Drainage Tube Placement for the Management of Rebleeding After Vascular Embolization in a Patient With Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF-1), a hereditary disease caused by a mutation of a gene on chromosome 17q11.2, is associated with manifestations in several organs. Although infrequent, vascular abnormalities are a complication of NF-1, and they are the second most common cause of death in patients with NF-1. Repairing the nutrient artery and achieving hemostasis are difficult once the artery has failed, thereby resulting in poor treatment outcomes. Herein, we report a case of a patient with NF-1 who presented with an enormous cervical hematoma caused by bleeding from a branch of the external carotid artery. Vascular embolization was performed initially; however, rebleeding from the embolized site occurred. Following the removal of the hematoma, drainage tube placement was effective in preventing micro-bleeding. Thus, drainage tube placement may be an effective treatment option in patients with rebleeding.

Comparison of different methods for evaluating the relationship between facial nerve and benign parotid tumors.

Objectives: The goals of benign parotid gland tumor resection are complete resection of the lesion and preservation of the facial nerve function. As the facial nerve cannot be directly visualized via imaging modalities, several methods, including the facial nerve line, Utrecht line, retromandibular vein, Stenon duct, and minimum fascia-tumor distance techniques, have been developed to estimate its location. However, there are no reports on their accuracy in determining tumor location. In the present study, we aimed to assess the diagnostic accuracy of these methods based on tumor location. Methods: This retrospective study analyzed medical records and histological reports of 359 patients with various types of benign parotid gland tumors who underwent a parotidectomy between April 2014 and March 2020. The tumor location was subdivided into the following sections: anterior, superior, inferior, and middle. The tumor location was estimated using five methods: facial nerve line, Utrecht line, retromandibular vein, Stenon duct, and minimum fascia-tumor distance. The final diagnosis of superficial or deep lobe tumor was made based on surgical findings. Results: Each method showed a higher accuracy for superficial tumors (was more than 90%) than for deep lobe tumors. In contrast, for deep lobe tumors, the accuracy of diagnosis with the facial nerve line, Utrecht line, and retromandibular vein methods was low, in the 30% range. Among all methods, the Stenon duct method had the highest accuracy in the diagnosis of deep lobe tumors. The SD method was most useful in cases where both the duct and tumors were detected. The minimum fascia-tumor distance method had the second highest diagnostic accuracy (63%); however, for anterior tumors, it tended to provide false negatives. Conclusions: All tested methods were useful in diagnosing superficial lobe tumors; however, they were not helpful in diagnosing deep lobe tumors, especially anterior tumors.

Impact of radiotherapy for head and neck cancer on obstructive sleep apnea: a prospective study.

BACKGROUND: In recent years, a relatively high prevalence of obstructive sleep apnea (OSA) in patients following radiotherapy (RT) for head and neck cancer (HNC) has been reported; however, little is known regarding the impact of RT on sleep disorders and the underlying mechanisms. This aim of this study was to elucidate the pathogenesis of OSA by comparing the clinical and sleep test parameters and magnetic resonance imaging (MRI) findings before and after HNC treatment with radiation. METHODS: This prospective study included patients scheduled for RT with or without chemotherapy or bioradiotherapy for HNC. Patients diagnosed with HNC between May 2017 and August 2020 were consecutively recruited. The results of the sleep tests were analyzed both before and after treatment. The clinical characteristics of the patients and cephalometric and MRI parameters were also measured. RESULTS: First, a total of 32 patients (64.8±11.8 years old; BMI, 22.7±3.6 kg/m2) underwent pre-treatment sleep tests. The prevalence of OSA [apnea hypopnea index (AHI) ≥5] in these patients was 81.3% (26 patients) before treatment, and the mean AHI was 20.8±19.0 events/hr. Next, 21 patients performed a sleep test both before and after treatment. Regarding subjective symptoms, there were no significant differences in the Epworth Sleepiness Scale (ESS) (P=0.142) or Pittsburgh Sleep Quality Index (PSQI) (P=0.935) after treatment; however, the BMI and neck circumference significantly decreased after treatment (P<0.0001 and P=0.0001, respectively). The incidence of OSA in these patients was 81.0% (17 patients) before treatment and 85.7% (19 patients) after treatment (P=1.0). Overall, the AHI was not significantly different, changing only from 14.5 to 14.9 after treatment (P=0.147). The MRI parameters showed that the retroglossal pharyngeal area increased significantly after treatment (P=0.007). CONCLUSIONS: This study found that the prevalence of OSA before and after RT for HNC was higher than that in the normal population, despite a significant decrease in BMI and increase in the retroglossal pharyngeal area after treatment. We suggest that physicians who manage patients with HNC should consider the occurrence of OSA before and after treatment.

