Vogt-Koyanagi-Harada disease developed during chemotherapy for Hodgkin lymphoma: a case report.

BACKGROUND: Ocular manifestations are known for non-Hodgkin lymphoma, but are rare for Hodgkin lymphoma. We report a case of Vogt-Koyanagi-Harada (VKH) disease presenting as serous retinal detachment and uveitis in both eyes in a child undergoing chemotherapy for Hodgkin lymphoma. CASE PRESENTATION: The patient was a 7-year-old boy with stage IIB Hodgkin lymphoma (nodular lymphocyte predominant type) who was undergoing chemotherapy, including 2 cycles of the OEPA regimen and 1 cycle of the COPDAC regimen. Two days after the end of the COPDAC regimen, the patient complained of headache and of blurred and decreased vision in both eyes. On the basis of optic symptoms, such as uveitis and serous retinal detachment in both eyes, increased cell counts in cerebrospinal fluid, and positivity for human leukocyte antigen (HLA)-DR4 in peripheral blood cells, incomplete VKH disease was diagnosed. Intravenous treatment with high-dose prednisolone (60mg/m2/day) for 7 days improved both visual acuity and serous retinal detachment and enabled the remains of the COPDAC chemotherapy cycle to be administered. With prednisolone treatment, visual acuity improved from 20/500 to 20/20 in the right eye and from 20/63 to 20/25 in the left eye. Because multiple vitiligo lesions later appeared in the abdomen, complete VKH disease was finally diagnosed. CONCLUSION: The onset of VKH disease occurred during chemotherapy for Hodgkin lymphoma. The patient was HLA-DR4-positive and might have had a predisposition to develop autoimmune diseases, including VKH disease. However, the anticancer drugs administered to this patient have not been reported to cause uveitis. Whether Hodgkin lymphoma triggered the development of VKH remains unclear. Early diagnosis of VKH disease and prompt treatment with high-dose prednisone enabled the patient to maintain good visual function despite chemotherapy for Hodgkin lymphoma.

[Real-World Experience and Complications with Intermittent Balloon Catheters : A Predictor Analysis].

Intermittent balloon catheterization with a reusable and temporary balloon catheter that could be implanted and removed by the patient was developed in Japan in 1995. Although the intermittent balloon catheter has the potential to improve the patient's quality of life (QOL), appropriate information and guidelines are needed to prevent complications such as hematuria and urinary tract infection. This study aimed to assess the real-world practice, complications, and problems associated with the use of intermittent balloon catheters and provide useful information for future medical care. We conducted a questionnaire survey on patients with spinal cord lesions who currently use or have used intermittent balloon catheters in the past. Seventy-six patients with spinal cord lesions who visited Kanagawa Rehabilitation Hospital from August 2020 to March 2021 and gave consent for participating in this study were included. QOL scores before and after intermittent balloon catheter use showed significant improvement after use. Forty-six of the 76 (61.3%) patients had complications. Overall complications were significantly associated with male sex and possibly linked to non-traumatic spinal cord lesions.

Clinical guidelines for the diagnosis and treatment of lower urinary tract dysfunction in patients with spinal cord injury.

The present article is an abridged English translation of the Japanese clinical guidelines for the diagnosis and treatment of lower urinary tract dysfunction in patients with spinal cord injury updated as of July 2019. The patients are adult spinal cord injured patients with lower urinary tract dysfunction; special consideration of pediatric and elderly populations is presented separately. The target audience is healthcare providers who are engaged in the medical care of patients with spinal cord injury. The mandatory assessment includes medical history, physical examination, frequency-volume chart, urinalysis, blood chemistry, transabdominal ultrasonography, measurement of post-void residual urine, uroflowmetry and video-urodynamic study. Optional assessments include questionnaires on the quality of life, renal scintigraphy and cystourethroscopy. The presence or absence of risk factors for renal damage and symptomatic urinary tract infection affects urinary management, as well as pharmacological treatments. Further treatment is recommended if the maximum conservative treatment fails to improve or prevent renal damage and symptomatic urinary tract infection. In addition, management of urinary incontinence should be considered individually in patients with risk factors for urinary incontinence and decreased quality of life.

