Three Case Reports of Adult-onset Still Disease Associated with Breast Implantation.

Autoimmune syndrome induced by adjuvants (ASIA) is an uncommon clinical condition reported by Shoenfeld et al. Although this syndrome is not scientifically validated, numerous reports on it have been published, and the manifestations are postulated to be diverse, including generalized symptoms such as chronic fatigue, myalgia, arthralgia, or dry mouth, induced by exogenous substances, specifically adjuvants, which can encompass vaccines, organisms, and silicone. Concurrently, adult-onset Still disease (AOSD) is also an infrequent ailment, characterized by spiking fever, arthritis, skin rash, lymphadenopathy, and serositis. Although the precise pathogenesis remains incompletely understood, some case reports suggest that ASIA may be at the root of AOSD development with the same instigator. In this context, we present three cases of patients diagnosed with AOSD, which possibly could be considered an association with ASIA, years after undergoing breast reconstruction with silicone breast implants. In one case, the patient solely received medical treatment due to her refusal to have the implant removed, resulting in multiple flares and severe complications related to glucocorticoid therapy. Conversely, in the other two cases, a combination of immunosuppressive therapy and silicone breast implant explantation led to the complete resolution of clinical symptoms. To the best of our knowledge, there are only 10 documented case reports of AOSD associated with silicone breast implants insertion. We believe this report serves as a complementary addition to prior research and offers further insights into the ongoing debate about whether explantation should be carried out early in the clinical course or not.

Leukocytoclastic Vasculitis Secondary to Severe Fever with Thrombocytopenia Syndrome.

A 75-year-old Japanese woman was admitted to our hospital and diagnosed with hemophagocytic syndrome secondary to severe fever with thrombocytopenia syndrome (SFTS). The patient recovered after steroid treatment and was discharged from the hospital. Two months after the onset of SFTS, the patient revisited our hospital with a fever and palpable purpura on the extremities and trunk. A histopathological examination of a punch skin biopsy specimen revealed leukocytoclastic vasculitis. Symptomatic treatment resolved the fever, and palpable purpura disappeared 14 days later. No other clinical symptoms or abnormal immunological findings contributed to the leukocytoclastic vasculitis. This is the first report to describe leukocytoclastic vasculitis secondary to SFTS, highlighting a potential association between the two conditions.

KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway.

Here, we investigated the detailed molecular oncogenic mechanisms of a novel receptor tyrosine kinase (RTK) fusion, KLC1-ROS1, with an adapter molecule, KLC1, and an RTK, ROS1, discovered in pediatric glioma, and we explored a novel therapeutic target for glioma that possesses oncogenic RTK fusion. When wild-type ROS1 and KLC1-ROS1 fusions were stably expressed in the human glioma cell lines A172 and U343MG, immunoblotting revealed that KLC1-ROS1 fusion specifically activated the JAK2-STAT3 pathway, a major RTK downstream signaling pathway, when compared with wild-type ROS1. Immunoprecipitation of the fractionated cell lysates revealed a more abundant association of the KLC1-ROS1 fusion with JAK2 than that observed for wild-type ROS1 in the cytosolic fraction. A mutagenesis study of the KLC1-ROS1 fusion protein demonstrated the fundamental roles of both the KLC1 and ROS1 domains in the constitutive activation of KLC1-ROS1 fusion. Additionally, in vitro assays demonstrated that KLC1-ROS1 fusion upregulated cell proliferation, invasion, and chemoresistance when compared to wild-type ROS1. Combination treatment with the chemotherapeutic agent temozolomide and an inhibitor of ROS1, JAK2, or a downstream target of STAT3, demonstrated antitumor effects against KLC1-ROS1 fusion-expressing glioma cells. Our results demonstrate that KLC1-ROS1 fusion exerts oncogenic activity through serum-independent constitutive activation, resulting in specific activation of the JAK-STAT pathway. Our data suggested that molecules other than RTKs may serve as novel therapeutic targets for RTK fusion in gliomas.

Dietary habits in Japanese patients with palmoplantar pustulosis.