Severe obstructive sleep apnea after concurrent chemoradiotherapy for laryngeal and hypopharyngeal cancer managed by CPAP.

Concurrent chemoradiotherapy (CCRT) is one of the most promising treatments for advanced head and neck cancer (HNC). On the other hand, CCRT may induce severe edema in laryngo-pharyngeal structures in association with radiation. This is a report of a 66-year-old man with severe obstructive sleep apnea (OSA) associated with edema in laryngo-hypopharynx after CCRT for advanced laryngeal and hypopharyngeal cancer. Tracheostomy was avoided and OSA was controlled by continuous positive airway pressure (CPAP). Subjective symptoms of sleepiness were improved. Though laryngeal edema appeared during the course of CCRT in this case, OSA was not evaluated until snoring had been pointed out and he complained of sleepiness. CCRT for laryngeal and hypopharyngeal cancer have a risk of occurrence of OSA due to irreversible mucous edema in the upper airway. Patients for whom CCRT is planned should be informed about the occurrence of OSA before the treatment because symptoms associated with OSA can negatively impact not only the daytime quality of life but also increase the risk of cardiovascular events. The OSA treatment for post CCRT would be expected to have a positive impact on not only cardiovascular and metabolic systems but also on the cancer treatment survival rate.

Blockade of endoplasmic reticulum stress-induced cell death by Ureaplasma parvum vacuolating factor.

Previously, we found that Ureaplasma parvum internalised into HeLa cells and cytosolic accumulation of galectin-3. U. parvum induced the host cellular membrane damage and survived there. Here, we conducted vesicular trafficking inhibitory screening in yeast to identify U. parvum vacuolating factor (UpVF). U. parvum triggered endoplasmic reticulum (ER) stress and upregulated the unfolded protein response-related factors, including BiP, P-eIF2 and IRE1 in the host cells, but it blocked the induction of the downstream apoptotic factors. MicroRNA library screening of U. parvum-infected cells and UpVF-transfected cells identified miR-211 and miR-214 as the negative regulators of the apoptotic cascade under ER stress. Transient expression of UpVF induced HeLa cell death with intracellular vacuolization; however, some stable UpVF transformant survived. U. parvum-infected cervical cell lines showed resistance to actinomycin D, and UpVF stable transformant cell lines exhibited resistance to X-ray irradiation, as well as cisplatin and paclitaxel. UpVF expressing cervical cancer xenografts in nude mice also acquired resistance to cisplatin and paclitaxel. A mycoplasma expression vector based on Mycoplasma mycoides, Syn-MBA (multiple banded antigen)-UpVF, reduced HeLa cell survival compared with that of Syn-MBA after 72 hr of infection. These findings together suggest novel mechanisms for Ureaplasma infection and the possible implications for cervical cancer malignancy. TAKE AWAYS: • Ureaplasmal novel virulence factor, UpVF, was identified. • UpVF triggered ER stress but suppressed apoptotic cascade via miR-211 and -214. • UpVF conferred resistance to anticancer treatments both in vivo and in vitro. • Dual expression of MBA and UpVF in JCVI-syn3B showed host cell damage.

A Case of Aspiration Pneumonia Caused by Cerebrospinal Fluid Leaks Associated with Delayed Identification of Iatrogenic Skull Base Injury during Endoscopic Sinus Surgery.

Cerebrospinal fluid (CSF) leaks associated with endoscopic sinus surgery (ESS) are a rare complication affecting approximately 0.09% of patients. Although meningitis is a well-known complication of CSF leaks, the case we present is a rare and cautionary case of CSF leakage associated with ESS leading to aspiration pneumonia. A 43-year-old man with CSF leaks after ESS was referred to our hospital. After the operation, sometimes, he reported having a serous nasal discharge from the right side when he bent over, and he woke up choking on something every day. He also experienced headache, fever, fatigue, and cough. Interestingly, chest computed tomography (CT) showed a consolidation and ground-glass opacity in the posterior segments of the right upper lobes and superior segments of the bilateral lower lobes. These CT imaging findings were similar to those of aspiration pneumonia in bedridden patients who are always in a supine position. These findings suggest that CSF caused aspiration pneumonia. To the best of our knowledge, no case of aspiration pneumonia caused by CSF during endoscopic sinus surgery has been reported until now. If a patient with CSF leakage after ESS experiences fever, cough, or fatigue, physicians should consider aspiration pneumonia in addition to meningitis.

