Efficacy of gefapixant, a P2X3 antagonist, for lung cancer-related cough: a case report.

Cough is a frequent symptom accompanied by lung cancer. More potent antitussive treatment for this complex and distressing symptom is required, but anti-cancer chemotherapy cannot fully manage the cough. Inhibition of vagal nerves might control coughing in patients with troublesome lung cancer-related cough and P2X3 inhibitory therapy may be useful for targeting neuronal function. We report the case of a woman in her late 70s who never smoked and had advanced lung cancer. She visited our hospital complaining of serious deterioration of a non-productive cough. She was diagnosed with relapse of lung cancer, but she requested 2-week anti-tussive therapy before second-line chemotherapy. Gefapixant (P2X3 antagonist) add-on at a dose of 90 mg/day (45 mg twice daily as the usual dosage in Japan) improved her cough as indicated by an improvement in the visual analog scale for cough from 70 to 20 mm and in the Japanese version of the Leicester Cough Questionnaire from 8.2 to 16.3, despite a deterioration in lung cancer after 2 weeks. There are no current guidelines for cough accompanied by lung cancer; however, our findings suggest that P2X3 inhibition is a potent therapeutic option for lung cancer-related cough.

Alectinib in a patient with ALK-positive non-small lung cancer unable to swallow capsules.

INTRODUCTION: The treatment landscape of metastatic non-small-cell lung cancer (NSCLC) has changed dramatically in the last decade. Anaplastic lymphoma kinase (ALK) rearrangement has been a focus of interest since ALK inhibitors produced outstanding clinical results compared with chemotherapy with cytotoxic agents in patients with ALK-positive NSCLC. CASE REPORT: We present the case of a 56-year-old woman with metastatic ALK-positive NSCLC and an inability to swallow capsules or tablets. Unfortunately, all ALK inhibitors are capsule or tablet formulations. MANAGEMENT AND OUTCOME: We, therefore, decided to administer alectinib orally by opening the capsules and suspending the contents in water. Clinical imaging performed 12 months after initiating alectinib therapy indicated a complete response (CR). After 54 months of follow-up, CR has been maintained, and oral alectinib therapy has continued with no recurrence of the swallowing disturbance. DISCUSSION: There are no current guidelines for oral targeted therapy in patients with swallowing disturbance, but alectinib administered orally by opening the capsules and suspending the contents in water can be a treatment option in patients with ALK-positive NSCLC and swallowing difficulty.

Abnormal keratinization and cutaneous inflammation in Mal de Meleda.

Mal de Meleda (MDM) is a rare, autosomal recessive form of palmoplantar keratoderma due to mutations in the gene, encoding for secreted lymphocyte antigen 6/urokinase-type plasminogen activator receptor related protein 1 (SLURP1). We report a four-year-old Taiwanese MDM female case whose biopsy specimen of hyperkeratotic lesions showed abnormal keratinization and cutaneous inflammation with characteristic transmission electron microscopic (TEM) findings and immunostaining results. The patient presented with pruritic and severely hyperkeratotic plaques on the bilateral palms and soles whichwere fringed with erythematous scaly areas. A homozygous c.256 G>A mutation, predicting a conversion of p.Gly86Arg, in SLURP1gene was detected. Histopathological examinations showed marked hyperkeratosis, acanthosis and hypergranulosis in the epidermis, accompanied by perivascular lymphocytic infiltrates in the dermis. The whole layers of the epidermis and perivascular infiltrates of the dermis were stained positive with anti-tumor necrosis factor alpha (TNFα) antibody in the biopsy specimen from the sole and the ankle. TEM examination of the biopsy specimen from the plantar hyperkeratotic plaque showed various-sized vacuoles surrounding nuclei of many keratinocytes in the spinous layer. In addition, there were numerous irregular keratohyaline granules in the granular layer. Several microorganisms and many lipid-like droplets were found in the thickened cornified layer. SLURP1 protein is known as a marker of late differentiation, predominantly expressed in the granular layer, and also known to have an inhibitory effect on TNFα release. Our results exhibited excessive TNFα expression in keratinocytes and perivascular infiltrates of the dermis, and several characteristic morphological observations of keratinocytes in MDM.

Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate Improves Inspiratory Capacity in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap.

Purpose: Asthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting ß2 agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone. Methods: A 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 µg/day on budesonide/formoterol fumarate (BUD/FORM) 640/18 µg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization. Results: A total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55-83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in (p < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods. Conclusion: The present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO.

Localized lymphadenopathy with myelodysplastic syndrome associated with tuberculosis.

We report the case of a man who developed myelodysplastic syndrome (MDS) and refractory cytopenia of unilineage dysplasia, 5 months after aortic valve replacement surgery. He also developed fever of unknown origin. After bone marrow- and other laboratory examinations, he was diagnosed with tuberculosis.

[Effect of Japanese Traditional Medicine, Ninjin-Youei-To(TJ-108), on the Quality of Life of Patients with Non-Small Cell Lung Cancer Receiving Outpatient Chemotherapy].

An increasing number of patients with lung cancer are undergoing outpatient chemotherapy, and thus, it is very important to maintain the quality of life(QOL)of these patients. Ninjin-Youei-To(TJ-108), a Japanese traditional medicine, has been reported to improve the QOL of patients with advanced cancer. However, the effect of TJ-108 in patients with lung cancer undergoing outpatient chemotherapy is unknown. Therefore, we conducted this study. To investigate factors influencing the QOL of these patients, we administered a QOL questionnaire,"The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs"(QOL-ACD)to 15 patients with non-small cell lung cancer. Factors related to the overall QOL scores and other categories indicating"activity","physical condition","psychological condition","social relationship", and"face scale" were analyzed. No significant decrease in each of the evaluated factors was observed in this study.

Immunohistochemical analysis of NANOG expression and epithelial-mesenchymal transition in pulmonary sarcomatoid carcinoma.

Pulmonary sarcomatoid carcinomas (PSCs) are defined as a group of poorly differentiated non-small cell lung cancers that demonstrate sarcoma-like differentiation. The mechanism of mesenchymal differentiation in PSC is epithelial-mesenchymal transition (EMT). The expression of homeobox protein NANOG (NANOG), which regulates the pluripotency of embryonic stem cells, is associated with the EMT process. Therefore, the present study aimed to assess the expression level of NANOG and the status of the EMT process in PSC. The data of patients with PSC were retrospectively reviewed and immunohistochemical analyses were performed on patient samples to examine the expression of NANOG and EMT-associated proteins. The comparator group included randomly selected patients with matched clinicopathological characteristics who had pulmonary adenocarcinoma (PA). In the present study, 12 patients with PSC (4 females and 8 males) were enrolled; their median age was 65 years (range, 36-79 years), and the number of patients with stage IB, IIB, IIIA, IIIB and IV disease were 1, 1, 1, 1 and 8, respectively. The immunoreactive score (IRS) for E-cadherin was significantly lower in the PSC group compared with the PA group (P<0.0001), whereas the IRS for vimentin was significantly higher in the PSC group compared with the PA group (P<0.0001). However, the IRS for NANOG was significantly decreased in the PSC group compared with the PA group (P<0.0001), which suggests that NANOG does not serve an essential role in EMT in PSC. In addition, the overall survival of patients with PSC was significantly lower compared with that of patients with PA (median survival time, 7.0 vs. 35.6 months, respectively; P=0.0256). However, no significant difference was observed in the OS of patients who expressed low compared with high levels of NANOG (P=0.4416). In conclusion, it was clearly demonstrated that cytoplasmic NANOG expression was significantly lower in PSC compared with PA, and that the EMT process in PSC was accelerated, compared with that in PA.

Microparticles as Biomarkers of Blood Coagulation in Cancer.