[Exploratory Study of the Risk Factors for Acute Kidney Injury in the Cisplatin Combination Chemotherapy for Solid Cancer].

In the present study, we investigated the rate of cisplatin(CDDP)-induced acute kidney injury(CIA)and examined its association with various clinical factors in the combination therapy with CDDP for solid cancers. A total of 726 cases of solid cancer that had been indicated for the CDDP combination regimen from December 2012 to December 2013 were enrolled. CIA occurred in 48 cases(6.6%). The multivariate analysis revealed that diabetes, the regular use of non-steroidal anti- inflammatory drugs(NSAIDs), first dose of CDDP, and severe hyponatremia(≥Grade 3)within one week after CDDP administration were significantly associated with an increased risk for CIA, whereas magnesium supplementation was associated with a significantly reduced risk for CIA. Particularly, diabetes and cardiovascular disease were identified as risk factors for CIA in patients with esophageal and head and neck cancers. Based on the results of this survey, it is important to formulate preventive measures, evaluate risk factors, and respond rapidly.

Roles of the PDZ-binding motif of HPV 16 E6 protein in oncogenic transformation of human cervical keratinocytes.

The high-risk human papillomavirus E6 proteins have been shown to interact with and lead to degradation of PDZ-domain-containing proteins through its carboxy-terminal motif. This PDZ-binding motif plays important roles in transformation of cultured cells and carcinogenesis of E6-transgenic mice. However, its biological effects on the natural host cells have not been elucidated. We have examined its roles in an in vitro carcinogenesis model for cervical cancer, in which E6 and E7 together with activated HRAS (HRASG12V ) can induce tumorigenic transformation of normal human cervical keratinocytes. In this model, E6Δ151 mutant, which is defective in binding to PDZ domains, almost lost tumorigenic ability, whereas E6SAT mutant, which is defective in p53 degradation showed activity close to wild-type E6. Interestingly, we found decreased expression of PAR3 in E6-expressing cells independently of E6AP, which has not been previously recognized. Therefore, we knocked down several PDZ-domain containing proteins including PAR3 in human cervical keratinocytes expressing E7, HRASG12V and E6Δ151 to examine whether depletion of these proteins can restore the tumorigenic ability. Single knockdown of SCRIB, MAGI1 or PAR3 significantly but partially restored the tumorigenic ability. The combinatorial knockdown of SCRIB and MAGI1 cooperatively restored the tumorigenic ability, and additional depletion of PAR3 further enhanced the tumorigenic ability surpassing that induced by wild-type E6. These data highlight the importance of the carboxy-terminal motif of the E6 protein and downregulation of PAR3 in tumorigenic transformation of human cervical keratinocytes.

Activation of NF-κB by human papillomavirus 16 E1 limits E1-dependent viral replication through degradation of E1.

UNLABELLED: NF-κB is a family of transcription factors that regulate gene expression involved in many processes, such as the inflammatory response and cancer progression. Little is known about associations of NF-κB with the human papillomavirus (HPV) life cycle. We have developed a tissue culture system to conditionally induce E1-dependent replication of the human papillomavirus 16 (HPV16) genome in human cervical keratinocytes and found that expression of HPV16 E1, a viral helicase, results in reduction of IκBα and subsequent activation of NF-κB in a manner dependent on helicase activity. Exogenous expression of a degradation-resistant mutant of IκBα, which inhibits the activation of NF-κB, enhanced E1-dependent replication of the viral genome. Wortmannin, a broad inhibitor of phosphoinositide 3-kinases (PI3Ks), and, to a lesser extent, VE-822, an ATR kinase inhibitor, but not KU55933, an ATM kinase inhibitor, suppressed the activation of NF-κB and augmented E1-dependent replication of the HPV16 genome. Interestingly, the enhancement of E1-dependent replication of the viral genome was associated with increased stability of E1 in the presence of wortmannin as well as the IκBα mutant. Collectively, we propose that expression of E1 induces NF-κB activation at least in part through the ATR-dependent DNA damage response and that NF-κB in turn limits E1-dependent replication of HPV16 through degradation of E1, so that E1 and NF-κB may constitute a negative feedback loop. IMPORTANCE: A major risk factor in human papillomavirus (HPV)-associated cancers is persistent infection with high-risk HPVs. To eradicate viruses from infected tissue, it is important to understand molecular mechanisms underlying the establishment and maintenance of persistent infection. In this study, we obtained evidence that human papillomavirus 16 (HPV16) E1, a viral DNA helicase essential for amplification of the viral genomes, induces NF-κB activation and that this limits E1-dependent genome replication of HPV16. These results suggest that NF-κB mediates a negative feedback loop to regulate HPV replication and that this feedback loop could be associated with control of the viral copy numbers. We could thus show for the first time that NF-κB activity is involved in the establishment and maintenance of persistent HPV infection.

