Teruhisa Sakurai

Involvement of acidic microenvironment in the pathophysiology of cancer-associated bone pain

Bone pain is one of the most common complications in cancer patients with bone metastases. Although the mechanism of cancer-associated bone pain is poorly understood, clinical observations that inhibitors of osteoclasts such as bisphosphonates (BPs) efficiently reduce bone pain suggest a potential role of osteoclasts, which play a central role in the development and progression of bone metastasis. Osteoclasts dissolve bone minerals by releasing protons through the a3 isoform of the vacuolar-H(+)-ATPase, creating acidic microenvironments. In addition, cancer cells, inflammatory cells and immune cells that reside in bone metastases also produce acidic conditions by releasing protons. It has been well-known that acidic conditions due to proton release cause pain. Our study showed that the sensory nociceptive neurons innervate bone and these neurons express acid-sensing nociceptors such as the acid-sensing ion channels and transient receptor potential channel-vanilloid subfamily members. Acid signals received by these nociceptors subsequently activate intracellular signaling pathways and transcription factors in sensory neurons. The understanding of the nociceptive events following proton release and subsequent creation of acidic microenvironments leads us to design novel molecular-based approaches for reducing bone pain associated with cancer and inflammation.

Acid Activation of Trpv1 Leads to an Up-Regulation of Calcitonin Gene-related Peptide Expression in Dorsal Root Ganglion Neurons via the CaMK-CREB Cascade: A Potential Mechanism of Inflammatory Pain

Increased CGRP expression in sensory neurons is associated with inflammatory pain. We examined the molecular basis of CGRP expression and found that acid-sensing nociceptor Trpv1 is activated under inflammatory acidic environments and up-regulates the CGRP expression through CaMK-CREB cascade.

Increased expression of integrin α3β1 in highly brain metastatic subclone of a human non‐small cell lung cancer cell line

To clarify the roles of integrin and extracellular matrix (ECM) in the process of non‐small cell lung cancer (NSCLC) brain metastasis, we established an in vivo model of brain metastasis of human NSCLC cell line EBC‐1/original in athymic mice, and established highly brain metastatic subclone EBC‐1/brain and highly bone metastatic subclone EBC‐1/bone. Integrin expression of these subclones was evaluated by flow cytometry. In vitro cell attachment, migration and proliferation assays with ECMs were performed using these subclones. Expression of integrin α3 subunit was higher in EBC‐1/brain than in both EBC‐1/original and EBC‐1/bone. In vitro cell attachment, migration, and proliferation assays revealed that EBC‐1/brain had higher affinity and higher reactivity to laminin than EBC‐1/original and EBC‐1/bone. Blocking of integrin α3β1 significantly (P<0.05) decreased brain metastasis by EBC‐1/brain. Interaction of integrin α3β1 and laminin plays important roles in the process of brain metastasis of non‐small cell lung cancer.

A case of granulomatous mastitis mimicking breast carcinoma

A 58-year-old woman presenting with idiopathic granulomatous mastitis mimicking breast carcinoma is described. The mass was elastic, hard and painless, and located in the upper outer quadrant of the right breast. Fine needle aspiration cytology did not provide any diagnostic information. Mammography, ultrasonography and magnetic resonance imaging (MRI) strongly suggested malignancy. Excisional biopsy was performed for definitive diagnosis, and idiopathic granulomatous mastitis was demonstrated histopathologically. Neither wound complication nor recurrence has been identified in the patient, although corticosteroids were not used post operatively. We reviewed the literature, and found that our present case is rare in older patients, and that mammography, ultrasonography and MRI provide little information for differentiating between granulomatous mastitis and carcinoma.

Bisphosphonate therapy for bone metastases from Breast Cancer: Clinical results and a new therapeutic approach

BackgroundWe evaluated the usefulness of bisphosphonate (BIS) monotherapy, the safety of rapid infusion of BIS and the efficacy of BIS-sequential therapy for bone metastases from breast cancer.Patients and MethodsTwenty-nine patients with bone metastasis or invasion were treated with BIS monotherapy. Each BIS (pamidronate 30 mg, alendronate 10 mg, or incadronate 10 mg) was infused over 30 minutes every two weeks a median of 12 times.ResultsWith BIS therapy, five patients (17%) showed partial response of the bone lesions, and eighteen patients (64%) had pain relief. Of the nine patients treated with BIS-sequential therapy, one (11%) showed a partial response of the bone metastases, three (33%) had pain relief, and one (11%) showed a decrease in the serum tumor marker level.ConclusionBIS therapy is effective against bone metastases from breast cancer, and rapid infusion of BIS is both safe and convenient for patients. BIS-sequential therapy can be a unique therapeutic option in some cases.