Cancer is associated with hypercoagulopathy and increased risk of thrombosis. This negatively influences patient morbidity and mortality. Cancer is also frequently complicated by the development of venous thromboembolism (VTE). Tumor-derived tissue factor (TF)-bearing microparticles (MPs) are associated with VTE events in malignancy. MPs are small membrane vesicles released from many different cell types by exocytic budding of the plasma membrane in response to cellular activation or apoptosis. MPs may also be involved in clinical diseases through expression of procoagulative phospholipids. The detection of TF-expressing MPs in cancer patients may be clinically useful. In lung and breast cancer patients, MPs induce metastasis and angiogenesis and may be indicators of vascular complications. Additionally, MPs in patients with various types of cancer possess adhesion proteins and bind target cells to promoting cancer progression or metastasis. Overexpression of TF by cancer cells is closely associated with tumor progression, and shedding of TF-expressing MPs by cancer cells correlates with the genetic status of cancer. Consequently, TF-expressing MPs represent important markers to consider in the prevention of and therapy for VTE complications in cancer patients.

Case series of patients with chronic foot ulcers treated with autologous platelet-rich plasma.

Treatment for patients with chronic wounds is entering a new era, and autologous platelet-rich plasma (PRP) is among the most promising treatments. PRP contains a concentration of platelets obtained by centrifuging the patient's blood. Because it contains fibrin and high concentrations of growth factors, PRP is known to promote wound healing. In this study, we present five patients with chronic foot ulcers successfully treated with PRP in our institution. The patients had various underlying diseases: diabetes (n = 2), peripheral arterial disease (n = 1), both diabetes and peripheral arterial disease (n = 1), and cutaneous polyarteritis nodosa (n = 1). Also, we provide a description of PRP's mechanisms, advantages, and limitations.

Prognostic impact of the mean platelet volume/platelet count ratio in terms of survival in advanced non-small cell lung cancer.

BACKGROUND: Mean platelet volume (MPV) is a platelet volume index. Classically, MPV was recognized as a hallmark of platelet activation. Recent studies have revealed that the MPV and MPV/platelet count (PC) ratio can predict long-term mortality in patients with ischemic cardio-vascular disease. In addition, these indices were correlated with the pathophysiological characteristics of patients with various disorders, including malignant tumors. PATIENTS AND METHODS: We retrospectively analyzed various hematological indices of patients with advanced non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the contribution of platelet volume indices to survival in these patients. RESULTS: A total of 268 patients were enrolled in the study. The median age of the patients was 68 years (range: 31-87 years). We compared various hematological indices between the NSCLC group and an age- and sex-matched comparator group. MPV was significantly decreased in the NSCLC group compared to the comparator group. In contrast, the PC was significantly increased in the NSCLC group. Consequently, the MPV/PC ratio was also decreased in the NSCLC group (0.397 vs. 0.501). In receiver operating characteristics (ROC) curve analysis, the MPV/PC ratio was associated with a sensitivity of 62.3% and a specificity of 74.6% at a cutoff value of 0.408730 (area under the curve [AUC], 0.72492)]. Univariate analysis revealed that overall survival (OS) was significantly shorter in the group with a low MPV/PC ratio than in the other group (median survival time [MST]: 10.3 months vs. 14.5 months, log-rank, P=0.0245). Multivariate analysis confirmed that a low MPV/PC ratio was an independent unfavorable predictive factor for OS (hazard ratio [HR]: 1.668, 95% confidence interval [CI]: 1.235-2.271, P=0.0008). CONCLUSION: These data clearly demonstrate that the MPV/PC ratio was closely associated with survival in patients with advanced NSCLC.

Primary intrahepatic malignant mesothelioma with multiple lymphadenopathies due to non-tuberculous mycobacteria: A case report and review of the literature.

