Angiographic evaluation of the distance from the top of the jugular bulb to the inferior petrosal sinus-internal jugular vein junction: simple classification and identification method for the orifice of the non-visualized inferior petrosal sinus during neuroendovascular surgery.

BACKGROUND: The inferior petrosal sinus (IPS) is the transvenous access route for neurointerventional surgery that is occasionally undetectable on digital subtraction angiography (DSA) because of blockage by a clot or collapse. This study was aimed at analyzing the distance from the jugular bulb (JB) to the IPS-internal jugular vein (IJV) junction and proposing a new anatomical classification system for the IPS-IJV junction to identify the non-visualized IPS orifice. METHODS: DSA of 708 IPSs of 375 consecutive patients were retrospectively investigated to calculate the distance from the top of the JB to the IPS-IJV junction, and a simple classification system based on this distance was proposed. RESULTS: The median distance from the top of the JB to the IPS-IJV junction was 20.8 ± 14.7 mm. Based on the lower (10.9 mm) and upper (31.1 mm) quartiles, IPS-IJV junction variants were: type I, 0-10 mm (22.3%); type II, 11-30 mm (45.8%); type III, > 31 mm (23.9%); and type IV, no connection to the IJV (8.0%). Bilateral distances showed a positive interrelationship, with a correlation coefficient of 0.86. The bilateral symmetry type (visualized IPSs bilaterally) according to our classification occurred in 267 of 300 (89.0%) patients. CONCLUSIONS: In this study, the IPS-IJV junction was located far from the JB (types II and III), with a higher probability (69.6%). This distance and the four-type classification demonstrated high degrees of homology with the contralateral side. These results would be useful for identifying the non-visualized IPS orifice.

A randomized phase III study of docetaxel alone versus docetaxel plus S-1 in patients with previously treated non-small cell lung cancer: JMTO LC09-01.

BACKGROUND: This study evaluated the efficacy and safety of the combination chemotherapy of docetaxel plus S-1 in patients with previously treated non-small cell lung cancer (NSCLC) compared to docetaxel alone. METHODS: Patients with previously treated NSCLC were randomly assigned to docetaxel alone (arm A) or a combination of docetaxel and S-1 (arm B) for a maximum of four cycles. The primary endpoint was overall survival (OS). RESULTS: The study was terminated early because of poor accrual. The number of patients evaluated were 74 and 77 in arm A and arm B, respectively. The median OS was 9.8 months (95% confidence interval [CI]: 6.8-15.2) and 12.3 months (95% CI: 9.2-14.5) in arms A and B, respectively. In arms A and B, the median progression-free survival was 3.5 months (95% CI: 2.7-4.0) and 4.1 months (95% CI: 3.2-4.7), respectively. No statistically significant difference was observed in OS (hazard ratio [HR]: 0.984, 95% CI: 0.682-1.419, p = 0.4569) or progression-free survival (HR: 0.823, 95% CI: 0.528-1.282, p = 0.0953). The major toxicity was myelosuppression. The incidence of grade 3 or more neutropenia was higher in arm A than in arm B (44.6% vs. 35.1%). However, the incidence of grade 3 or more febrile neutropenia and infection with neutropenia (12.2% vs. 22.1%) was more frequently observed in arm B. CONCLUSIONS: The prematurely terminated study did not show the benefit of two cytotoxic agents over single-agent therapy for previously treated NSCLC patients.