Intrapleural administration of a large amount of diluted fibrin glue for intractable pneumothorax. A clinical study based on 57 cases: including 2 unsuccessful cases.

OBJECTIVE Pleurodesis using chemical agents has been applied to high-risk patients with pneumothorax. This treatment, however, is sometimes unsuccessful in patients with intractable pneumothorax. We have developed intrapleural administration of diluted fibrin glue as an effective treatment for such patients. METHODS Fibrin glue was diluted 4-fold with saline and/or contrast media. Pleurodesis with a large amount of the diluted fibrin glue was performed in 55 high risk patients (57 cases, bil.2 patients) with intractable pneumothorax. RESULTS The air leaks were stopped by administration of the glue in all except 2 patients. During the follow-up period, a recurrence rate of 10.5% was observed. These recurrent pneumothoraces were successfully treated using the same procedure with no further recurrence. Pyrexia (12.3%) and chest discomfort (8.8%) were observed as side effects, and there was no occurrence of severe chest pain or thoracic empyema. CONCLUSIONS These results suggested that intrapleural administration of a large amount of diluted fibrin glue was an effective treatment for intractable pneumothoraces in high-risk patients.

Colonoscopic Diagnosis of Lymphoid Hyperplasia Causing Recurrent Intussusception: Report of a Case

This paper describes a 6-year-old boy with recurrent ileocecal intussusception due to lymphoid hyperplasia in the terminal ileum, which was diagnosed preoperatively by colonoscopy. At the age of 3 years, he developed diarrhea and a tender abdominal mass. He was diagnosed as having intussusception by ultrasound and was treated by hydrostatic barium enema. After resolution, he had three recurrent episodes of intussusception. A contrast barium enema revealed a small mass in the ileocecal region. Colonoscopy showed several exaggerated folds of the terminal ileum and a biopsy showed lymphoid hyperplasia. Because the repeated intussusception seemed to have been caused by the lymphoid hyperplasia in the terminal ileum, he underwent an ileocecal resection without any subsequent recurrence. Based on the above findings, we conclude that a colonoscopy may thus be useful both for diagnosing lymphoid hyperplasia in the terminal ileum as a cause of recurrent intussusception and for deciding how to manage it.

Molecular events of acid-induced bone pain

Pain is one of the most common and feared complications in patients with any disease. Pain causes discomfort, depression and anxiety and occasionally induces secondary diseases due to its immunosuppressive effects, making quality of life and prognosis worse. Pain is triggered following the recognition of local noxious stimuli by specialized afferent sensory neurons called nociceptors. The nociceptors can sense diverse noxious stimuli including thermal, mechanical and chemical agents that are released from inflammatory cells, immune cells, cancer cells and/or bone-destroying osteoclasts invading disease sites and injured tissues. Protons are one of these noxious stimuli and have long been known as a cause of pain. Sensory neurons innervating peripheral tissues can sense protons via acid-sensing nociceptors such as transient receptor potential channel vanilloid subfamily members. Noxious acid stimulus received by these nociceptors subsequently activates intracellular signaling pathways and transcription factors, leading to the release of neurotransmitters, including calcitonin gene-related peptide, in sensory neuronal cells. This Perspective describes intracellular molecular events propagated in sensory neurons as a consequence of acid activation of nociceptors, with a special emphasis on bone pain. Understanding the molecular events underlying acid-induced bone pain may lead to the design of novel mechanism-based approaches for the management of bone pain associated with inflammation and cancer metastasis. IBMS BoneKEy. 2011 April;8(4):195-204. 2011 International Bone & Mineral Society

A case of serum CEA disappearance curve after resection of breast carcinoma.

