A Multicentre Retrospective Study of Fulvestrant Use and Efficacy in Advanced/Metastatic Breast Cancer.

AIMS: Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres. MATERIALS AND METHODS: Medical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored. RESULTS: Data from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21-95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0-1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0-5) prior lines of endocrine therapy and median 0 (range 0-6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1-88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0-88). CONCLUSIONS: This is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients.

MIB-1 index is unlikely to predict relapse-free survival in patients who underwent R0-esophagectomy for esophageal squamous cell carcinoma.

MIB-1 is a cell proliferation marker and has previously been investigated as a diagnostic or prognostic indicator of malignancy. Previous studies have investigated MIB-1 index and clinicopathological factors in relation to prognosis of patients with esophageal cancer, with conflicting results. The aim of this study is to assess the prognostic significance of MIB-1 index in patients with thoracic esophageal squamous cell carcinoma. A total of 78 patients who underwent R0-esophagectomy for thoracic esophageal squamous cell carcinoma were enrolled in this study. Preoperatively, 29 patients underwent chemotherapy, six underwent chemoradiotherapy, and the remaining did not undergo any preoperative therapy. The MIB-1 labeling index was reported by counting 500 tumor cells in the hot spots of nuclear labeling. Correlations between MIB-1 index, clinicopathological factors, and relapse-free survival (RFS) were investigated. The mean MIB-1 index was 39.3 ± 21.0 (range: 0-91.3). There was no significant correlation between clinicopathological factors and MIB-1 index in the study patients, irrespective of whether they underwent preoperative therapy. Univariate analysis revealed no significant association between MIB-1 index and RFS. However, depth of tumor invasion, lymph node metastasis and stage, all showed a significant correlation to RFS. Multivariate analysis of RFS revealed that stage was the only significant factor. Conversely, MIB-1 index was not significantly related to RFS (p = 0.41). In conclusion, MIB-1 index is unlikely to be a significant prognostic indicator for esophageal cancer.

Erosion bleeding as a late complication of chest wall reconstruction with a Dacron mesh silicone prosthesis.

A 71-year-old man who had undergone chest wall resection and reconstruction with a Dacron mesh silicone prosthesis for chondrosarcoma 23 years previously presented with a chest wall hematoma. Since the hematoma was found to increase in size over time, we performed an operation to achieve hemostasis. Operative findings showed that the prosthesis had separated into three sheets.

Lung adenocarcinoma with a micropapillary pattern: a clinicopathological study of 25 cases.

Lung adenocarcinoma with a micropapillary pattern has recently been described, but its biological behavior is as yet uncertain. In this article we present a clinicopathological study of lung adenocarcinoma with micropapillary morphology. We selected 25 patients with lung adenocarcinoma with micropapillary morphology from the 2001-2004 pathology files (age range 54 to 81 years; mean 64.5 years). Micropapillary carcinoma is predominantly located at the periphery of the tumor nodule or mass and occurs irrespective of the subtype of the adenocarcinoma. A micropapillary component was seen against a mucinous background in three cases and microcalcifications resembling psammoma bodies were seen in one case. Four cases showed intensive invasive growth such as micropapillary adenocarcinoma of the breast and 21 showed alveolar type morphology with piling-up of the neoplastic cells with or without stromal invasion. Seven of twenty-three (30.4%) showed lymph node metastases at time of operation. Twelve of twenty-five (48%) showed pleural invasion. Regarding clinical outcome, 14 patients were alive without disease, 5 were alive with disease, and 5 died of the lung adenocarcinoma. No significant relationship was found between the extent of the micropapillary component and prognosis. However, the carcinoma seen in the five patients who died showed breast type histology with intensive invasive growth in three cases and alveolar type histology with intensive stromal invasion in two. Lung micropapillary carcinoma of breast type may behave more aggressively than the alveolar type.

Comparison of the activities of multinucleated bone-resorbing giant cells derived from CD14-positive cells in the synovial fluids of rheumatoid arthritis and osteoarthritis patients.