Palmoplantar pustulosis (PPP) is a chronic dermatitis characterized by sterile intra-epidermal pustules associated with erythema and scales on the palms and soles. Tumor necrosis factor (TNF)-α/interleukin (IL)-23/IL-17 inflammatory pathway may be involved in the pathogenesis of PPP, and the skin lesions manifest the enhanced expression of IL-8 in keratinocytes and increased levels of antimicrobial peptide cathelicidin, leucine leucine-37 in vesicles/pustules. Some PPP patients are associated with arthro-osteitis, called pustulotic arthro-osteitis (PAO). Dietary habits may modulate the pathogenesis of PPP, however, have not been investigated in PPP patients. We evaluated dietary habits in adult Japanese PPP patients, using a validated, brief-type self-administered diet history questionnaire, and compared their results to those of age- and sex-matched healthy controls. The results in PPP patients with PAO were compared to those in the patients without. Japanese PPP patients showed higher body mass indices (BMIs), higher intakes of pulses and sugar/sweeteners, and lower intake of vitamin A, compared to those of healthy controls. The bivariate and multivariable logistic regression analysis showed that PPP was associated with high BMI, high intake of pulses, and low intake of vitamin A. The sodium intake and BMI were positively correlated with palmoplantar pustulosis area and severity index (PPPASI). The linear multivariate regression analysis revealed that sodium intake and BMI were predictors of PPPASI. The age and sodium intake in the patients with PAO were lower than those in the patients without. The bivariate and multivariable logistic regression analysis showed that PAO was negatively associated with age and sodium intake. This is the first study showing the dietary habits in patients with PPP. Further studies should clarify if the dietary intervention to correct the BMI and sodium intake will alter the progress of PPP.

Enhanced Malignant Phenotypes of Glioblastoma Cells Surviving NPe6-Mediated Photodynamic Therapy are Regulated via ERK1/2 Activation.

To manage refractory and invasive glioblastomas (GBM)s, photodynamic therapy (PDT) using talaporfin sodium (NPe6) (NPe6-PDT) was recently approved in clinical practice. However, the molecular machineries regulating resistance against NPe6-PDT in GBMs and mechanisms underlying the changes in GBM phenotypes following NPe6-PDT remain unknown. Herein, we established an in vitro NPe6-mediated PDT model using human GBM cell lines. NPe6-PDT induced GBM cell death in a NPe6 dose-dependent manner. However, this NPe6-PDT-induced GBM cell death was not completely blocked by the pan-caspase inhibitor, suggesting NPe6-PDT induces both caspase-dependent and -independent cell death. Moreover, treatment with poly (ADP-ribose) polymerase inhibitor blocked NPe6-PDT-triggered caspase-independent GBM cell death. Next, it was also revealed resistance to re-NPe6-PDT of GBM cells and GBM stem cells survived following NPe6-PDT (NPe6-PDT-R cells), as well as migration and invasion of NPe6-PDT-R cells were enhanced. Immunoblotting of NPe6-PDT-R cells to assess the behavior of the proteins that are known to be stress-induced revealed that only ERK1/2 activation exhibited the same trend as migration. Importantly, treatment with the MEK1/2 inhibitor trametinib reversed resistance against re-NPe6-PDT and suppressed the enhanced migration and invasion of NPe6-PDT-R cells. Overall, enhanced ERK1/2 activation is suggested as a key regulator of elevated malignant phenotypes of GBM cells surviving NPe6-PDT and is therefore considered as a potential therapeutic target against GBM.

Validation study of the modified HEART and HEAR scores in patients with chest pain who visit the emergency department.