Carcinoembryonic antigen (CEA) elimination kinetics after tumor resection were measured in a case of breast cancer. A 45-year-old woman with a left breast carcinoma underwent surgery after neoadjuvant chemotherapy. The serum CEA level before surgery was 34.3 ng/ml. After sequential monitoring of serum CEA levels, postoperative serum CEA elimination kinetics were calculated using non-linear least square analysis with the fitting equation C(t) = (CO — Cp)exp(-kt) + Cp, where C(t) was the postoperative CEA level, t was the number days after surgery, CO was the CEA level at postoperative time zero, Cp was the CEA at plateau, and k was the rate constant of elimination.Cp was calculated as 6.9 ng/ml, which was above the cut-off level and indicated residual malignancy. After adjuvant chemotherapy, CEA normalized to 1.8 ng/ml. In breast cancer patients with high preoperative serum CEA levels, our analytical method for CEA elimination might be useful for the detection of residual malignancies.

Abstract P2-12-09: Long-term follow-up of nipple-sparing mastectomy for early-stage breast cancer without radiotherapy: A single-center study at a Japanese institution

Introduction: Achievement of a good cosmetic outcome is one of the most important goals of surgical treatment of breast cancer. However, most patients must undergo a mastectomy if the outcome of breast-conserving surgery is discordant. All potential techniques that maintain oncological safety should be considered to maximize the cosmetic outcome for patients who require a mastectomy. We began performing nipple-sparing mastectomy (NSM) in 1978. Recent reports have suggested that NSM is oncologically as safe as mastectomy and affords a better cosmetic outcome. Conversely, the surgical complications and recurrence associated with NSM remain controversial. Objective: In the present study, we review the safety of the NSM surgical technique, discuss nipple–areola recurrence and skin flap recurrence after NSM, and compare recurrence and prognosis between NSM and mastectomy based on our long-term follow-up data. Patients and Methods: We retrospectively analyzed 723 patients with early-stage breast cancer who underwent NSM from 1985 to 2007. The patients9 median age, tumor size, and tumor–areola distance were 50 y, 2.1 cm, and 1.5 cm, respectively. We used a thick skin flap method to avoid surgical complications including nipple and skin flap necrosis. We analyzed nipple–areola recurrence and skin flap recurrence after NSM. We also analyzed 100 patients who underwent mastectomy for early-stage breast cancer during the same period as those who underwent NSM. We compared the local recurrence rate (LRR), disease-free survival (DFS) rate, and overall survival (OS) rate among all 723 patients who underwent NSM and 100 patients who underwent mastectomy. No patients in either group received radiotherapy. Results: Among all patients who underwent NSM, stage 0, 1, 2A, and 2B disease was present in 21, 320, 253, and 129 patients, respectively. Notably, no nipple necrosis occurred during the average 114-month follow-up period. Local recurrence developed in 49 patients (6.7%), including recurrence at the nipple–areola complex in 24 (3.3%) and recurrence at the skin flap in 25 (3.4%). The average disease-free interval in patients with nipple–areola recurrence was 50 months, and that in patients with skin flap recurrence was 68 months. The clinical features of nipple–areola recurrence were a low rate of ER positivity (27%), high rate of Her2/neu positivity (60%), Paget type recurrence rate of 52%, and small tumor–areola distance (0.5 cm). The clinical features of skin flap recurrence were a relatively high rate of ER positivity (55%), solitary type recurrence rate of 88%, and diffuse type recurrence rate of 12%. The prognosis of diffuse type skin flap recurrence was significantly worse than that of solitary type recurrence (p = 0.01). There were no significant differences between the NSM and mastectomy groups in the LLR (6.7% vs. 4.0%, respectively), 10-y DFS rate (88% vs. 90%, respectively), or 10-y OS rate (92% vs. 91%, respectively). Conclusion: Our long-term follow-up data show that NSM should be considered as an alternative option for mastectomy when the outcome of breast-conserving surgery is discordant in patients with early-stage breast cancer. Citation Format: Sakurai T, Suzuma T, Yoshimura G, Jinta E, Umemura T, Sakurai T. Long-term follow-up of nipple-sparing mastectomy for early-stage breast cancer without radiotherapy: A single-center study at a Japanese institution. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-12-09.