Machine learning for prediction of immunotherapeutic outcome in non-small-cell lung cancer based on circulating cytokine signatures.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has substantially improved the overall survival (OS) in patients with non-small-cell lung cancer (NSCLC); however, its response rate is still modest. In this study, we developed a machine learning-based platform, namely the Cytokine-based ICI Response Index (CIRI), to predict the ICI response of patients with NSCLC based on the peripheral blood cytokine profiles. METHODS: We enrolled 123 and 99 patients with NSCLC who received anti-PD-1/PD-L1 monotherapy or combined chemotherapy in the training and validation cohorts, respectively. The plasma concentrations of 93 cytokines were examined in the peripheral blood obtained from patients at baseline (pre) and 6 weeks after treatment (early during treatment: edt). Ensemble learning random survival forest classifiers were developed to select feature cytokines and predict the OS of patients undergoing ICI therapy. RESULTS: Fourteen and 19 cytokines at baseline and on treatment, respectively, were selected to generate CIRI models (namely preCIRI14 and edtCIRI19), both of which successfully identified patients with worse OS in two completely independent cohorts. At the population level, the prediction accuracies of preCIRI14 and edtCIRI19, as indicated by the concordance indices (C-indices), were 0.700 and 0.751 in the validation cohort, respectively. At the individual level, patients with higher CIRI scores demonstrated worse OS [hazard ratio (HR): 0.274 and 0.163, and p<0.0001 and p=0.0044 in preCIRI14 and edtCIRI19, respectively]. By including other circulating and clinical features, improved prediction efficacy was observed in advanced models (preCIRI21 and edtCIRI27). The C-indices in the validation cohort were 0.764 and 0.757, respectively, whereas the HRs of preCIRI21 and edtCIRI27 were 0.141 (p<0.0001) and 0.158 (p=0.038), respectively. CONCLUSIONS: The CIRI model is highly accurate and reproducible in determining the patients with NSCLC who would benefit from anti-PD-1/PD-L1 therapy with prolonged OS and may aid in clinical decision-making before and/or at the early stage of treatment.

Coexistence of anterior cranial fossa dural arteriovenous fistula and arteriovenous malformation with the same drainage system: illustrative case.

BACKGROUND: The authors report a rare case of coexistence of dural arteriovenous fistula (DAVF) and arteriovenous malformation (AVM), with a common trunk drainer from both DAVF and AVM in the left anterior cranial fossa (ACF) with simple DAVF in the right ACF. OBSERVATIONS: A 63-year-old female presented with seizure. Cerebral angiography showed bilateral DAVFs in the ACF and AVM in the left frontal lobe. A dilated frontal vein acted as a simple drainer of the right DAVF. In contrast, a dilated vein with large varix was the common drainer of both the left DAVF and the AVM. During surgery, indocyanine green videoangiography was performed with direct observation. In the left ACF, the drainer occlusion of the DAVF resulted in partial shrinkage of the varix and decreased distal blood flow. Additional main feeder occlusion of the AVM could decrease the blood flow further, but not completely because of the residual pial supplies for the AVM. Finally, the nidus of the AVM with varix was removed by en bloc resection. LESSONS: Neurosurgeons should be aware of the coexistence of DAVF and AVM with a common trunk drainer. Only simple occlusion of the drainer from DAVF is not sufficient, so removal of the AVM is essential.

Asymptomatic acute ischemic lesions in intracerebral hemorrhage: Its frequency, MRI features, and risk factors.

BACKGROUND: Asymptomatic acute ischemic lesions (AIL) may be coincidentally found on brain magnetic resonance imaging (MRI) obtained during the acute phase of intracerebral hemorrhage, but its clinical significance has yet to be determined. The objective of this study is to determine the frequency of asymptomatic AIL, its characteristic features of brain MRI and risk factors in patients with acute intracerebral hemorrhage. METHODS: We retrospectively reviewed the clinical information of 108 patients with intracerebral hemorrhage who underwent brain MRIs within 30 days of hospitalization between April 2013 and January 2018. We determined the frequency of asymptomatic AIL, its brain MRI features, and risk factors. RESULTS: AIL was found in 26 of 108 patients; symptomatic in 2 and asymptomatic in 24 (22.2%). Asymptomatic AIL were small, multiple, mainly distributed to the white matter in the anterior circulation (22/24, 91.7%), and occasionally seen in deep watershed areas (15/24, 62.5%). Only 2 patients had severe major vessel stenosis. Asymptomatic AIL was associated with high mean blood pressure (BP) on admission (> 145 mmHg), excessive drug-induced reduction in mean BP (≥ 55 mmHg), and large hemorrhage (> 31 mL in volume). CONCLUSIONS: Asymptomatic AIL were found in 22.2% of patients with intracerebral hemorrhage within 30 days of hospitalization. Asymptomatic AIL were often small, multiple and occasionally developed in deep watershed areas despite the absence of major vessel stenosis. High mean BP on admission, excessive drug-induced BP reduction, and larger hemorrhage may be a risk factor for development of asymptomatic AIL.

