Relevance of level IIb neck dissection in patients with papillary thyroid carcinoma.

BACKGROUND: Cervical nodal metastasis is a key prognostic factor in patients with papillary thyroid carcinoma. The role of lymph nodes in papillary thyroid carcinoma management and prognosis remains controversial. METHODS: Level IIb lymph nodes obtained from 44 patients with papillary thyroid carcinoma were histopathologically examined retrospectively. Specimens were classified as ipsilateral or contralateral. The number of dissected nodes and prevalence of level IIb metastasis were compared according to pre-operative clinical nodal stage. RESULTS: In the node-negative neck, the prevalence of contralateral and ipsilateral IIb nodes was 0 out of 20 and 0 out of 3, respectively. In the node-positive neck, the prevalence of contralateral and ipsilateral IIb nodes was 1 out of 13 (7.70 per cent) and 3 out of 41 (7.32 per cent), respectively. Clinically determined and pathologically confirmed level IIb node negativity were significantly associated. Thirty-four patients (77.3 per cent) developed accessory nerve complications from level IIb dissection. CONCLUSION: Level IIb neck dissection for papillary thyroid carcinoma may be required if pre-operative examination reveals multilevel, level IIa or suspicious level IIb metastasis.

Emergent thyroidectomy with sternotomy due to acute respiratory failure with severe thyroid storm.

Huge cervical and mediastinal masses may lead to acute respiratory failure caused by laryngotracheal compression and airway obstruction. Thyroid storm is also a life-threatening endocrine emergency originating almost exclusively from uncontrolled Graves' disease. We report a case of a 42-year-old man with acute upper airway obstruction and tachycardia from progressive swelling of a giant thyroid, in conjunction with thyroid storm resulting from uncontrolled Graves' disease. Fibreoptic-assisted nasal intubation was performed while the patient was awake, immediately followed by emergency total thyroidectomy via a cervical and sternal approach. The patient had an uneventful postoperative course and recovered well. Respiratory failure due to swelling of a giant thyroid is a life-threatening condition and should be treated immediately with endotracheal intubation while the patient is awake following emergent total thyroidectomy, even with a sternotomy.

Survival outcomes after surgical resection of pulmonary metastases of head and neck tumours.

BACKGROUND: There is limited information available regarding the benefits and outcomes of resection of pulmonary metastases arising from head and neck cancers. METHODS: A retrospective review was performed of 21 patients who underwent resection of pulmonary metastases of primary head and neck malignancies at Hamamatsu University Hospital. Clinical staging, treatment methods, pathological subtype (particularly squamous cell carcinoma), disease-free interval and overall survival were evaluated. RESULTS: The 5- and 10-year overall survival rates of the study participants were 67.0 per cent and 55.0 per cent, respectively, as determined by the Kaplan-Meier method. The prognosis for patients with a disease-free interval of less than 24 months was poor compared to those with a disease-free interval of greater than 24 months (p = 0.0234). CONCLUSION: Patients with short disease-free intervals, and possibly those who are older than 60 years, should be categorised as having severe disease. However, pulmonary metastases from head and neck malignancies are potentially curable by surgical resection.

Protracted dormancy of pre-leukemic stem cells.

Cancer stem cells can escape therapeutic killing by adopting a quiescent or dormant state. The reversibility of this condition provides the potential for later recurrence or relapse, potentially many years later. We describe the genomics of a rare case of childhood BCR-ABL1-positive, B-cell precursor acute lymphoblastic leukemia that relapsed, with an acute myeloblastic leukemia immunophenotype, 22 years after the initial diagnosis, sustained remission and presumed cure. The primary and relapsed leukemias shared the identical BCR-ABL1 fusion genomic sequence and two identical immunoglobulin gene rearrangements, indicating that the relapse was a derivative of the founding clone. All other mutational changes (single-nucleotide variant and copy number alterations) were distinct in diagnostic or relapse samples. These data provide unambiguous evidence that leukemia-propagating cells, most probably pre-leukemic stem cells, can remain covert and silent but potentially reactivatable for more than two decades.