Dispersion of mean consecutive differences in single-fiber electromyography increases diagnostic sensitivity for myasthenia gravis.

INTRODUCTION: In this study we aimed to investigate the dispersion of mean consecutive difference (MCD) of concentric needle jitter studies of patients with myasthenia gravis (MG) and its effect on diagnostic sensitivity for MG. METHODS: One hundred fifty-three patients, including 76 patients with MG and 77 controls with possible MG who later received another diagnosis, underwent stimulated concentric needle jitter studies of the frontalis muscle. MCD mean, standard deviation (SD), and coefficient of variation (CV) were calculated. Diagnostic sensitivity and specificity were determined using receiver operating characteristic (ROC) analyses. RESULTS: MG patients showed a significantly greater MCD mean (MG: control, 26.3 µs; 13.5 µs [median]; P < .0001), MCD SD (MG: control, 12.8 µs; 5.1 µs [median]; P < .0001), and MCD CV (MG: control, 46.1; 37.5 [median]; P < .001) than those without MG. An ROC curve of SD showed a large area under the curve (0.88), and a cut-off value of 7.2 µs, which was calculated by maximum Youden index, exhibited high diagnostic sensitivity (86%) for MG. Combined MCD mean, outliers, and SD criteria showed higher sensitivity (88%) than conventional criteria alone (82%), at the expense of lower specificity. Five MG patients with normal MCD mean and abnormal MCD SD had only ocular symptoms. DISCUSSION: The dispersion of MCD as measured by MCD SD greater than 7.2 µs is significantly increased in patients with MG and may be a useful measure of abnormal jitter in the diagnosis of MG, especially for identifying patients with mild disease.

EGFR Protein Expression Relates with Tumor Histology, Methylation Status of EGFR and HPV16 E6 Viral Load in Oropharyngeal Carcinoma.

The epidermal growth factor receptor (EGFR) pathway is important in tumorigenesis of oropharyngeal carcinoma (OPC). However, the molecular mechanisms contributing to EGFR expression in OPC are not well-known. To detect relating factors and clinicopathological impact of EGFR protein expression in OPC, gene amplification/loss, point mutations including synonymous mutations, and promoter methylation of EGFR, and the viral genome load of human papillomavirus type 16 (HPV16)-E5, -E6, and -E7, after extracting HPV16-related OPCs with qPCR of HPV16-E6 and E7, were investigated in 74 OPC surgical cases, including 52 HPV-related (HPV-OPC) and 22 HPV-unrelated (nHPV-OPC). Immunohistochemical (IHC) data of EGFR expression (high, weak, and negative), validated by the qPCR of EGFR mRNA, were compared with molecular, viral, and clinicopathological data of patients. All nHPV-OPC cases were EGFR-IHC-high, whereas 21.2%, 65.4%, and 13.5% of HPV-OPC cases showed EGFR-IHC-high, -weak, -negative (p < 0.01), respectively. In HPV-OPC cases, EGFR-IHC-weak/negative status was related to promoter methylation of EGFR (p = 0.009), but not with gene amplification/loss or the point mutation of EGFR and was more often seen in HPV16-OPC cases (p = 0.049). Among HPV16-OPC cases, EGFR-IHC-weak/negative was related to high E6 expression. EGFR protein-loss was related to the tumor histology of non-keratinizing squamous cell carcinoma (SCC) (p = 0.035) but not with patient prognosis. In conclusion, decreased EGFR protein expression was more frequent in HPV-OPC than in nHPV-OPC and was related to EGFR methylation, infection of HPV16, and the viral genome load of HPV16-E6. Clinicopathologically, it was related to the tumor histology of non-keratinizing SCC.

Treatment response and prognosis of POEMS syndrome coexisting with Castleman disease.