OBJECTIVE: To investigate the morphology and function of multinucleated bone-resorbing giant cells derived from CD14-positive cells in the synovial fluids (SF) of patients with rheumatoid arthritis (RA) or osteoarthritis (OA). METHODS: CD14-positive cells were obtained by magnetic-activated cell sorting of primary cultures of mononuclear cells from the SF. Multinucleated bone-resorbing giant cells were induced from the CD14-positive cells in the presence or absence of cytokines. We examined various characteristics, including osteoclast markers, fusion index and bone-resorption activities of the multinucleated giant cells. RESULTS: Multinucleated giant cells were induced from the CD14-positive cells in the SF of the RA and OA patients by the addition of interleukin (IL)-3, IL-5 and IL-7, or granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively. These multinucleated giant cells were positive for tartrate-resistant acid phosphatase (TRAP), carbonic anhydrase II, actin, vitronectin receptor and the calcitonin receptor. However, the average values for the number of nuclei, fusion index and bone-resorption functions of the SF cells from the RA patients were significantly higher than those derived from the OA patients. CONCLUSION: These results suggest that the induction and activities of multinucleated bone-resorbing giant cells may play a pivotal role in bone destruction, and that these processes may be enhanced significantly in RA patients.

[Metastatic sternal tumor from thyroid papillary carcinoma; report of a case].

A 68-year-old male was referred to our department for treatment of a metastatic sternal tumor in the manubrium sterni. Primary lesion was papillary carcinoma of the left lobe of the thyroid gland. Total thyroidectomy, cervical lymph node dissection, resection of manubrium sterni with concomitant resection of bilateral clavicles, 1st ribs and 2nd ribs, and chest wall reconstruction using Marlex Mesh were performed on January 29, 2001. Considering relatively good prognosis and good response to multimodality therapy, surgical resection of sternal metastatic lesion from differentiated thyroid cancer seems to be a choice of therapy as a part of multimodality approach, including surgery, radioiodine and external radiation therapy, to thyroid cancer with systemic spread.

Efficient generation of dendritic cells from alveolar and pleural macrophages as well as blood monocytes in patients with lung cancer.

In this study, we investigated the generation of dendritic cells (DCs) from blood monocytes and mature macrophages from untreated primary lung cancer patients. Blood monocytes were separated by adherence from blood mononuclear cells (MNC) from ten lung cancer patients and ten control subjects, and cultured for 7 days in medium with granulocyte/macrophage colony-stimulating factor (GM-CSF) plus interleukin (IL-) 4. In all cases examined, DCs with typical characteristics were obtained even in lung cancer patients after 7 days culture with these cytokines, and there was no significant difference in phenotype and stimulatory activity in allogeneic lymphocyte proliferation between DCs derived from monocytes from lung cancer patients and those from control subjects. Next, we examined whether alveolar and pleural macrophages in malignant pleural effusion separated by magnetic beads could differentiate to immunostimulatory DCs. Conventional culture conditions with GM-CSF and IL-4 did not induce efficient numbers of DCs from mature macrophages, whereas the addition of tumor necrosis factor-alpha (TNF-alpha) to GM-CSF and IL-4 effectively contributed to generate DCs. These findings suggest that both mature macrophages and blood monocytes from lung cancer patients could differentiate to DCs, and might be a useful source of DCs for immunotherapy.

Complete response of a stage IV mucinous cystadenocarcinoma of the ovary to systemic chemotherapy employing paclitaxel and carboplatin.

BACKGROUND: The survival rate of patients with advanced-stage mucinous cystadenocarcinoma of the ovary is dismal and no best treatment is known. We report a case of complete response of a stage IV mucinous cystadenocarcinoma of the ovary to systemic chemotherapy employing paclitaxel and carboplatin. CASE: A 51-year-old nullipara diagnosed with International Federation of Gynecology and Obstetrics stage IV mucinous cystadenocarcinoma of the ovary underwent cytoreductive surgery followed by systemic chemotherapy employing paclitaxel and carboplatin every 4 weeks for 3 courses. The patient tolerated chemotherapy well, demonstrated a remarkable response showing no evidence of malignancy at a second-look laparotomy. As a consolidation chemotherapy after negative second-look laparotomy, she underwent another three courses of chemotherapy of the same regimen, and is showing no evidence of disease. CONCLUSION: Paclitaxel and carboplatin may be effective in treating mucinous cystadenocarcinoma of the ovary.

Tonsillar metastasis from large cell carcinoma of the lung.