Cholesterol crystal embolism-related cerebral infarction: Magnetic resonance imaging and clinical characteristics.

BACKGROUND AND AIMS: Cholesterol crystal embolism-related cerebral infarction (CCE-CI) is frequently misdiagnosed due to the lack of specific symptoms. To aid in differential diagnosis, this study comprehensively characterized the magnetic resonance imaging (MRI) and clinical manifestations of CCE-CI and compared these features to those of atherothrombotic cerebral infarction (ACI). METHODS: This single-center, retrospective, observational study was conducted at Kitasato University Hospital, Kanagawa, Japan. We identified 37 clinically or histopathologically confirmed CCE-CI cases and 110 ACI cases treated from January 2006 to May 2020. Groups were compared for mean age, sex ratio, clinical presentations, imaging manifestations, precipitating factors, comorbid conditions, medications, and smoking history. RESULTS: Of 37 eligible patients with CCE-CI, 10 (27.0%) received brain MRI, of which 8 (21.6%) exhibited high-intensity signals indicative of brain lesions on diffusion-weighted imaging (DWI). However, two patients with DWI lesions exhibited no detectable neurological abnormalities. Patients with CCE-CI frequently demonstrated bilateral DWI lesions involving the bilateral anterior and posterior circulation, a pattern absent in ACI (50% vs. 0%, p < 0.001). Compared to patients with ACI, CCE-CI patients also demonstrated significantly lower estimated glomerular filtration rate (p < 0.001) as well as more frequent eosinophilia (p = 0.006), atherosclerotic plaques ≥4-mm thick in the ascending aorta or proximal arch (p = 0.001), and aortic aneurysm (p < 0.001). CONCLUSIONS: Patients with CCE-CI develop multiple DWI lesions across several vascular territories, even in the absence of neurological symptoms. Comorbid aortic aneurysm may increase CCE-CI risk. These findings could help in the differential diagnosis of CCE-CI.

Tumor invasion in the central airway is a risk factor for early-onset checkpoint inhibitor pneumonitis in patients with non-small cell lung cancer.

BACKGROUND: Anti-programmed death-1 (PD-1) immunotherapy can cause immune-related pneumonitis, also known as checkpoint inhibitor pneumonitis (CIP). CIP that develops early after the initiation of anti-PD-1 immunotherapy is important because it is more severe than CIP that develops later. However, only a few studies have examined the risk factors for early-onset CIP. Previous studies have reported several risk factors for CIP, including imaging findings of airway obstruction adjacent to lung tumors. However, the utility of this factor is debatable. Therefore, we investigated potential risk factors for early-onset CIP, including tumor invasion in the central airway (TICA), in patients with non-small cell lung cancer (NSCLC) receiving anti-PD-1 therapy. METHODS: We retrospectively analyzed the medical records and chest computed tomography scans of patients with NSCLC treated with anti-PD-1 antibodies at the Kanagawa Cancer Center in Japan between 1 January 2016, and 30 June 2018. The clinical characteristics and imaging findings, including TICA, were compared between patients with and without early-onset CIP. RESULTS: Data from 181 eligible patients (114 receiving nivolumab and 67 receiving pembrolizumab) were analyzed. Early-onset CIP occurred in 13 of 79 patients (16.5%) with TICA and 2 of 102 patients (2.0%) without TICA. In multivariate analysis, the odds ratio of early-onset CIP for patients with TICA was 8.2 (95% confidence interval [CI]: 1.98-34.0, P = 0.0037). CONCLUSIONS: TICA was strongly associated with early-onset CIP in patients with NSCLC. Clinicians should carefully observe patients with TICA, especially within three months of anti-PD-1 antibody administration because of high CIP risk. KEY POINTS: Significant study findings Tumor invasion in the central airway (TICA) was a predictor of early-onset checkpoint inhibitor pneumonitis (CIP) TICA had good interobserver variability, indicating its utility in clinical practice Patients with TICA might have a higher immune status than patients without What this study adds This is the first study focusing on risk factors for CIP limited to early-onset CIP.