AIM: To validate the efficacy of the history, electrocardiogram, age, risk factors, and troponin (HEART) and history, electrocardiogram, age, and risk factors (HEAR) scores in a Japanese cohort. METHODS: We used the data of patients who visited our emergency department between 1 December, 2015 and 31 May, 2017. Patients aged ≥20 years who presented with non-traumatic and undifferentiated chest pain were eligible for the study. On the basis of the total score, the patients were stratified as low risk (HEART and HEAR scores of 0-3), intermediate risk (HEART and HEAR scores of 4-6), and high risk (HEART score of 7-10 and HEAR score of 7-8). The major adverse cardiac events (MACEs) that occurred within 6 weeks were investigated, and the diagnostic value and efficiency of both scores were analyzed. RESULTS: In total, 132 patients were included in the HEART score analysis and 220 patients in the HEAR score analysis. The incidence rates of MACEs in patients with low, intermediate, and high risks were 0%, 23.2%, and 63.6% in the HEART score analysis and 4.7%, 22.9%, and 62.5% in the HEAR score analysis (P < 0.001), respectively. The identification of MACEs in low-risk patients had a negative predictive value in the HEART score (1.00; 95% confidence interval, 0.90-1.00) and HEAR score (0.95; 95% confidence interval, 0.89-0.99) analyses. CONCLUSION: The modified HEART and HEAR scores were effective in identifying patients with chest pain who are at low risk of MACEs at an emergency department in Japan.

[Hemifacial Spasm Caused by Vertebral Artery Fusiform Aneurysm and the Anterior Inferior Cerebellar Artery].

We report a case of hemifacial spasm in which the root exit zone(REZ)of the facial nerve was compressed by both the vertebral artery(VA)aneurysm and the anterior interior cerebellar artery(AICA). A 60-year-old female had suffered left hemifacial spasm for 2 years. Three-dimensional rotational angiography with selective arterial infusion of contrast medium(3DRA-IA)revealed that a distal part of the left AICA looping at the cisternal region was contacting the dome of the left VA aneurysm, although other imaging modalities did not show the exact course of the ipsilateral AICA. Constructive interference steady state magnetic resonance imaging revealed that both the left VA aneurysm and the left AICA had compressed the REZ of the left facial nerve. She underwent aneurysm clipping and decompression of the REZ by transposition of both the clipped aneurysm and the AICA using TachoSil®. Her hemifacial spasm disappeared immediately after surgery without complication. Some fine arteries might compress the REZ in patients with hemifacial spasm associated with VA aneurysms. 3DRA-IA was more effective for accurate evaluation than other imaging modalities. Transposition of vascular structures using TachoSil® is safe and effective for microvascular decompression surgery in such complicated cases.

[A Case of Retro-Odontoid Pseudotumor in a Very Elderly Individual].

Retro-odontoid pseudotumors are mainly caused by aging or rheumatoid arthritis. We treated a very elderly patient with retro-odontoid pseudotumor. A 92-year-old man was admitted with the chief complaints of difficulty walking and progressive numbness in the right upper and lower extremities. Neurological examination revealed muscle weakness and exaggerated tendon reflexes of the right upper and lower extremities, and disturbance in skilled motor activities of the fingers, bilaterally. He had no bladder or rectal disturbances. The Japanese Orthopaedic Association(JOA)score for cervical myelopathy was 10/17. Rheumatoid arthritis was interpreted as negative. Radiography of the neck showed no atlanto-axial instability. Cervical magnetic resonance(MR)imaging revealed a mass located posterior to the C2 odontoid process, severely compressing the cervical cord. The patient underwent a C1 laminectomy and C2 half laminectomy without fixation to achieve cord decompression. Postoperatively, muscle weakness in the right upper and lower extremities was remarkably improved, and gait disturbance was also improved. However, skilled motor activities of the fingers on the right hand during tasks such as writing letters, holding a cup, and using chopsticks, were not improved. JOA score was improved to 14/17. Postoperative radiography revealed no atlanto-axial instability and MR imaging revealed adequate decompression of the spinal canal. Laminectomy without fixation is recommended as an effective and less invasive treatment for retro-odontoid pseudotumor, especially in very elderly patients without atlanto-axial instability.

[Surgical Treatment for Traumatic Acute Subdural Hemorrhage in the Posterior Cranial Fossa:Three Cases Reports and Review of the Literature].