Carcinoma of the external auditory canal: histological and treatment groups.

OBJECTIVE: Evaluation of the clinical and pathological factors associated with the treatment and outcomes of external auditory canal (EAC) carcinomas. METHODOLOGY: A retrospective review of clinical and pathological analysis was performed on 23 patients who were histologically diagnosed with EAC carcinomas and treated at Hamamatsu University hospital. We evaluated the clinical staging, treatment methods, pathological diagnosis (particularly squamous cell carcinoma, SCC), and patient outcomes. Main outcome measures include staging, treatment procedures, pathological features, and estimated survival rates. RESULTS: The 5-year overall survival (OS) of study participants was 75.2% and the 10-year OS was 60.2% using the Kaplan-Meier method. The prognosis for SCC was poor compared with other carcinomas (p= 0.0462). The prognoses for SCC patients after treatment with surgery alone and after postoperative radiotherapy or chemoradiotherapy were significantly better than for patients with unresectable tumours (p = 0.0004 and p = 0.0001, respectively). There was no significant difference among the four tumour stage groups. Information about patients' survival status was obtained after a median follow-up period of 57.5 months (range, 7-151 months). CONCLUSION: Our survival analysis data for carcinoma of the EAC demonstrates that SCC and unresectable cases are associated with poor outcomes. Outcomes for patients with operable disease more closely parallel the survival curves of patients with advanced stage T4 disease. Patients with SCC should be strictly categorized as cases with severe disease.

Clinical study of mucosa-associated lymphoid tissue lymphomas of the head and neck.

BACKGROUND: Limited information is available on mucosa-associated lymphoid tissue lymphomas arising in the head and neck. METHOD: A retrospective analysis was conducted of 20 patients who were histologically diagnosed with mucosa-associated lymphoid tissue lymphoma and treated at our institution between January 1990 and December 2009. RESULTS: Treatment consisted of surgical resection alone in two patients (10 per cent), surgical resection with consecutive radiotherapy in one (5 per cent), and radiotherapy alone in eight (40 per cent). Three patients (15 per cent) were treated with systemic chemotherapy, and three (15 per cent) received chemoradiotherapy. Three patients (15 per cent) were informed of the diagnosis but not treated for their condition. CONCLUSION: All of the 20 patients were still alive after a mean follow-up period of 50.8 months. Local treatment for mucosa-associated lymphoid tissue lymphoma of the head and neck should be the first choice in early-stage disease. However, prolonged follow up is important to determine these patients' long-term response to treatment.

Long-term outcomes after hematopoietic SCT for adult T-cell leukemia/lymphoma: results of prospective trials.

We have previously conducted clinical trials of allogeneic hematopoietic SCT with reduced-intensity conditioning regimen (RIC) for adult T-cell leukemia/lymphoma (ATLL)-a disease caused by human T-lymphotropic virus type 1 (HTLV-1) infection and having a dismal prognosis. Long-term follow-up studies of these trials revealed that 10 of the 29 patients have survived for a median of 82 months (range, 54-100 months) after RIC, indicating a possible curability of the disease by RIC. However, we have also observed that the patterns of post-RIC changes in HTLV-1 proviral load over time among the 10 survivors were classified into three patterns. This is the first report to clarify the long-term outcomes after RIC for ATLL patients.

TBI and melphalan followed by allogeneic hematopoietic SCT in children with advanced hematological malignancies.

We evaluated the efficacy and safety of the conditioning regimen that consisted of TBI and melphalan (L-PAM), followed by hematopoietic SCT (HSCT) in 23 children with advanced hematological malignancies. The median age at HSCT was 9 (range, 2-15) years. The underlying diseases were ALL in 16 patients (5 in CR2, 3 in CR3, 6 in relapse (RP) and 2 in induction failure (IF)), AML in 4 patients (3 in RP and 1 in IF) and non-Hodgkin's lymphoma in 3 patients (1 in CR3, 1 in CR4 and 1 in RP). The stem cell sources were BM for 19 patients and cord blood for 4 patients. All patients received the conditioning regimen that consisted of TBI 12 or 13.2 Gy and L-PAM 210 mg/m(2). In all, 22 patients engrafted on the median of day 16 (range, 10-23). The regimen was well tolerated and common regimen-related toxicities (RRTs) included grade II stomatitis and grade I hepatic toxicity. The cumulative incidences of RP and TRM were 47.6 and 21.5%, respectively. At a median follow-up of 24.4 months, the probability of disease-free survival was 41.0%. The regimen may provide sufficient anti-leukemic effect without increased RRT for advanced pediatric hematological malignancies.