POEMS (polyneuropathy, organomegaly, endocrinopathy monoclonal gammopathy, and skin changes) syndrome is occasionally associated with Castleman disease (CD) and their prognosis is considered as poorer than that in POEMS alone patients. To elucidate recent prognosis of POEMS syndrome coexisting with CD, we reviewed clinical data of 102 patients with POEMS syndrome treated at our institution between 2000 and 2018 and compared clinical characteristics, response to treatment, and prognosis between POEMS patients with biopsy-proven CD (POEMS-CD) and those without it. Fourteen POEMS-CD patients and 56 POEMS alone patients were identified, and the remaining 32 patients with unbiopsied lymphadenopathy were excluded. POEMS-CD patients significantly showed earlier onset and less severe neuropathic symptoms. Most of the POEMS-CD patients were treated with thalidomide and dexamethasone (n = 10, 71%), and subsequently received autologous stem cell transplantation (n = 6, 43%). Response to thalidomide was better in patients with POEMS-CD than those with POEMS alone (90% vs 43% clinical response, [p = .012]; 80% vs 45% normalization of serum VEGF levels, [p = .079]). The 10-year overall survival (95% confidence interval) was 89% (50-98%) in POEMS-CD patients and 61% (42-77%) in those with POEMS alone. POEMS syndrome associated with CD constitutes a subgroup of POEMS syndromes characterized by earlier onset, mild polyneuropathy, and favorable response to treatment. Recognition of this subgroup is significant for determination of therapeutic strategy.

Lenalidomide Treatment for Thalidomide-refractory POEMS Syndrome: A Prospective Single-arm Clinical Trial.

Objective A randomized controlled trial has shown the efficacy of thalidomide against polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome; however, there are still refractory patients. We studied the effects of lenalidomide, a derivative of thalidomide, on patients refractory to thalidomide. Methods This prospective single-arm trial evaluated the safety and efficacy of lenalidomide plus dexamethasone in refractory or recurrent patients with POEMS syndrome. The regimen was administered as six 28-day cycles with lenalidomide on days 1-21 (15 mg in cycle 1, and 25 mg in cycle 2-6) plus dexamethasone once a week (20 mg). The primary endpoints were the rate of reduction in the serum vascular endothelial growth factor (VEGF) level at 24 weeks and the incidence of adverse events. This trial was registered with ClinicalTrial.gov, NCT02193698. Results Between July 2014 and December 2015, five men were enrolled. All patients had been refractory to thalidomide plus dexamethasone for more than 24 weeks. The mean rate of reduction in the serum VEGF level at 24 weeks was 59.6%±8.3% (p=0.0003). The mean serum VEGF level decreased from 2,466±771 pg/mL to 974±340 pg/mL. No serious adverse events were observed, and all patients completed six cycles treatment. Discussion Lenalidomide is a therapeutic option for thalidomide-refractory patients with POEMS syndrome.

Prevalence, clinical profiles, and prognosis of POEMS syndrome in Japanese nationwide survey.

OBJECTIVE: To elucidate current epidemiological, clinical profiles, and treatment of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome. METHODS: We conducted a nationwide survey in 2015 using an established epidemiologic method. Data processing sheets were sent to all neurology and hematology specialist departments throughout Japan to identify patients with POEMS who were seen between April 2012 and March 2015. RESULTS: The estimated number of patients with POEMS was 392 (95% confidence interval [CI] 320-464), and the prevalence was 0.3 per 100,000. Detailed clinical profiles were available for 167 patients. Median age at onset was 54 years (range, 21-84 years), and the ratio of male to female was 1.5. All patients showed polyneuropathy; 89% had monoclonal plasma cell proliferation; and 84% had elevated vascular endothelial growth factor level in whom pretreatment serum or plasma was available (n = 87). Other common features were skin changes (84%), edema/effusion (81%), and organomegaly (76%). A total of 160 patients were treated with any of the following: radiation, corticosteroids, melphalan, thalidomide, lenalidomide, bortezomib, or autologous stem cell transplantation. Primary therapeutic options were thalidomide (n = 86) and autologous stem cell transplantation (n = 71). Thirty-nine patients (24%) were initially treated with corticosteroid alone. The 10-year overall survival was 93% (95% CI 86%-96%). DISCUSSION: This study showed current epidemiologic and clinical status of POEMS syndrome in Japan. A quarter of patients were still inadequately treated with corticosteroid alone, whereas either autologous stem cell transplantation or immunomodulatory drugs improved the prognosis.

The Human Microbiome and Cancer.