Primary intrahepatic malignant mesothelioma (PIHMM) is an extremely rare tumor with clinicopathological characteristics that remain to be elucidated. The current study presents the case of a 68-year-old female with PIHMM and multiple lymphadenopathies due to non-tuberculous mycobacteria. The patient presented with an intrahepatic tumor, 70 mm in diameter, in the right lobe of the liver. An ultrasound-guided fine-needle aspiration biopsy of the liver tumor revealed findings that were consistent with an intrahepatic malignant mesothelioma. The systemic lymph node swellings were due to epithelioid granulomas that were caused by non-tuberculous mycobacteria. However, a hepatic rupture occurred due to the rapid growth of the liver tumor and consequently, a surgical resection was not performed. A review of the literature revealed that the clinicopathological characteristics of PIHMM are similar to those of non-occupational mesothelioma. However, PIHMM is usually a solitary tumor and is rarely associated with cavity effusion in contrast with conventional mesothelioma. Therefore, surgical resection with curative intent is often recommended for patients with PIHMM.

Nail alterations as a surrogate marker for the efficacy of low-dose metronomic chemotherapy.

Docetaxel is a well-known causative agent of nail alterations. The aim of this study was to reveal the impact of nail alterations associated with low-dose metronomic (LDM) docetaxel chemotherapy on the survival of non-small cell lung cancer (NSCLC) patients. Clinical information, survival data and nail alterations in patients treated with LDM docetaxel chemotherapy (docetaxel 15 mg/m2 per week) were retrospectively reviewed. Forty-nine patients were included in this study. Various nail alterations were observed in 17 of the 49 patients (34.7%). Onycholysis and subungual hyperkeratosis were observed in 22.4% and 10.2% of patients, respectively. The number of docetaxel administration cycles was correlated with the incidence and severity of nail alterations. Univariate and multivariate analysis clearly demonstrated that the occurrence of nail alterations was an independent favorable prognostic factor for overall survival. Nail alterations associated with treatment may act as a surrogate marker for the efficacy of low-dose metronomic docetaxel chemotherapy.

Comparative analysis of carboplatin and paclitaxel combination chemotherapy schedules in previously untreated patients with advanced non-small cell lung cancer.

The combination of carboplatin and paclitaxel is one of the most commonly used regimens for the treatment of non-small cell lung cancer (NSCLC). We aimed to compare the standard tri-weekly and weekly schedules of this treatment, while considering treatment-related hematological toxicities. We retrospectively analyzed the weekly [paclitaxel, 70 mg/m(2)/week on days 1, 8 and 15, and carboplatin, area under the curve (AUC)=6, every 4 weeks] and standard tri-weekly (paclitaxel, 200 mg/m(2), and carboplatin, AUC=6, on day 1 every 3 weeks] schedules in patients with previously untreated advanced NSCLC. A total of 167 patients were enrolled in this study. The median age of the patients was 65 years (range, 31-79 years). The weekly and standard arms included 73 and 94 patients, respectively. The incidence of grade 3 or 4 neutropenia and neuropathy was significantly decreased in the weekly arm compared with the standard arm (37.0 vs. 70.2%). The median survival and progression-free survival times were 11.8 and 4.2 months, respectively, in the weekly arm and 11.6 and 3.1 months, respectively, in the standard arm. The results of the multivariate analysis indicated that the weekly schedule [hazard ratio (HR)=0.634, P=0.0262] and grade 3 or 4 neutropenia (HR=0.372, P=0.0007) were independent favorable prognostic factors for overall survival time. In conclusion, the weekly schedule of carboplatin and paclitaxel was less toxic than and potentially superior to the standard tri-weekly schedule. However, further optimization of the dose and schedule is warranted.

A pilot study of a metronomic chemotherapy regimen with weekly low-dose docetaxel for previously treated non-small cell lung cancer.

BACKGROUND: Low-dose metronomic (LDM) chemotherapy is a novel approach that involves frequent administration of a low dose of chemotherapeutic agent without a long interval. PURPOSE: The aim of this clinical pilot study was to evaluate the toxicity and efficacy of LDM chemotherapy with weekly low-dose docetaxel for previously treated non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The enrolled patients received 15 mg/m2 of docetaxel intravenously on a weekly basis without any interval. RESULTS: Twenty-seven patients were enrolled in the study; 20 were men, and seven were women. The median age was 62 years (range: 32-75). Eleven patients were stage IIIB, and 16 were stage IV. The Eastern Cooperative Oncology Group performance status was 0 or 1. There was no severe hematological adverse effect; importantly, there was no neutropenia or thrombocytopenia. The objective response rate was 7.4% and the disease control rate was 51.9%. The median survival time was 16.4 months (95% CI: 5.7-36.4). CONCLUSION: Our preliminary results indicate that our metronomic regimen was well tolerated and active in patients with previously treated NSCLC. Thus, further investigation of this LDM regimen is warranted.