CD34+CD38+CD19+ as well as CD34+CD38-CD19+ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL.

The presence of rare malignant stem cells supplying a hierarchy of malignant cells has recently been reported. In human acute myelogenous leukemia (AML), the leukemia stem cells (LSCs) have been phenotypically restricted within the CD34+CD38- fraction. To understand the origin of malignant cells in primary human B-precursor acute lymphocytic leukemia (B-ALL), we established a novel in vivo xenotransplantation model. Purified CD34+CD38+CD19+, CD34+CD38-CD19+ and CD34+CD38-CD19- bone marrow (BM) or peripheral blood (PB) cells from three pediatric B-ALL patients were intravenously injected into sublethally irradiated newborn NOD/SCID/IL2rgamma(null) mice. We found that both CD34+CD38+CD19+ and CD34+CD38-CD19+ cells initiate B-ALL in primary recipients, whereas the recipients of CD34+CD38-CD10-CD19- cells showed normal human hematopoietic repopulation. The extent of leukemic infiltration into the spleen, liver and kidney was similar between the recipients transplanted with CD34+CD38+CD19+ cells and those transplanted with CD34+CD38-CD19+ cells. In each of the three cases studied, transplantation of CD34+CD38+CD19+ cells resulted in the development of B-ALL in secondary recipients, demonstrating self-renewal capacity. The identification of CD34+CD38+CD19+ self-renewing B-ALL cells proposes a hierarchy of leukemia-initiating cells (LICs) distinct from that of AML. Recapitulation of patient B-ALL in NOD/SCID/IL2rgamma(null) recipients provides a powerful tool for directly studying leukemogenesis and for developing therapeutic strategies.

Low-dose MTX for the treatment of acute and chronic graft-versus-host disease in children.

We report the results of a retrospective analysis in 27 pediatric patients who received low-dose MTX as the second-line treatment for steroid-refractory or -dependent acute and chronic GVHD. Between July 2000 and May 2006, 10 patients with aGVHD and 17 with cGVHD were treated with MTX at a dose of 3-10 mg/m(2) weekly. Seven of ten patients (70%) with aGVHD responded well to MTX, thus resulting in the achievement of either a complete response (CR) or a partial response (PR). The dose of prednisone could be reduced to equal to or lower than 1 mg/kg in the responding patients at the end of MTX therapy. The median number of MTX administrations was five (range, 1-7). Ten (58.8%) of seventeen patients with cGVHD achieved CR or PR. The dose of prednisone could be reduced to lower than 0.4 mg/kg in 16 of 17 patients and seven patients could discontinue prednisone. The median duration of MTX administration was 18 months (range, 1-68). The toxicities of grade III to IV occurred in only six patients presenting cytopenias or elevated levels of serum transaminases. Low-dose MTX was tolerable and effective for the steroid-refractory or -dependent GVHD in reducing the dose of steroid without increasing the risk of opportunistic infection.

Allogeneic hematopoietic stem cell transplantation provides sustained long-term survival for patients with adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a distinct peripheral T-cell neoplasm that is highly resistant to chemotherapy. Several groups, including ours, have reported encouraging results of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with ATLL. To confirm our previous report and to establish the basis for a phase II clinical study, we analyzed 40 allo-HSCT for acute and lymphoma types of ATLL in seven institutions in Japan between 1997 and 2002. All evaluable cases entered complete remission (CR) after allo-HSCT and the median survival time was 9.6 months for all patients. The estimated 3-year overall and relapse-free survival, and disease relapse were 45.3, 33.8 and 39.3%, respectively. Among 10 cases with ATLL relapse, five cases achieved CR again: three by the reduction or cessation of immunosuppressive agents, which suggested a graft-versus-ATLL (GvATLL) effect. However, univariate or multivariate analysis did not show any benefit of graft-versus-host disease (GVHD) on the prevention of relapse. These results suggested that allo-HSCT was effective for some patients with aggressive ATLL, and that the GvATLL effect could be achieved even without GVHD. A new phase II trial to test the efficacy of allo-HSCT for ATLL is warranted.

