Localization of nectin‐2α at the boundary between the adjacent somata of the clustered cholinergic neurons and its regulatory role in the subcellular localization of the voltage‐gated A‐type K+ channel Kv4.2 in the medial habenula

The medial habenula (MHb), implicated in stress, depression, memory, and nicotine withdrawal syndromes, receives septal inputs and sends efferents to the interpeduncular nucleus. We previously showed that the immunoglobulin‐like cell adhesion molecules (CAMs) nectin‐2α and nectin‐2δ are expressed in astrocytes in the brain, but their expression in neurons remains unknown. We showed here by immunofluorescence microscopy that nectin‐2α, but not nectin‐2δ, was prominently expressed in the cholinergic neurons in the developing and adult MHbs and localized at the boundary between the adjacent somata of the clustered cholinergic neurons where the voltage‐gated A‐type K⁺ channel Kv4.2 was localized. Analysis by immunoelectron microscopy on this boundary revealed that Kv4.2 was localized at the membrane specializations (MSs) with plasma membrane darkening in an asymmetrical manner, whereas nectin‐2α was localized on the apposed plasma membranes mostly at the outside of these MSs, but occasionally localized at their edges and insides. Nectin‐2α at this boundary was not colocalized with the nectin‐2α‐binding protein afadin, other CAMs, or their interacting peripheral membrane proteins, suggesting that nectin‐2α forms a cell adhesion apparatus different from the Kv4.2‐associated MSs. Genetic ablation of nectin‐2 delayed the localization of Kv4.2 at the boundary between the adjacent somata of the clustered cholinergic neurons in the developing MHb. These results revealed the unique localization of nectin‐2α and its regulatory role in the localization of Kv4.2 at the MSs in the MHb.     

Necl-5/PVR enhances PDGF-induced attraction of growing microtubules to the plasma membrane of the leading edge of moving NIH3T3 cells

Microtubules (MTs) search for and grow toward the leading edge of moving cells, followed by their stabilization at a specific structure at the rear site of the leading edge. This dynamic re-orientation of MTs is critical to directional cell movement. We previously showed that Necl-5/poliovirus receptor (PVR) interacts with platelet-derived growth factor (PDGF) receptor and integrin α(v) β(3) at the leading edge of moving NIH3T3 cells, resulting in an enhancement of their directional movement. We studied here the role of Necl-5 in the PDGF-induced attraction of growing MTs to the leading edge of NIH3T3 cells. Necl-5 enhanced the PDGF-induced growth of MTs and attracted them near to the plasma membrane of the leading edge of NIH3T3 cells in an integrin α(v) β(3) -dependent manner. Furthermore, Necl-5 enhanced the PDGF-induced attraction of the plus-end-tracking proteins (+TIPs), including EB1, CLIP170, an intermediate chain subunit of cytoplasmic dynein, and p150(Glued) , a subunit of dynactin, near to the plasma membrane of the leading edge. Thus, Necl-5 plays a role in the attraction of growing MTs to the plasma membrane of the leading edge of moving cells.     

Randomized phase III trial of trastuzumab monotherapy followed by trastuzumab plus docetaxel versus trastuzumab plus docetaxel as first-line therapy in patients with HER2-positive metastatic breast cancer: the JO17360 Trial Group