[Cerebral Amyloid Angiopathy-related Inflammation Demonstrating Early Venous Filling on Digital Subtraction Angiography:A Case Report].

Cerebral amyloid angiopathy-related inflammation(CAA-RI)is a rare condition thought to be caused by an inflammatory response to amyloid beta(Aß)protein in the walls of the small arteries and capillaries of the cerebral cortex. A 73-year-old female presented with left hemiparesis and dysarthria. Fluid-attenuated inversion recovery(FLAIR)imaging disclosed progressive enlargement of infiltrative white matter abnormalities in the right temporo-occipito-parietal lobes. Interestingly, digital subtraction angiography(DSA)demonstrated early venous filling. Pathological examination of the biopsy specimen demonstrated lymphocytes infiltration surrounding the blood vessels and in the thickened walls with amyloid-beta deposition. The diagnosis given was CAA-RI. The patient was successfully treated with high dose corticosteroids and clinical improvement was associated with shrinkage of the high intensity lesion on FLAIR imaging. Early venous filling resolved on the follow-up DSA. Most patients with CAA-RI can be treated with corticosteroids. However, the clinical condition will worsen without appropriate treatment. Early diagnosis is the key. If an expanding disease of the white matter appears in an elderly patient, we should exclude other cerebrovascular diseases by DSA, followed by biopsy without delay. The present case demonstrated that early venous filling on DSA may appear until inflammation is resolved by the treatment of CAA-RI.

A Case of Subcortical Hemorrhage in the Left Temporal Lobe Caused by Multiple Dural Arteriovenous Fistulas.

Transverse sinus-sigmoid sinus (TS-SS) dural arteriovenous fistula (dAVF) is common type of dAVF, on the other hand, anterior condylar confluence (ACC) dAVF is relatively rare. There has been no report presenting patients with TS-SS dAVF and ACC dAVF identified simultaneously yet. We present a case of TS-SS dAVF and ACC dAVF that developed subcortical hemorrhage of left temporal lobe. A 66-year-old woman with no past history was transferred to our hospital for sudden-onset consciousness disturbance, and was urgently admitted after the detection of a subcortical hemorrhage in the left temporal lobe. We suspected a dAVF based on magnetic resonance angiography and performed digital subtraction angiography (DSA). DSA revealed that the left occipital artery, left ascending pharyngeal artery, left middle meningeal artery, left tentorial artery, and posterior meningeal artery flowed into the TS-SS and ACC. DSA also showed outflow from the TS-SS to the brain surface through the vein of Labbé and the vein of Trolard. We performed transvenous embolization to prevent re-bleeding, she was then discharged from our hospital and her remaining sensory aphasia gradually improved. In the present study, the active investigation to determine the cause of subcortical hemorrhage led to a definitive diagnosis. The combination of ACC dAVF and TS-SS dAVF has not been reported thus far and this is considered a valuable case.

Importance and Difficulty of Differentiating BMA-induced AFF Prodromal Symptoms from Hormonal Therapy-related Femoral Pain.

We herein report a case of breast cancer in a 74-year-old woman treated with exemestane as fourth-line hormonal therapy and bone-modifying agents for long time. She suddenly developed a right femoral shaft fracture during treatment. Her femoral fracture had a beaking sign on radiogram. Given this finding, her fracture was ultimately diagnosed as atypical femoral fracture (AFF). In this case, it was difficult to recognize the difference between groin pain as a prodromal symptom of AFF and that due to an adverse reaction to hormonal therapy. Therefore, clinicians should recognize the difficulty of this differentiation and consider the situation with caution.

Successful Treatment with Taxane-Based Chemotherapy in Advanced Sebaceous Carcinoma: A Case Report and Literature Review.

For sebaceous carcinoma (SC), a rare malignant tumor, no standard chemotherapy regimen for patients with distant metastasis has been studied. We experienced a case of eyelid SC with multiple lung metastases that responded to combination chemotherapy with carboplatin and paclitaxel with 11-month progression-free survival (PFS). This patient also responded to second-line treatment with docetaxel, another taxane, with 7-month PFS, resulting in at least 18 months of survival at the time of reporting. This report shows that taxane-based chemotherapy may be effective for advanced SC, for which no standard therapy has been established.