Clinical characteristics and the prognosis of rhabdomyosarcoma - a report from the Study Group for Pediatric Solid Malignant Tumors in the Kyushu Area, Japan.

AIM: There have been no nationwide group studies for patients with rhabdomyosarcoma in Japan. This study aims to assess the actual state of treatments and their outcome. PATIENTS AND METHODS: From 1982 to 1996, 79 rhabdomyosarcomas were registered by the Study Group for Pediatric Solid Malignant Tumors in the Kyushu Area. The prognostic factors and treatments were assessed based on the 5-year survival rate. The staging was done according to the Intergroup Rhabdomyosarcoma Study (IRS) Clinical Grouping Classification. RESULTS: The 5-year survival rate for all patients was 39.1 %. The survival rates for each factor were as follows, according to 1) group; 77.8 % for Group I, 51.9 % for Group II, 33.7 % for Group III, and 20.2 % for Group IV; 2) primary site: 56.3 % for the head and neck, 43.8 % for the parameningeal region, 12.5 % for the extremity, 58.3 % for the genitourinary region, and 30.5 % for the others; 3) histology: 35.8 % for the embryonal type, 36.8 % for the alveolar type. CONCLUSIONS: Altogether, the outcome of this study was poor. To improve outcomes, a new nationwide group study for rhabdomyosarcoma, which we belong to, has just started in Japan.

Morphological and physiological identification of medulla interneurons in the visual system of the tiger beetle larva.

The morphology of visual interneurons in the tiger beetle larva was identified after recording their responses. Stained neurons were designated as either medulla or protocerebral neurons according to the location of their cell bodies. Medulla neurons were further subdivided into three groups. Afferent medulla neurons extended processes distally in the medulla neuropil and a single axon to the brain through the optic nerve. They received their main input from stemmata on the ipsilateral side. Two distance-sensitive neurons, near-by sensitive and far-sensitive neurons, were also identified. Atypical medulla neurons extended their neurites distally in the medulla and proximally to the brain, as afferent medulla neurons, but their input patterns and the shapes of their spikes differed from afferent neurons. Protocerebral neurons sent a single axon to the medulla neuropil. They spread collateral branches in the posterior region of the protocerebrum on its way to the medulla neuropil. They received main input from stemmata on the contralateral side. Medulla intrinsic neurons did not extend an axon to the brain, and received either bilateral or contralateral stemmata input only. The input patterns and discharge patterns of medulla neurons are discussed with reference to their morphology.

Improved survival outcome for hepatoblastoma based on an optimal chemotherapeutic regimen--a report from the study group for pediatric solid malignant tumors in the Kyushu area.