We evaluated the efficacy and safety of sequential therapy with trastuzumab monotherapy (H-mono) followed by H plus docetaxel (D) after disease progression (H → H + D) versus combination therapy with H + D as first-line therapy. Patients with human epidermal growth factor receptor type 2 (HER2)-positive metastatic breast cancer (MBC) and left ventricular ejection fraction >50% were randomly assigned to either (a) H → H + D [H, once weekly 2 mg/kg (loading dose, 4 mg/kg); D, once every 3 weeks 60 mg/m²] or (b) H + D. Primary endpoints were progression-free survival (PFS) for the H-mono stage of the H → H + D group and H + D group and overall survival (OS) for both groups. Secondary endpoints were overall response rate, time to treatment failure, second PFS and safety. The planned number of patients was 160 patients in total. Of 112 patients enrolled, 107 were eligible. After 112 patients were enrolled, the Independent Data Monitoring Committee recommended stopping enrollment because PFS and OS were greater in the H + D group than the H → H + D group. Median PFS was 445 days in the H + D group versus 114 days for H-mono in the H → H + D group [hazard ratio (HR), 4.24; P < 0.01]. OS was significantly longer in the H + D group (HR, 2.72; P = 0.04). H + D therapy is significantly superior to H → H + D therapy as first-line therapy in patients with HER2-positive MBC, especially in terms of OS.     

Cisplatin with dose-dense paclitaxel before and after radical hysterectomy for locally advanced cervical cancer: a prospective multicenter phase II trial with a dose-finding study

The aim of this study is to evaluate the outcome and safety of the multidisciplinary strategy using cisplatin plus dose-dense paclitaxel (dose-dense TP) before and after radical hysterectomy (RH) for stage IB2, IIA2, or IIB patients with cervical cancer. In the dose-finding phase, 12 patients received 3 cycles of cisplatin (75 mg/m², day 1) with paclitaxel (70 or 80 mg/m², days 1, 8, and 15) every 21 days as neoadjuvant chemotherapy (NAC). In the phase II study, 51 patients received 3 cycles of dose-dense TP at the recommended dose as NAC, and another 2 cycles of the same regimen after RH. The primary endpoint was 2-year progression-free survival (PFS). The secondary endpoints were 2-year overall survival (OS), adverse events (AEs), response rate (RR), and pathological complete response (pCR) rates. The recommended dose of paclitaxel at dose-finding phase was 80 mg/m². In the phase II study, 34 patients (66.7%) had FIGO stage IIB disease. The RR and pCR rates were 94 and 28%. With a median follow-up duration of 58 months, each of the 2- and 5-year PFS rates was 88.2%, the 2- and 5-year OS rates were 94.1 and 88.2%, respectively. The incidence of grade 3/4 AEs was neutropenia (34%), nausea (12%), appetite loss (10%), fatigue (6%), and anemia (6%). Febrile neutropenia was uncommon (2%). Dose-dense TP before and after RH achieved a good long-term survival and was feasible for patients with locally advanced cervical cancer.     

Tarsal tunnel syndrome in athletes

BACKGROUND: The details of the occurrence of tarsal tunnel syndrome in athletes have not been well documented in the literature, and more data on tarsal tunnel syndrome related to sporting activity are necessary to enable better recognition of this condition. HYPOTHESIS: Sporting activities make athletes vulnerable to the occurrence of tarsal tunnel syndrome under specific conditions. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between 1986 and 2002, 18 patients with tarsal tunnel syndrome related to sporting activities were surgically treated, of whom 15 patients (21 feet; mean age, 17.8 years) were competitive athletes and 3 were recreational sports amateurs (4 feet; mean age, 52.7 years). To assess the role of physical factors and sporting activities in making athletes vulnerable to the occurrence of tarsal tunnel syndrome, the authors reviewed the medical charts and evaluated the results of treatment. The mean duration of follow-up was 58.6 months. RESULTS: Activities that triggered tarsal tunnel syndrome were those that applied a heavy burden on the ankle joint such as sprinting, jumping, and performing ashibarai in judo under specific physical conditions. Predisposing underlying physical factors were flatfoot deformity and an existence of talocalcaneal coalition, accessory muscles, and bony fragments around the tarsal tunnel. The majority of patients were able to return to the same sport after treatment. CONCLUSION: Tarsal tunnel syndrome occurs in athletes involved in strenuous sporting activities, especially when predisposing physical factors are present.     