[Associations between Clinical Factors and Acute Renal Failure Due to Cisplatin Combination Chemotherapy for Lung Cancer].

In this study, we investigated the clinical factors associated with acute kidney injury (AKI) due to combination therapy with cisplatin (CDDP) for treating lung cancer. We classified cases according to the presence or absence of adequate hydration and magnesium(Mg)administered above the regulations of the registered regimen to evaluate the effect due to differences in hydration on AKI. We also investigated clinical factors before and after administration of CDDP in each case group, and examined their association with AKI. Seventy-four patients with lung cancer that were indicated for treatment with a CDDP combination regimen between December 2012 and April 2013 were studied. The patients whose conditions progressed to AKI of Bgrade 2 accounted for 0% (0/33) in the Mg administration group and 7.3%(3/41)in the Mg non-administration group. In particular, 2 cases of serious AKI (grade 4) were observed in the Mg non-administration without additional hydration group. When compared with other groups, a high antiemetic rate and favorable urine volume were observed in the Mg administration with additional hydration group. In the patients with AKI, many developed hyponatremia of Bgrade 3 within 1 week after administration of CDDP. Although Mg administration and ample hydration seem to be effective measures to deal with CDDP-caused AKI, comprehensive monitoring, including antiemesis therapy, after CDDP administration and correction of electrolytes is important.

Yeast transformation mediated by Agrobacterium strains harboring an Ri plasmid: comparative study between GALLS of an Ri plasmid and virE of a Ti plasmid.

Agrobacterium strains containing a Ti plasmid can transfer T-DNA not only to plants but also to fungi, including the yeast Saccharomyces cerevisiae. However, no Agrobacterium strain harboring an Ri plasmid has been evaluated in fungal transformation. Some Ri plasmids have GALLS , instead of virE1 and virE2. GALLS protein can functionally substitute in plant transformation for a structurally different protein VirE2. In this study, we compared the yeast transformation ability among Agrobacterium donors: a strain containing a Ti plasmid, strains harboring either an agropine-type or a mikimopine-type Ri plasmid, and a strain having a modified Ri plasmid supplemented with a Ti plasmid type virE operon. Agrobacterium strains possessing GALLS transformed yeast cells far less efficiently than the strain containing virE operon. Production of GALLS in recipient yeast cells improved the yeast transformation mediated by an Agrobacterium strain lacking neither GALLS nor virE operon. A reporter assay to detect mobilization of the proteins fused with Cre recombinase revealed that VirE2 protein is much more abundant in yeast cells than GALLS. Based on these results, we concluded that the low yeast transformability mediated by Agrobacterium strains having the Ri plasmid is because of low amount of mobilized GALLS in yeast cells.

Transkingdom genetic transfer from Escherichia coli to Saccharomyces cerevisiae as a simple gene introduction tool.