A 52-year-old female was referred to our department for treatment of a left lung tumor, 80 mm in diameter, arising in the left S1 + 2. The patient's chief complaint was persistent dry cough and spiking fever. Left upper lobectomy with hilar and mediastinal lymph node dissection (ND2a) was performed, and the pathological diagnosis was primary large cell carcinoma of the lung, p-T3N0M0. At one week after being discharged, the patient visited our outpatient clinic complaining of a sore throat. A tumor in the right tonsil was discovered, and excisional biopsy revealed it to be metastasis from the large cell carcinoma of the lung. Right cervical lymph node metastasis was also detected, and the patient was treated by combined chemo-radiotherapy, resulting in a complete remission.

Thoracoscopic surgery and conventional open thoracotomy in metastatic lung cancer.

BACKGROUND: We performed a retrospective comparison of the oncological outcome of thoracoscopic surgery for pulmonary metastasis with that of conventional open thoracotomy. METHODS: The patient population for our retrospective comparison was comprised of 45 patients undergoing pulmonary resections via video-assisted thoracoscopy (thoracoscopy group) and 55 undergoing similar resections by open thoracotomy (open group) for pulmonary metastases between 1994 and 1999. RESULTS: Solitary metastasis was resected more frequently with thoracoscopy than open thoracotomy. There were no significant intergroup differences in rates of local recurrence from the initial pulmonary resection site. The actuarial 1-year, 2-year, and 3-year survival rates were, respectively, 82.8%, 70.0%, and 62.3% in the thoracoscopy group and 93.6%, 64.6%, and 52.7% in the open group. The rates of pulmonary recurrence and survival also did not differ significantly between the two groups with solitary metastases. CONCLUSION: Thoracoscopic surgery for metastatic lung disease appears to be feasible as long as the preoperative metastatic tumor evaluation using chest computed tomography (CT) is accurate.

Localization and expression of osteopontin in the rotator cuff tendons in patients with calcifying tendinitis.

Calcifying tendinitis of rotator cuff tendons is a common and painful condition caused by ectopic calcification in humans. To examine the involvement of osteopontin (OPN), a potent regulator of calcium deposition on connective tissues, localization and expression of OPN protein and messenger (m)RNA were investigated in human tissue samples of calcified rotator cuff tendons. Immunohistochemistry demonstrated that OPN was localized in cells surrounding the calcified area. OPN was localized in two distinct cell types, i.e., fibroblast-like cells negative for CD68 and tartrate-resistant acid phosphatase (TRAP) and multinucleated macrophages positive for CD68 and TRAP. In situ hybridization revealed that the mRNA expression of OPN in these cells coincided with the immunohistochemistry results, and these results were supported by reverse transcriptase polymerase chain reaction analysis using human OPN-specific oligonucleotides. Cells located away from the calcified area did not express OPN. The present findings indicate the involvement of OPN in the process of calcification of rotator cuff tendons and suggest that OPN plays a role in such painful disorders through the actions of at least two cell types.

Analysis of models for crustacean stretch receptors.

The mechanisms underlying the diverse responses to step current stimuli of models [Edman et al. (1987) J Physiol (Lond) 384: 649-669] of lobster slowly adapting stretch receptor organs (SAO) and fast-adapting stretch receptor organs (FAO) are analyzed. In response to a step current, the models display three distinct types of firing reflecting the level of adaptation to the stimulation. Low-amplitude currents evoke transient firing containing one to several action potentials before the system stabilizes to a resting state. Conversely, high-amplitude stimulations induce a high frequency transient burst that can last several seconds before the model returns to its quiescent state. In the SAO model, the transition between the two regimes is characterized by a sustained pacemaker firing at an intermediate stimulation amplitude. The FAO model does not exhibit such a maintained firing; rather, the duration of the transient firing increases at first with the stimulus intensity, goes through a maximum and then decreases at larger intensities. Both models comprise seven variables representing the membrane potential, the sodium fast activation, fast inactivation, slow inactivation, the potassium fast activation, slow inactivation gating variables, and the intra cellular sodium concentration. To elucidate the mechanisms of the firing adaptations, the seven-variable model for the lobster stretch receptor neuron is first reduced to a three-dimensional system by regrouping variables with similar time scales. More precisely, we substituted the membrane potential V for the sodium fast activation equivalent potential Vm, the potassium fast inactivation Vn for the sodium fast inactivation Vh, and the sodium slow inactivation Vl for the potassium slow inactivation Vr. Comparison of the responses of the reduced models to those of the original models revealed that the main behaviors of the system were preserved in the reduction process. We classified the different types of responses of the reduced SAO and FAO models to constant current stimulation. We analyzed the transient and stationary responses of the reduced models by constructing bifurcation diagrams representing the qualitatively distinct dynamics of the models and the transitions between them. These revealed that (1) the transient firings prior to reaching the stationary state can be accounted for by the sodium slow inactivation evolving more slowly than the other two variables, so that the changes during the transient firings reflect the bifurcations that the two-dimensional system undergoes when the sodium slow inactivation, considered as a parameter, is varied; and (2) the stationary behaviors of the models are captured by the standard bifurcations of a two-dimensional system formed by the membrane potential and the potassium fast inactivation. We found that each type of firing and the transitions between them is due to the interplay between essentially three variables: two fast ones accounting for the action potential generation and the post-discharge refractoriness, and a third slow one representing the adaptation.