Acute subdural hemorrhage(ASDH)in the posterior cranial fossa is rare. Extremely unfavorable outcomes are reported among cases accompanied by supratentorial hematoma, brainstem contusion, or intracerebellar contusion. We report three cases surgically evacuated several times for traumatic ASDH in the posterior cranial fossa simultaneously accompanied by supratentorial hematomas. In our three presented cases, the mean age was 72.3 years, and all patients were male. The mechanisms of injury included traffic accidents in two cases and fall in one. The median Glasgow Coma Scale score on admission was 6. On admission, the patients had traumatic ASDH in the posterior cranial fossa accompanied by supratentorial hematoma, so they first underwent external decompression or ICP sensor insertion for the supratentorial lesions. However, after their first surgery, all patients developed upward herniation, and subsequently underwent suboccipital craniotomy and evacuation of hematomas. Glasgow Outcome Scales were death in one case, persistent vegetable state in one case, and severe disability in one case. The patients with ASDH in the posterior cranial fossa accompanied by supratentorial hematoma should immediately undergo suboccipital craniotomy and supratentorial decompression simultaneously when the hematomas compress the brainstem and upward herniation develops.

[Surgical Treatment of a Giant Olfactory Groove Schwannoma:A Case Report].

Schwannomas originating from the olfactory nerve are extremely rare because the olfactory nerve does not normally contain Schwann cells. We describe a case of a giant schwannoma of the olfactory groove. A 73-year-old woman presented with anosmia persisting for 10 months. Head computed tomography(CT)for head trauma at another hospital demonstrated a tumor lesion located in the left frontal lobe and paranasal sinus. She had never suffered epilepsy, and past medical history and family history identified no indicators. Neurological examination revealed anosmia and dementia. Head CT demonstrated a tumor lesion with bone erosion, causing a defect of about 5cm in the frontal base. Head magnetic resonance(MR)imaging with contrast medium indicated a lesion that was 6cm in diameter, with heterogeneous enhancement and severe perifocal edema in the left frontal base, extending into the paranasal cavity. The tumor was resected through a left extradural subfrontal approach with bicoronal frontal craniotomy. The endoscopic approach was also performed simultaneously to remove the tumor in the paranasal sinus. The cystic tumor was soft and easy to bleed. Intraoperatively the right olfactory nerve was confirmed, but the left olfactory nerve could not be identified because of replacement by the tumor, suggesting that the tumor had originated from the left olfactory nerve. The defect of the dura was repaired with femoral fascia, the pedunculated periosteal flap was laid over the frontal base, and the bone defect was repaired with the inner plate of the frontal calvaria. Postoperative head MR imaging with contrast medium revealed no residual lesion. The patient was discharged 25 days after surgery, without new neurological deficits. Histological examination identified mixed Antoni type A and Antoni type B schwannoma on hematoxylin and eosin staining and S-100 protein on immunostaining.

[A Case of Coexistent Glossopharyngeal Neuralgia and Hemifacial Spasm Successfully Treated with Transposition of the Vertebral Artery].

A case of coexistent glossopharyngeal neuralgia and hemifacial spasm was treated by transposition of the vertebral artery. A 60-year-old man was referred to our hospital due to pain in the left posterior part of the tongue that was difficult to control with oral medication at a local hospital. The diagnosis was left glossopharyngeal neuralgia based on the symptoms, imaging findings, and lidocaine test results. Moreover, the patient had left hemifacial spasm. Microvascular decompression was performed, which confirmed that the vertebral artery was compressing the lower cranial nerve and the posterior inferior cerebellar artery was compressing the root exit zone of the facial nerve. The vertebral artery and posterior inferior cerebellar artery were transposed using TachoSil®. After the surgery, both glossopharyngeal neuralgia and hemifacial spasm disappeared, and the patient was discharged.

Squamous Cell Carcinomas on Bilateral Feet Arising in Long-Standing Eczematous Lesions.

We present a woman with squamous cell carcinomas on both feet in long-standing eczematous lesions. Histopathological examination of biopsies from the both feet revealed highly atypical cells invading the reticular layer of the dermis in the hyperkeratotic lesion and they were associated with surrounding dermatitis with spongiosis. Although the cause and etiology of eczema in our case is unclear, we speculate that the exceptionally long-lasting dermatitis might have induced double SCCs on bilateral feet with an unusual constitution. To the best of our knowledge, this is a first case of SCC on bilateral feet arising in long-standing eczematous lesions.