Therapeutic effect of bortezomib for primary plasma cell leukemia followed by auto/allo stem cell transplantation.

Plasma cell leukemia (PCL) is a rare disease that represents approximately 4% of plasma cell malignant disorders. PCL consists of two variants: primary PCL presents in patients with no previous history of multiple myeloma, while secondary PCL consists of a leukemic transformation in a previously recognized multiple myeloma. Primary PCL is an extremely resistant, rapidly progressive, fatal disease, with a median overall survival of 6.8 months. There is no standard therapeutic strategy, because no treatment option has been prospectively evaluated. We describe a successful case of newly diagnosed primary PCL, treated with a regimen that included bortezomib, followed by auto stem cell transplantation and nonmyeloablative allogeneic stem cell transplantation. Our patient has maintained remission status for over 12 months since undergoing the allogeneic stem cell transplantation. This strategy is promising for PCL, which, though an extremely resistant disease, may become curable.

Fibroadenoma of the axillary accessory breast: diagnostic value of dynamic magnetic resonance imaging.

Accessory breast is synonymous with polymastia or supernumerary breast tissue. An accessory breast without a nipple or areola is rare. We report a case of fibroadenoma of an accessory breast with no nipple or areola in a 41-year-old woman who presented with a right axillary mass associated with five small nodules in the normally situated breast. Magnetic resonance imaging (MRI) showed the accessory breast surrounding the tumor. We ignored the presence of the component surrounding the mass and made a preoperative diagnosis of an axillary mass of possible metastases from multiple breast cancers or breast cancer of unknown origin associated with multiple breast fibroadenomas. From a retrospective view, based on the histological results, MRI and dynamic MRI demonstrated a tiny component of breast-like tissue surrounding the axillary mass and an enhancement pattern typical of fibroadenoma for the axillary mass. For the later diagnosis of the axillary mass, the interpretation of whether the component of breast tissue surrounding the axillary mass was present is crucial. If the component exists, a tumor that originated from the accessory breast should be foremost in the differential diagnosis. Dynamic MRI appears to contribute to the diagnosis of fibroadenoma of an accessory breast before biopsy or surgical resection.

[Histoculture drug response assay guided adjuvant chemotherapy in patients with ERCC1-positive non-small cell lung cancer].

PURPOSE: A previous large randomized control study(IALT)revealed that cisplatin(CDDP)-based adjuvant chemotherapy was not effective for patients with ERCC1-positive non-small cell lung cancer(NSCLC). We evaluated the chemosensitivity of surgically resected specimens of NSCLC using in vitro chemosensitivity test and searched for promising adjuvant chemotherapy protocols in the ERCC1-positive subgroup of NSCLC. PATIENTS AND METHODS: Chemosensitivities of 10 anticancer agents including cisplatin were evaluated by histoculture drug response assay(HDRA) using 28 surgically resected NSCLC specimens. ERCC 1 status was evaluated by immunohistochemistry. RESULTS: ERCC1 was positive in 22 and negative in 6 specimens. All ERCC1-negative specimens were sensitive for CDDP in HDRA, and all CDDP-resistant specimens in HDRA showed positive ERCC1 staining. ERCC1 status was significantly correlated with CDDP sensitivity(p=0.01). HDRA showed average 3(0-6)sensitive anticancer agents except for CDDP even in ERCC1-positive specimens. CONCLUSION: HDRA may provide effective non-platinum adjuvant chemotherapy protocols for patients with ERCC1-positive, i.e. CDDP resistant, NSCLC.