Transkingdom conjugation (TKC) permits transfer of DNA from bacteria to eukaryotic cells using a bacterial conjugal transfer system. However, it is not clear whether the process of DNA acceptance in a recipient eukaryote is homologous to the process of conjugation between bacteria. TKC transfer requires mobilizable shuttle vectors that are capable of conjugal transfer and replication in the donor and recipient strains. Here, we developed TKC vectors derived from plasmids belonging to the IncP and IncQ groups. We also investigated forms of transfer of these vectors from Escherichia coli into Saccharomyces cerevisiae to develop TKC as a simple gene introduction method. Both types of vectors were transferred precisely, conserving the origin of transfer (oriT) sequences, but IncP-based vectors appeared to be more efficient than an IncQ-based vector. Interestingly, unlike in agrobacterial T-DNA (transfer DNA) transfer, the efficiency of TKC transfer was similar between a wild-type yeast strain and DNA repair mutants defective in homologous recombination (rad51Δ and rad52Δ) or nonhomologous end joining (rad50Δ, yku70Δ, and lig4Δ). Lastly, a shuttle vector with two repeats of IncP-type oriT (oriT(P)) sequences flanking a marker gene was constructed. TKC transfer of this vector resulted in precise excision of both the oriT(P) loci as well as the marker gene, albeit at a low frequency of 17% of all transconjugants. This feature would be attractive in biotechnological applications of TKC. Taken together, these results strongly suggest that in contrast to agrobacterial T-DNA transfer, the circularization of vector single-stranded DNA occurs either before or after transfer but requires a factor(s) from the donor. TKC is a simple method of gene transfer with possible applications in yeast genetics and biotechnology.

Ramelteon combined with an α1-blocker decreases nocturia in men with benign prostatic hyperplasia.

BACKGROUND: Nocturia is defined as waking one or more times during the night due to the urge to void. Recently, the effectiveness of several sedatives and analgesics for nocturia has been reported. We herein investigated the effects of ramelteon, an antioxidant and sleep inducer, on nocturia unresponsive to α1-blocker monotherapy in males with lower urinary tract symptoms (LUTS) as a pilot study. METHODS: Subjects were 19 patients who had LUTS suggestive of benign prostate hyperplasia, received α1-blockers (tamsulosin, silodosin, or naftopidil), and continued to have two or more episodes of nocturia per night before starting ramelteon. Ramelteon at 8 mg once daily for one month was added to the α1-blocker. A self-administered questionnaire including the International Prostate Symptom Score (IPSS), quality of life (QoL) index, Overactive Bladder Symptom Score (OABSS), and Nocturia Quality-of-Life Questionnaire (N-QOL) were assessed before and one month after starting ramelteon. RESULTS: The mean score on IPSS question 7 (nocturia) decreased significantly from 2.88 before starting ramelteon to 2.41 one month after starting the medication (P = 0.03). The mean total OABSS decreased significantly from 6.31 to 5.38 (P = 0.03), and the mean for OABSS question 2 (nighttime frequency of nocturia) also significantly decreased from 2.63 to 2.13 (P = 0.01). The mean total N-QOL score did not change significantly. Two patients had dizziness; the remaining patients had no adverse drug-related events. CONCLUSIONS: Ramelteon in combination with an α1-blocker could be a treatment option for reducing nocturia in men with BPH.

Potential roles of hyperbaric oxygenation in the treatments of brain tumors.

Over the past 50 years hyperbaric oxygen (HBO2) therapy has been used in a wide variety of medical conditions, and one of them is cancer. Many clinical studies have been conducted to evaluate potential therapeutic effects of HBO2 as a part of cancer treatment. This review briefly summaries the potential role of HBO2 therapy in the treatment of malignant tumors and radiation injury of the brain. HBO2 therapy is used for the enhancement of radiosensitivity in the treatment of some cancers, including malignant brain tumors. Radiotherapy within 15 minutes following HBO2 exposure, a relatively new treatment regimen, has been studied at several institutes and has demonstrated promising clinical results for malignant gliomas of the brain. HBO2 therapy also increases sensitivity to some antineoplastic agents; non-randomized clinical trials using carboplatin-based chemotherapy combined with HBO2 show a significant advantage in survival for recurrent malignant gliomas. The possibilities of combining HBO2 therapy with radiotherapy and/or chemotherapy to overcome newly diagnosed and recurrent malignant gliomas deserve extensive clinical trials. HBO2 therapy also shows promising potential for the treatment and/or prevention of radiation injury of the brain after stereotactic radiosurgery for brain lesions. The possibilities with HBO2 to enhance the therapeutic effect of irradiation per se, and to even increase the radiation dose if there are ways to combat the side effects, should boost new scientific interest into the whole field of oncology looking for new armamentaria to fight cancer.

[A case of aggressively growing bladder cancer in patient with long-term cystostomy due to spinal cord injury].