BACKGROUND/PURPOSE: The survival outcome for patients with hepatoblastoma normally depends on the resectability of the tumor. In Japan, the pre and/or postoperative chemotherapy protocol using a combination of cisplatin (CDDP) and tetrahydropyranyl-Adriamycin (THP-ADR) has been the standard treatment since 1991. This study aims to assess exactly what influence the establishment of this chemotherapy protocol has had on both the tumor resectability and the outcome of patients with hepatoblastoma. METHODS: From 1982 to 1997, 60 patients with hepatoblatoma were treated in the Kyushu area, Japan. Based on the pretreatment extent of disease (PRETEXT), the outcome and tumor resectability were compared between group A (1982 to 1990, n = 27, PRETEXT I:5, II:8, III:6, IV:8) and group B (1991 to 1997, n = 33, PRETEXT I:9, II:9, III:5, IV:10). RESULTS: The 5-year survival rates (group A and group B) were 33% and 73% for all cases (P <.01), 100% and 89% for PRETEXT I, 38% and 89% for II (P <.05), 17% and 80% for III (P <.01), and 0% and 40% for IV (P <.01), respectively. The 5-year survival rates for patients with metastases were 0% for group A (n = 5) and 57% for group B (n = 7; P <.01). The rates of a complete resection of primary tumor were 48% for group A and 67% for group B. In particular, a significant difference was found regarding the complete resection rate between groups A and B in the patients with PRETEXT III (17% for group A and 80% for group B; P <.01). In the patients with an incomplete tumor resection (14 for group A, 11 for group B), the 5-year survival rates were 0% for group A and 45% for group B (P <.01). CONCLUSIONS: The optimal chemotherapeutic regimen of CDDP and THP-ADR was thus found to greatly contribute to the improved survival rate of hepatoblastoma patients. Preoperative chemotherapy resulted in an increased resectability of the tumor, whereas postoperative chemotherapy played an important role in the increased cure rate of cases with either an incomplete tumor resection or metastasis. However, refractory cases with PRETEXT IV or metastasis may still require the development of an even more effective treatment modality, including the use of blood stem cell transplantation.

Methotrexate vs Cyclosporin A as a single agent for graft-versus-host disease prophylaxis in pediatric patients with hematological malignancies undergoing allogeneic bone marrow transplantation from HLA-identical siblings: a single-center analysis in Japan.

The efficacy of methotrexate (MTX) as a single graft-versus-host disease (GVHD) prophylaxis agent was compared to that of cyclosporin A (CSA) in 62 pediatric patients (median age: 8 years) with hematological malignancies who had undergone bone marrow transplantation (BMT) from HLA-identical sibling donors at National Kyushu Cancer Center since 1977. In all, 30 patients received MTX by intravenous bolus injection, with a dose of 15 mg/m(2) on day +1, followed by 10 mg/m(2) on days +3, +6, and +11, and then once a week until day +100. A total of 32 patients were treated with CSA, which was given intravenously in the early stages and orally thereafter until day +100, and then gradually tapered and stopped 6 months after BMT. There were no differences between the groups in terms of rates of hematopoietic recovery after BMT. The probabilities of acute GVHD (grades II-IV) and chronic GVHD were 29.6 vs 40.6% (P=0.294) and 19 vs 20% (MTX vs CSA), respectively. Relapse rates and event-free survival were identical. These results suggest that MTX and CSA were equally effective when given after BMT in Japanese pediatric patients with hematological malignancies. Since MTX was given over a shorter time than CSA, it might be more practical in the management of such patients.

Lack of clinical utility of minimal residual disease detection in allogeneic stem cell recipients with childhood acute lymphoblastic leukemia: multi-institutional collaborative study in Japan.

The clinical utility of minimal residual disease (MRD) measurements following allogeneic stem cell transplantation (SCT) in childhood ALL is controversial. We therefore performed a multi-institutional study of MRD in bone marrow samples taken before SCT and at 1, 3, 6 and 12 months after SCT. Case-specific clonal rearrangements of IgH and TCR genes and expression levels of Wilms' tumor 1 (WT1) mRNA were determined by PCR or RT-PCR methods. In total, 95 cases met all criteria for analysis of informative IgH/TCR markers and quantitative WT1 mRNA expression levels. During the 2-year (median 414 days) study period, 20 patients relapsed. Although the proportion of patients with a positive IgH/TCR result before SCT was significantly reduced at 1 month after treatment (P<0.001), attesting the efficacy of SCT, serial measurements of IgH/TCR rearrangements did not correlate with leukemic relapse. Clonal switch was demonstrated in 11 of the 14 patients with bone marrow relapse, indicating that the poor predictive power of the MRD assay most likely reflected the loss of PCR targets. WT1 expression was not related to either MRD detection by IgH/TCR assays or to clinical leukemic relapse. The clinical value of serial MRD monitoring would be limited in ALL patients undergoing SCT.