Clinicopathologic features of brain metastases from gynecologic malignancies: A retrospective study of 139 cases (KCOG-G1001s trial)

ObjectiveAlthough brain metastases from gynecologic malignancies are rare, such cases have been gradually increasing in number. The aim of the present study was to evaluate the clinicopathologic features and prognostic factors of brain metastases from gynecologic malignancies.MethodsRetrospective analysis of 139 patients with brain metastases from gynecologic malignancies was carried out as a multi-institutional study. The clinicophathological data of the patients were collected from medical records.ResultsMedian survival time of the patients with brain metastases was 12.5 months for the ovarian cancer group, 6.2 months for the corpus cancer group, and 5.0 months for the cervical cancer group; two-year overall survival rates were 19.7%, 6.1%, and 4.8%, respectively. Multivariate analysis revealed ovarian/tubal/peritoneal origin, KPS > 70, single brain metastasis, absence of extracranial disease, cranial surgery, cranial radiotherapy, and chemotherapy to be independent favorable prognostic factors associated with overall survival.ConclusionIt is considered that aggressive multimodal therapy is warranted in the treatment of brain metastases from gynecologic malignancies in carefully selected patients. The present study may provide a platform for the discussion of management strategies in these rare clinical scenarios.     

Correction to: Risk assessment in the patients with uterine cervical cancer harboring intermediate risk factors after radical hysterectomy: a multicenter,retrospective analysis by the Japanese Gynecologic Oncology Group

International Journal of Clinical Oncology -     

Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208

A randomized controlled trial was conducted to evaluate the efficacy of high-dose chemotherapy (HDC) as consolidation of the treatment of high-risk postoperative breast cancer. Patients under 56 years of age with stage I to IIIB breast cancer involving 10 or more axillary lymph nodes were eligible. The primary endpoint was relapse-free survival (RFS). Between May 1993 and March 1999, 97 patients were enrolled, and two patients became ineligible. The median age of the 97 patients was 46 years (range 27–55 years), and 72 (74%) were premenopausal. The median number of involved axillary nodes was 16 (range 10–49). All patients had undergone a radical mastectomy. Major characteristics were well balanced between the treatment arms. Forty-eight patients in the standard-dose (STD) arm received six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen. Forty-nine patients were assigned to undergo HDC with cyclophosphamide and thiotepa after six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen; however, 15 of these patients (31%) did not undergo HDC. HDC was well tolerated without any treatment-related mortality. At a median follow-up of 63 months, the 5-year RFS of 47 eligible patients in the STD arm and 48 eligible patients in the HDC arm was 37% and 52% on an intent-to-treat basis, respectively ( P  = 0.17). Five-year overall survival of all randomized patients was 62% for the STD arm and 63% for the HDC arm ( P  = 0.78). Although the prespecified values of the two arms were not so accurate as to allow detection of the observed difference, no advantage of HDC was observed in terms of RFS or overall survival. ( Cancer Sci 2008; 99: 145–151)     

Chemotherapy consisting of paclitaxel and carboplatin benefits a patient with malignant mixed müllerian tumor of the fallopian tube

Malignant mixed müllerian tumors (MMMT) of the fallopian tube are extremely rare, and optimal therapy for them is unknown. A 71-year-old woman presented to us with symptoms of abdominal distension and nausea. A right salpingo-oophorectomy was performed. Pathological examination determined International Federation of Gynecology and Obstetrics (FIGO) stage IIIc MMMT of the right fallopian tube. Of note, multiple tumoral nodules were attached to the sigmoid colon. The patient received three courses of chemotherapy, consisting of 175 mg/m² paclitaxel and AUC = 5 carboplatin (TC therapy), administered at 3-week intervals. A second, debulking, surgery was then performed, consisting of total abdominal hysterectomy, left salpingo-oophorectomy, and pelvic and paraaortic lymphadenectomy. The tumor attached to the sigmoid colon had shrunk by 60% after chemotherapy. The patient received an additional five courses of adjuvant TC therapy. The patient is alive and free of disease 28 months after the debulking surgery. TC therapy may be effective for MMMT of the fallopian tube.