Expression of proteinases and inflammatory cytokines in subchondral bone regions in the destructive joint of rheumatoid arthritis.

OBJECTIVE: We previously described abnormalities in the bone marrow of patients with rheumatoid arthritis (RA), but were able to shed little light on the pathogenic roles of inflammatory cytokines and proteinases in joint destruction in the subchondral region in RA. This is the first report to describe the co-localization of cytokines and proteinases in this area. METHODS: Decalcified paraffin-embedded sections from 10 patients with RA and five patients with osteoarthritis (OA) were examined for the immunolocalization of cathepsins B, K and L and the localization of messenger RNAs for interleukin 1beta (IL-1beta), tumour necrosis factor alpha (TNF-alpha) and matrix metalloproteinase 9 (MMP-9). The cells were double-stained with anti-CD68 or anti-prolyl 4-hydroxylase (PH) antibody. RESULTS: An immunohistochemical study confirmed the expression of cathepsins B and L by CD68-positive mononuclear cells at the sites of significant cartilage and bone erosion from the subchondral region in all RA specimens. Osteoclast-like cells showed intense staining for cathepsin K and MMP-9. Osteoblast-like cells strongly expressed MMP-9. Analysis of serial sections revealed that expression of the IL-1beta and TNF-alpha genes occurred near that of the cathepsins and MMP-9 in the subchondral region. CONCLUSION: We conclude that inflammatory cytokines and tissue-damaging proteinases play important roles in joint destruction in the subchondral region in RA.

Ectopic arachnoid granulomatosis: a case report.

BACKGROUND: Arachnoid granulation can sometimes show hypertrophy, developing extensively apart from the venous sinus, and in that case, a differential diagnosis should be made between this granulation and tumors. In this case, we hypothesized that cerebrospinal fluid was absorbed in the region of abnormal stains revealed by angiography. CASE DESCRIPTION: A 67-year-old female with headache was admitted to our hospital. A plain radiograph revealed accumulated numerous osteolytic lesions in the right frontal bone. T1-weighted magnetic resonance (MR) images demonstrated mixed-intensity lesions. On the T2-weighted MR images, we observed that the lesions were mixed, with areas of the same intensities as gray matter and cerebrospinal fluid. An abnormal vascular stain from the frontal branch of the middle meningeal artery was confirmed. After a craniotomy, numerous white granular masses were observed. These masses had penetrated the dura mater and adhered rigidly to the arachnoid membrane. Histological examination revealed them to be normal arachnoid granulations and villi. CONCLUSION: This case was diagnosed as an ectopic arachnoid granulomatosis. No case report has previously been published describing numerous arachnoid granulations away from the venous sinuses.

Humanized anti-ganglioside GM2 antibody is effective to induce antibody-dependent cell-mediated cytotoxicity in mononuclear cells from lung cancer patients.