Significance of Earlier Initiation of Chemotherapy for Lung Cancer Complicated with Primary or Secondary Nephrotic Syndrome following Its Appropriate Differential Diagnosis.

We encountered a case of primary lung cancer complicated with membranous nephropathy as primary nephrotic syndrome. Because treatment approaches vary greatly for primary and secondary nephrotic syndrome, a renal biopsy was performed for diagnosis. Much time was required to make a definitive diagnosis of primary nephrotic syndrome, as opposed to paraneoplastic nephrotic syndrome. Consequently, the subsequent chemotherapy was ineffective and caused significant toxicity due to reduced performance status (PS) and progression of hypoalbuminemia. Therefore, it is imperative that a diagnosis be made and treatment be initiated without delay before PS declines and hypoalbuminemia progresses.

Need for Flexible Adjustment of the Treatment Schedule for Aprepitant Administration against Erlotinib-Induced Refractory Pruritus and Skin Rush.

Common dermatological side-effects associated with erlotinib, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), include pruritus and skin rash, which are mediated by substance P, leading to the occasional discontinuation of cancer treatment. Aprepitant is an antagonist of neurokinin-1 receptor, through which substance P activates the pruritogens. Thus, aprepitant is expected to offer a promising option for the treatment of erlotinib-induced pruritus. However, the appropriate treatment schedule for aprepitant administration is under consideration. Here, we discuss the need for flexible adjustment of the treatment schedule for aprepitant administration against erlotinib-induced refractory pruritus and skin rush. A 71-year-old female smoker presented with stage IV EGFR-mutated lung adenocarcinoma. She was started on erlotinib at 150 mg/day. However, by 28 days, severe pruritus and acneiform skin rush resistant to standard therapies occurred, resulting in the interruption of erlotinib therapy. After recovery, she was restarted on erlotinib at 100 mg/day. However, severe pruritus and skin rush developed again within 2 weeks. Then, we started the first 3-day dose of aprepitant (125 mg on day 1, 80 mg on day 3, and 80 mg on day 5) based on the results of the previous prospective study, which showed the success rate of 100% with at least the second dose of aprepitant. However, the pruritus and skin rush exacerbated again within 4 weeks. Therefore, we started the second 3-day dose of aprepitant, but in vain. At this point, as the patient-centered medicine, bi-weekly schedule of the 3-day dose of aprepitant was considered and, then, adopted. As the results, the pruritus and skin rush remained well-controlled throughout the subsequent treatment with erlotinib.

Promising Combination Therapy with Bevacizumab and Erlotinib in an EGFR-Mutated NSCLC Patient with MET Amplification Who Showed Intrinsic Resistance to Initial EGFR-TKI Therapy.

In lung cancer, several potential mechanisms of intrinsic and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been explored, including mesenchymal-epithelial transition factor (MET) signaling pathway activation. On the other hand, vascular endothelial growth factor (VEGF) production of EGFR-mutated lung cancer cells is stimulated by predominantly activated MET signaling pathway. Therefore, the inhibition of VEGF axis as the downstream target of MET signaling pathway seems promising. Here, for the first time, we report the potential efficacy of combination therapy with bevacizumab and erlotinib in an EGFR-mutated NSCLC patient with MET amplification who showed intrinsic resistance to initial EGFR-TKI therapy. The patient was a 60-year-old male smoker, showing performance status (PS) 2, who presented with stage IV lung adenocarcinoma (cT4N2M1a) harboring the EGFR exon 19 deletion mutation. He was started on gefitinib at 250 mg/day. However, by 28 days, his symptoms further deteriorated along with the increased tumor size, resulting in PS 3. Then, repeat biopsy was performed, showing the positive MET amplification and the preserved EGFR exon 19 deletion mutation. Therefore, on the basis of the potential efficacy for activated MET signaling pathway as well as the confirmed safety by the known phase II trial for EGFR-mutated patients, the patient was started on combination therapy with bevacizumab at 15 mg/kg every 3 weeks plus erlotinib at 150 mg/day. By 21 days, his symptoms gradually improved along with the decreased tumor size, resulting in better PS with no severe toxicities.