Induction of langerin+ Langerhans cell-like cells expressing reduced TLR3 from CD34+ cord blood cells stimulated with GM-CSF, TGF-ß1, and TNF-α.

Langerhans cells (LCs), a subset of dendritic cells (DCs), reside in body surface presenting antigens from various pathogens and activate immune system after migrating to vicinal lymph nodes. We recently demonstrated that the E-cadherin interaction allowed peripheral blood (PB) CD14+ cells to differentiate into LC-like cells that closely resemble primary LCs. Here, with a combination of GM-CSF, TGF-ß, and TNF-α, we induced LC-like cells from umbilical cord blood (UCB)derived CD34+ cells and compared them with those induced from PB CD14+ cells. In contrast to PB CD14+ cell-derived LC-like cells with an undetectable surface level of toll-like receptor (TLR)4 and an unresponsiveness feature to bacterial lipopolysaccharide (LPS), CB CD34+ cellsderived LC like cells expressed a low, but apparent, surface level of TLR4 and a reduced level of intracellular TLR3. Consistent with this result, they responded to bacterial LPS, but poorly to poly(I:C) reflecting viral RNA. These findings suggest that LC-precursors from circulating PB CD14+ cells seem to be arranged in the outer barrier of skin, while LC-precursors from local undifferentiated UCB-derived CD34+ cells may be arranged in the inner barrier of mucosal tissues and work together to combat against external pathogens as well as internal malignancies throughout body surface.

[A Surgical Case of Tuberculoma with Visual Disturbance].

We herein report a surgical case of multiple cerebral calculi located within the chiasmatic cistern resulting in visual disturbance. A 61-year-old man experienced homonymous lower right quadrantanopsia a few years prior. Non-enhanced head CT revealed multiple calcified lesions of about 7-mm within the basal cistern. MRI showed the lesion compressing the left optic tract. We could not remove the entire lesion because of severe adhesion to the optic tract. A pathological test showed calcified lesions with lymphocyte infiltration. We diagnosed tuberculoma caused by tuberculous meningitis with degeneration of the calcified lesion because of a history of tuberculosis at a fetal age. After the surgery, the patient was discharged without improvement of the visual disturbance.

Case of paraneoplastic pemphigus with immunoglobulin (Ig)G and IgA antibodies to various antigens.

A 63-year-old Japanese man with non-Hodgkin B-cell lymphoma presented with erythematous skin lesions on his entire body, with oral, ocular and anal mucosal lesions. The patient was diagnosed with paraneoplastic pemphigus. Immunofluorescence showed both immunoglobulin (Ig)G and IgA antibodies to keratinocyte cell surfaces. Various immunoblot and enzyme-linked immunosorbent assays showed both IgG and IgA antibodies to various autoantigens, including desmogleins, desmocollins, envoplakin, periplakin and bullous pemphigoid antigens. This was a unique case with a very rare autoantibody profile in paraneoplastic pemphigus.

Identification of Novel HLA-A*24:02-Restricted Epitope Derived from a Homeobox Protein Expressed in Hematological Malignancies.

The homeobox protein, PEPP2 (RHOXF2), has been suggested as a cancer/testis (CT) antigen based on its expression pattern. However, the peptide epitope of PEPP2 that is recognized by cytotoxic T cells (CTLs) is unknown. In this study, we revealed that PEPP2 gene was highly expressed in myeloid leukemia cells and some other hematological malignancies. This gene was also expressed in leukemic stem-like cells. We next identified the first reported epitope peptide (PEPP2(271-279)). The CTLs induced by PEPP2(271-279) recognized PEPP2-positive target cells in an HLA-A*24:02-restricted manner. We also found that a demethylating agent, 5-aza-2'-deoxycytidine, could enhance PEPP2 expression in leukemia cells but not in blood mononuclear cells from healthy donors. The cytotoxic activity of anti-PEPP2 CTL against leukemic cells treated with 5-aza-2'-deoxycytidine was higher than that directed against untreated cells. These results suggest a clinical rationale that combined treatment with this novel antigen-specific immunotherapy together with demethylating agents might be effective in therapy-resistant myeloid leukemia patients.