Ganglioside GM2 is one of the major gangliosides expressed on the cell surface of human tumors including lung cancer. We have previously reported that a mouse-human chimeric monoclonal antibody (mAb), KM966, against GM2 promotes the lysis of lung cancer cells by human blood mononuclear cells (MNC) of healthy donors. In this study, we examined antibody-dependent cell-mediated cytotoxicity (ADCC) of MNC, using KM966 mAb and its humanized counterpart, KM8969, in 16 lung cancer patients and 18 control patients. The ADCC activity was assessed by 4-h (51)Cr release from GM2 positive SBC-3 small cell lung cancer cells. MNC from lung cancer patients exhibited similar ADCC activity to those from control patients when KM966 and KM8969 were used as mAb. Moreover, effective ADCC activity was observed even in MNC from advanced lung cancer patients. These observations suggest the potential activity of humanized anti-GM2 mAb (KM8969), as well as chimeric KM966, in biological therapy for lung cancer patients.

Effects of lung metastasectomy on respiratory function.

OBJECTIVE: The effects of lung metastasectomy on respiration were evaluated. SUBJECTS: From 1961 to 1999, 203 patients underwent lung metastasectomy. Of these, 102 patients who had undergone only partial lung resection, had undergone sufficient respiratory function testing, and had not suffered from other lung disease were included. RESULTS: Unilateral thoracoscopic surgery caused less decrease in percent vital capacity than surgery through a posterolateral thoracotomy, in both the early (rate of decrease: 16.2 +/- 9.1 vs. 33.0 +/- 12.0%, p < 0.01), and the late postoperative period (2.0 +/- 4.5 vs. 17.8 +/- 6.0%, p < 0.0001). Two thoracoscopic operations caused less decrease in percent vital capacity than 2 operations through a posterolateral thoracotomy (21.3 +/- 13.8 vs. 61.1 +/- 8.1%, p = 0.02). Bilateral metastasectomy through a median sternotomy caused less decrease in percent vital capacity than that through posterolateral thoracotomies (45.5 +/- 13.7 vs. 60.8 +/- 8.8%, p < 0.05). Four (36%) of 11 patients who had undergone 3 or more metastasectomies exhibited dyspnea of degree 3 or higher on the Hugh-Jones classification. CONCLUSIONS: Thoracoscopic metastasectomy and metastasectomy through a median sternotomy caused less restrictive respiratory dysfunction than metastasectomy through a posterolateral thoracotomy. Since metastatic lung disease often necessitates repeated metastasectomy, and repeated metastasectomy often causes severe restrictive respiratory dysfunction, metastasectomy should be performed with a less invasive procedure.

Interleukin (IL-)15 has less activity than IL-2 to promote type 2 cytokine predominance in tumour-associated mononuclear cells from lung cancer patients.

Deviation of type 1/type 2 cytokine balance to type 2 predominance may contribute to tumour progression. We investigated effect of interleukin (IL-)15 on modulation of type 1/type 2 balance in addition to non-major histo-compatibility complex (MHC)-restricted killer induction in the tumour-growing site. IL-15 induced significant killer activity in mononuclear cells (MNC) in malignant pleural effusion as well as those in peripheral blood. Pleural MNC produced more IFN-gamma (type 1 cytokine) by incubation with IL-15 or IL-2 than blood MNC. Moreover, IL-4 and IL-5 (type 2 cytokines) production by pleural MNC were observed only by incubation with IL-2, but not with IL-15. These observations suggest that IL-15 has a potent activity to restore type 1/type 2 balance in addition to killer induction in tumour-growing site.

Endoscopic neck surgery for thyroid carcinoma.

In the past 5 years, endoscopic neck surgery has been performed by various surgeons in Japan. However, many problems remain to be solved, including indications for this related in malignant thyroid tumors. For small thyroid cancers and legions suspected of malignancy, we found that we could obtain radicality in endoscopic neck surgery that was comparable to that attainable by conventional methods. Here, we describe our recent endoscopic surgical experience in five patients with preoperative diagnoses of definite or suspected thyroid carcinoma.

Malignant fibrous histiocytoma in the anterior mediastinum.

The origin of a malignant fibrous histiocytoma in the anterior mediastinum is rare. A 71-year-old man was referred to our department for treatment of a tumor 15 cm in diameter originating in the anterior mediastinum. Malignant fibrous histiocytoma was suspected after a percutaneous needle biopsy. Systemic screening showed no other organ involvement, and the tumor was considered to be a primary mediastinal tumor. The tumor, resected through a median sternotomy, was well encapsulated and resection was complete. The pathological diagnosis was malignant fibrous histiocytoma originating in the anterior mediastinum.