Practical issues in measuring autoantibodies to neuronal cell-surface antigens in autoimmune neurological disorders: 190 cases.

OBJECTIVES: To address practical issues in measuring autoantibodies to neuronal cell-surface antigens (NSAs) in various autoimmune neurological disorders (ANDs). METHODS: We retrospectively reviewed the clinical information of 221 patients with clinically suspected ANDs who underwent antibody testing for NSAs between January 2007 and September 2017. 31 were excluded. In 190 patients, antibody-detection rate (ADR) and antibody-phenotype association were assessed. RESULTS: Fifty-four patients had NSA-antibodies: NMDA receptor (NMDAR) (n = 39), AMPA receptor (n = 3), leucine-rich glioma inactivated 1 (LGI1) (n = 3), glycine receptor (GlyR) (n = 3), GABA(A) receptor (n = 2), GABA(B) receptor (n = 1), metabotrophic glutamate receptor 5 (n = 1), or unknown (n = 6); 3 had multiple NSA-antibodies. ADR in patients with diagnostic criteria for "possible autoimmune encephalitis (AE)", "probable anti-NMDAR encephalitis", "definite autoimmune limbic encephalitis (ALE)", and "stiff-person spectrum disorder (SPSD)", was 34% (46/134), 85% (34/40), 46% (11/24), and 22% (4/18), respectively, but NSA-antibodies were not identified in 11 patients with systemic autoimmune disorders (SADs). Among 134 patients with "possible AE" criteria, NMDAR-antibodies were more frequently identified in patients with typical anti-NMDAR encephalitis than those without (34/40 [85%] vs. 4/94 [4%], p < 0.0001). LGI1-antibodies were identified in patients with ALE but not in the others (3/24 [13%] vs. 0/110 [0%], p = 0.005). GlyR-antibodies were identified in those with stiff-person syndrome plus (2/8, 25%) or stiff-limb syndrome (1/6, 17%). CONCLUSIONS: NSA-antibodies were most frequently identified in "probable anti-NMDAR encephalitis", followed by "definite ALE", "possible AE", and "SPSD", but not identified in SADs. NMDAR, LGI1 and GlyR were associated with clinical phenotype. Cell-surface antigens should be determined based on individual phenotype.

A Patient with Advanced Gastric Cancer Who Achieved a Long-Term Prognosis by Early Diagnosis of Sister Mary Joseph's Nodule.

The patient was a 66-year-old woman. An induration of approximately 15 mm in size that accompanied redness was palpable in the umbilical fossa. She did not respond to 1-month antibiotic treatment provided by the previous physician. For this reason, a biopsy of the site was performed with the possibility of neoplastic disease in mind, resulting in the detection of adenocarcinoma. Subsequent detailed whole-body examination revealed advanced gastric cancer and peritoneal dissemination, and the induration in the umbilical fossa was diagnosed as a direct infiltration from the peritoneal dissemination. Metastasis or infiltration of malignant tumor to the umbilicus is called Sister Mary Joseph's nodule (SMJN), and considered as a sign of poor prognosis. However, this case was successfully treated and achieved a long-term prognosis by the early diagnosis of SMJN. In routine clinical practice, it is considered necessary to examine patients carefully, as not to overlook SMJN.

Paraneoplastic IgA Vasculitis in an Adult with Lung Adenocarcinoma.

A 50-year-old man with lung adenocarcinoma (c-T1aN2M1b) experienced reddish purpura mainly on the lower legs after receiving 12 cycles of second-line chemotherapy with docetaxel. There was tumor enlargement on computed tomography performed to assess the therapeutic response, so paraneoplastic IgA vasculitis was considered. IgA vasculitis was diagnosed based on a biopsy of the skin lesion and histology of an upper gastrointestinal hemorrhagic mucosal erosion. As IgA vasculitis can lead to serious gastrointestinal or systemic complications, IgA vasculitis should be considered as a differential diagnosis for rashes in patients with malignancy.