Recent scientific advances have significantly contributed to our understanding of the complex connection between the microbiome and cancer. Our bodies are continuously exposed to microbial cells, both resident and transient, as well as their byproducts, including toxic metabolites. Circulation of toxic metabolites may contribute to cancer onset or progression at locations distant from where a particular microbe resides. Moreover, microbes may migrate to other locations in the human body and become associated with tumor development. Several case-control metagenomics studies suggest that dysbiosis in the commensal microbiota is also associated with inflammatory disorders and various cancer types throughout the body. Although the microbiome influences carcinogenesis through mechanisms independent of inflammation and immune system, the most recognizable link is between the microbiome and cancer via the immune system, as the resident microbiota plays an essential role in activating, training, and modulating the host immune response. Immunologic dysregulation is likely to provide mechanistic explanations as to how our microbiome influences cancer development and cancer therapies. In this review, we discuss recent developments in understanding the human gut microbiome's relationship with cancer and the feasibility of developing novel cancer diagnostics based on microbiome profiles. Cancer Prev Res; 10(4); 226-34. ©2017 AACR.

Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor.

The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in ScPMA1 do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace ScPma1p from the plasma membrane. Using an in vitro cell-free assay, we demonstrate that KAE609 directly inhibits ScPma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a ScPma1p homology model identifies a binding mode that supports genetic resistance determinants and in vitro experimental structure-activity relationships in both P. falciparum and S. cerevisiae. This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity.

Genetic redundancy masks diverse functions of the tumor suppressor gene PTEN during C. elegans development.

Genetic redundancy is associated with a large percentage of genes. We investigated PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor gene functions that eluded single mutant analyses, using a Caenorhabditis elegans genome-wide screen. We show that at least 27 genes collaborate with the worm PTEN homolog daf-18 for various functions previously concealed by genetic redundancy, including embryogenesis, cuticle turnover, egg laying, and oocyte maturation. In one example, daf-18 appears to constitute a cell-autonomous germline signal that converges with a somatic gonad signal mediated by ceh-18 at a kinase inhibition. We provide evidence that daf-18 elicits some functions independent of the downstream gene daf-16.

Estrogen, insulin, and dietary signals cooperatively regulate longevity signals to enhance resistance to oxidative stress in mice.

To investigate the biological significance of a longevity mutation found in daf-2 of Caenorhabditis elegans, we generated a homologous murine model by replacing Pro-1195 of insulin receptors with Leu using a targeted knock-in strategy. Homozygous mice died in the neonatal stage from diabetic ketoacidosis, whereas heterozygous mice showed the suppressed kinase activity of the insulin receptor but grew normally without spontaneously developing diabetes during adulthood. We examined heterozygous insulin receptor mutant mice for longevity phenotypes. Under 80% oxygen, mutant female mice survived 33.3% longer than wild-type female mice, whereas mutant male mice survived 18.2% longer than wild-type male mice. These results suggested that mutant mice acquired more resistance to oxidative stress, but the benefit of the longevity mutation was more pronounced in females than males. Manganese superoxide dismutase activity in mutant mice was significantly upregulated, suggesting that the suppressed insulin signaling leads to an enhanced antioxidant defense. To analyze the molecular basis of the gender difference, we administered estrogen to mutant mice. It was found that the survival of mice under 80% oxygen was extended when they were administered estradiol. In contrast, mutant and wild-type female mice showed shortened survivals when their ovaries were removed. The influence of estrogen is remarkable in mutant mice compared with wild-type mice, suggesting that estrogen modulates insulin signaling in mutant mice. Furthermore, we showed additional extension of survival under oxidative conditions when their diet was restricted. Collectively, we show that three distinct signals; insulin, estrogen, and dietary signals work in independent and cooperative ways to enhance the resistance to oxidative stress in mice.

A Caenorhabditis elegans TGF-beta, DBL-1, controls the expression of LON-1, a PR-related protein, that regulates polyploidization and body length.

Using cDNA-based array analysis combined with double-stranded RNA interference (dsRNAi), we have identified yk298h6 as a target gene of Caenorhabditis elegans TGF-beta signaling. Worms overexpressing dbl-1, a TGF-beta ligand, are 16% longer than wild type. Array analysis shows yk298h6 to be one of several genes suppressed in such worms. Disruption of yk298h6 function by dsRNAi also resulted in long worms, suggesting that it is a negative regulator of body length. yk298h6 was then mapped to, and shown to be identical to, lon-1, a known gene that affects body length. lon-1 encodes a 312 amino acid protein with a motif sequence that is conserved from plants to humans. Expression studies confirm that LON-1 is repressed by DBL-1, suggesting that LON-1 is a novel downstream component of the C.elegans TGF-beta growth regulation pathway. Consistent with this, LON-1 is expressed mainly in the larval and adult hypodermis and has dose-dependent effects on body length associated with changes in hypodermal ploidy, but not hypodermal cell proliferation.