The patient was a 38-year-old man. A cystostomy catheter had been inserted when he was 23 years of age for neuropathic bladder due to cervical spinal cord injury at 20 years of age. Purulent discharge from around the cystotomy had continued for approximately 4 months. Examination revealed the formation of a subcutaneous tumor around the cystostomy, with elevated carcinoembryonic antigen (CEA) levels (459.4 ng/ml) in the blood. Urothelial carcinoma was detected using open biopsy. It was considered that primary urothelial carcinoma of the bladder had progressed along the cystostomy, and clinical stage 4 cT4N2M0 was diagnosed, with intrapelvic lymph node metastasis evident on imaging. Four courses of gemcitabine-cisplatin chemotherapy were administered; a partial response was obtained, after which cystectomy and ileal conduit formation were performed with the main aim of improving difficulty in urination. However, retroperitoneal lymph node and liver metastases were observed 1 month postoperation with rapid enlargement; the patient died approximately 2 months after the surgery. The CEA level was observed to be 18,998 ng/ml before he died. Here, we have reported this case with a discussion of the literature concerning the association between long-term indwelling catheter in patients with spinal cord injury and the development of bladder cancer.

In Vitro and In Vivo Antidiabetic Effects of Acidic Polysaccharides Extracted from Seaweeds.

We evaluated the α-glucosidase inhibitory activity of acidic polysaccharides (APs) extracted from seaweeds in vitro and their antidiabetic effects in KK-Ay mice. The α-glucosidase inhibitory activity of APs was differed among various seaweed species. Some APs showed higher inhibitory activity in the high-molecular-weight range, whereas others showed higher inhibitory activity in the low-molecular-weight range. Mice were fed low-molecular-weight APs from hijiki (LMWAPsH), which showed higher α-glucosidase inhibitory activity. Fasting blood glucose and HbA1c levels were significantly lower in the LMWAPsH group than in the control group (p<0.01). The calculated homeostasis model assessment-insulin resistance in the LMWAPsH group was significantly lower than that in the control group (p<0.05). These results suggest that α-glucosidase inhibitory activity differ among APs from different seaweed species, and each have an optimum molecular-weight range, and that LMWAPsH prevents the hyperglycemia in KK-Ay mice.

An in vitro carcinogenesis model for cervical cancer harboring episomal form of HPV16.

Deregulated expression of viral E6 and E7 genes often caused by viral genome integration of high-risk human papillomaviruses (HR-HPVs) into host DNA and additional host genetic alterations are thought to be required for the development of cervical cancer. However, approximately 15% of invasive cervical cancer specimens contain only episomal HPV genomes. In this study, we investigated the tumorigenic potential of human cervical keratinocytes harboring only the episomal form of HPV16 (HCK1T/16epi). We found that the HPV16 episomal form is sufficient for promoting cell proliferation and colony formation of parental HCK1T cells. Ectopic expression of host oncogenes, MYC and PIK3CAE545K, enhanced clonogenic growth of both early- and late-passage HCK1T/16epi cells, but conferred tumor-initiating ability only to late-passage HCK1T/16epi cells. Interestingly, the expression levels of E6 and E7 were rather lower in late-passage than in early-passage cells. Moreover, additional introduction of a constitutively active MEK1 (MEK1DD) and/or KRASG12V into HCK1T/16epi cells resulted in generation of highly potent tumor-initiating cells. Thus an in vitro model for progression of cervical neoplasia with episomal HPV16 was established. In the model, constitutively active mutation of PIK3CA, PIK3CAE545K, and overexpression of MYC, in the cells with episomal HPV16 genome were not sufficient, but an additional event such as activation of the RAS-MEK pathway was required for progression to tumorigenicity.

A critical role of MYC for transformation of human cells by HPV16 E6E7 and oncogenic HRAS.

