodermatitis enteropathica, psoriasis, contact dermatitis, and many others. We also discuss the diagnosis and management of other entities including infantile hemangiomas, Langerhans cell histiocytosis, and fibrous hamartoma of infancy.

Granular Parakeratosis: A Comprehensive Review and a Critical Reappraisal.

Granular parakeratosis (GP) is a rare, idiopathic, and benign skin condition that presents classically as erythematous to brown hyperkeratotic papules that can coalesce into plaques. Axillary GP was initially observed by Northcutt and colleagues and has since been described in various other areas of the body including other intertriginous and non-intertriginous sites. The term "granular parakeratosis" is now used to describe not only the skin condition, but also a distinctive histological reactive pattern on biopsy specimens that are either regarded as the disease itself, or merely as an incidental finding. Upon review of the current findings, opinions, and associations of this entity, we propose the reappraisal of GP as a reactive pattern, rather than a distinct entity.

Human in vitro skin organ culture as a model system for evaluating DNA repair.

BACKGROUND: UV-exposures result in accumulation of genetic lesions that facilitate the development of skin cancer. Numerous pharmacologic agents are currently under development to both inhibit formation of DNA lesions and enhance repair. Drugs must be evaluated in vitro, currently performed in cell culture systems, before being tested on humans. Current systems do not account for the architecture and diverse cellularity of intact human skin. OBJECTIVE: To establish a novel, functionally viable, and reproducible in vitro skin organ culture system for studying the effects of various pharmacologic agents on DNA repair. METHODS: Human skin was obtained from neonatal foreskins. Intact skin punches derived from foreskins were cultured in vitro prior to exposure to UV-irradiation, and evaluated for DNA-damage using a DNA dot blot. Serial skin biopsies were obtained from patients with actinic keratoses treated with topical imiquimod. Expression of immune-stimulating and DNA repair genes was evaluated in ex vivo and in vitro samples. RESULTS: DNA dot blots revealed active repair of UV induced lesions in our in vitro skin organ culture. The photo-protective effect of sunscreen was detected, while imiquimod treatment did not enhance DNA repair in vitro. The DNA repair molecules XPA and XPF were up-regulated in the skin of imiquimod treated patients with actinic keratoses and imiquimod treated bone marrow-derived cell lines, but not keratinocytes. CONCLUSION: Our in vitro human skin organ culture model detected repair of UV-induced DNA lesions, and may be easily adapted to investigate various photo-protective drugs intended to prevent or treat skin cancer.

Use of lenalidomide in treating refractory prurigo nodularis.

Prurigo nodularis is a chronic, relapsing neurodermatitis that is often resistant to standard therapies with topical corticosteroids and oral antihistamines. Thalidomide, while efficacious in treating recalcitrant cases of prurigo nodularis, causes significant toxicity. Thalidomide-induced peripheral neuropathy frequently results in drug discontinuation. Lenalidomide (Revlimid; Celgene Corporation, Summit, NJ) is a derivative of thalidomide with less neurotoxicity approved for the treatment of multiple myeloma and myelodysplastic syndromes that has not been widely studied in dermatologic disorders. Here, we report a case of refractory prurigo nodularis effectively treated with lenalidomide. Given its favorable side-effect profile, lenalidomide may offer a superior alternative to thalidomide in the treatment of this condition.

Imiquimod-induced TLR7 signaling enhances repair of DNA damage induced by ultraviolet light in bone marrow-derived cells.

Imiquimod is a TLR7/8 agonist that has anticancer therapeutic efficacy in the treatment of precancerous skin lesions and certain nonmelanoma skin cancers. To test our hypothesis that imiquimod enhances DNA repair as a mechanism for its anticancer activity, the nucleotide excision repair genes were studied in bone marrow-derived cells. Imiquimod enhanced the expression of xeroderma pigmentosum (XP) A and other DNA repair genes (quantitative real-time PCR analysis) and resulted in an increased nuclear localization of the DNA repair enzyme XPA. This was dependent on MyD88, as bone marrow-derived cells from MyD88(-/-) mice did not increase XPA gene expression and did not enhance the survival of MyD88(-/-)-derived bone marrow-derived cells after UV B exposure as was observed in bone marrow-derived cells from MyD88(+/+) mice. Imiquimod also enhanced DNA repair of UV light (UVL)-irradiated gene expression constructs and accelerated the resolution of cyclobutane pyrimidine dimers after UVL exposures in P388 and XS52. Lastly, topical treatment of mouse skin with 5% imiquimod cream prior to UVL irradiation resulted in a decrease in the number of cyclobutane pyridimine dimer-positive APC that were found in local lymph nodes 24 h after UVL irradiation in both wild-type and IL-12 gene-targeted mice. In total, these data support the idea that TLR7 agonists such as imiquimod enhance DNA repair in bone marrow-derived cells. This property is likely to be an important mechanism for its anticancer effects because it protects cutaneous APC from the deleterious effects of UVL.