Human papillomaviruses (HPVs) are the primary causal agents for development of cervical cancer, and deregulated expression of two viral oncogenes E6 and E7 is considered to contribute to disease initiation. Recently, we have demonstrated that transduction of oncogenic HRAS (HRAS(G12V)) and MYC together with HPV16 E6E7 is sufficient for tumorigenic transformation of normal human cervical keratinocytes (HCKs). Here, we show that transduction of HRAS(G12V) on the background of E6E7 expression causes accumulation of MYC protein and tumorigenic transformation of not only normal HCKs but also other normal primary human cells, including tongue keratinocytes and bronchial epithelial cells as well as hTERT-immortalized foreskin fibroblasts. Subcutaneous transplantation of as few as 200 HCKs expressing E6E7 and HRAS(G12V) resulted in tumor formation within 2 months. Dissecting RAS signaling pathways, constitutively active forms of AKT1 or MEK1 did not result in tumor formation with E6E7, but tumorigenic transformation was induced with addition of MYC. Increased MYC expression endowed resistance to calcium- and serum-induced terminal differentiation and activated the mammalian target of rapamycin (mTOR) pathway. An mTOR inhibitor (Rapamycin) and MYC inhibition a level not affecting proliferation in culture both markedly suppressed tumor formation by HCKs expressing E6E7 and HRAS(G12V). These results suggest that a single mutation of HRAS could be oncogenic in the background of deregulated expression of E6E7 and MYC plays a critical role in cooperation with the RAS signaling pathways in tumorigenesis. Thus inhibition of MYC and/or the downstream mTOR pathway could be a therapeutic strategy not only for the MYC-altered but also RAS-activated cancers.

Ureteral stent exchange under fluoroscopic guidance using the crochet hook technique in women.

PURPOSE: We developed a method for ureteral stent exchange in female patients under fluoroscopic guidance using a crochet hook technique (CHEX). PATIENTS AND METHODS: A total of 45 female patients (51 stents) underwent exchange of ureteral stents. In these patients, 21 ureteral stents were exchanged using CHEX. All procedures were carried out with the patients under conscious sedation. At the time of the procedures, we extracted the ureteral stent from the external urethral orifice using CHEX under fluoroscopic guidance and inserted the new stent under fluoroscopic guidance without cystoscopy. RESULTS: 20 of the 21 stents (95.2%) were successfully exchanged. Ureteral stent exchange using CHEX was unsuccessful in 1 patient, including migration to the ureter. CONCLUSIONS: Ureteral stent exchange using a crochet hook is easy, safe and cost-effective. This technique was also easy to learn.

Effective use of a new quality and safety checklist for the steady and safe supply of fluorine-18 fluorodeoxyglucose for positron emission tomography/computed tomography.

Fluorine-18-fluorodeoxyglucose ((18)F-FDG ) positron emission tomography/computed tomography (PET/CT) with the in-hospital synthesis of (18)F-FDG was initiated in our hospital on April 1, 2010. We aim to perform stable supply of (18)F-FDG for patients and to avoid unnecessary radiation exposure due to mis-preparation of (18)F-FDG. Pharmacists perform quality control tests to determine whether (18)F-FDG meets official regulations. After the quality control test, we give (18)F-FDG that conforms to these standards to patients to conduct (18)F-FDG PET/CT. After a quality control test is initiated, various problems can occur including leakage and staff radiation exposure. We recorded daily radiation exposure in the hot lab and calculated the average daily radiation exposure on a monthly basis for a period of one year. We developed a checklist to safely and quickly synthesize(18)F-FDG for patients. The total radiation exposure of the three pharmacists was 394, 180, and 214µSv/y and overall lower than the occupational maximum values (≤50mSv/year and ≤100mSv/5years for males). In conclusion, using the new checklist, pharmacists and the operator of the Sumitomo Heavy Industries Accelerator service Co., Ltd. were able to practice their daily work effectively during the synthesis and quality control testing of (18)F-FDG. Notably the usual radiation exposure reported in the present study was quite lower than the allowable maximum.

[Three dysuria adults without continuous medical treatment after surgery for spina bifida in infancy].

We encountered three patients with dysuria who had undergone spinal surgery for spina bifida during infancy. The patients presented with mental disability and dysbasia. Difficulty in urination, urinary incontinence, and a residual sensation of urine were resolved through intermittent self-catheterization in all patients. It was speculated that treatment for dysuria in these patients was delayed because they were not aware of its association with their condition during infancy, dysuria was relatively mild, and they had no history of febrile urinary tract infection. It is important for attending physicians to explain to parents of such infants the possible association of spina bifida with the future risk of dysuria, and to consider long-term follow-up to monitor their outcome.