Successful treatment of a patient with recurrent metastatic clear cell carcinoma of the uterine cervix.

Clear cell carcinoma (CCC) of the uterine cervix is a rare gynecologic cancer that accounts for 4-9% of adenocarcinoma of the uterine cervix. Two types of uterine cervical CCCs are known: A type that is associated with in utero exposure to diethylstilbestrol (DES) and idiopathic type that is unrelated to DES exposure. Due to its rare incidence, the clinical behavior and pathological characteristics of CCCs are not fully described and treatment recommendations are not standardized. Moreover, only a few cases are reported on the recurrent metastatic CCCs and the results of various treatment trials are inconsistent. We present a case of successfully treated idiopathic metastatic CCC of the uterine cervix that recurred after concurrent chemoradiotherapy.

Successful treatment results of external radiotherapy without brachytherapy in advanced uterine cervical cancer.

In advanced uterine cervical cancer, external radiotherapy with intracavitary brachytherapy has been established as a curative treatment method. However, in an environment where brachytherapy is difficult to perform, there has been an attempt to use only external radiotherapy. We report the results of eight patients over 65 years of age with advanced uterine cervical cancer who refused brachytherapy and obtained successful results through external radiotherapy alone.

S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells.

S100A8 and S100A9 function as essential factors in inflammation and also exert antitumor or tumorigenic activity depending on the type of cancer. Chronic eosinophilic leukemia (CEL) is a rare hematological malignancy having elevated levels of eosinophils and characterized by the presence of the FIP1L1-PDGFRA fusion gene. In this study, we examined the pro-apoptotic mechanisms of S100A8 and S100A9 in FIP1L1-PDGFRα+ eosinophilic cells and hypereosinophilic patient cells. S100A8 and S100A9 induce apoptosis of the FIP1L1-PDGFRα+ EoL-1 cells via TLR4. The surface TLR4 expression increased after exposure to S100A8 and S100A9 although total TLR4 expression decreased. S100A8 and S100A9 suppressed the FIP1L1-PDGFRα-mediated signaling pathway by downregulating FIP1L1-PDGFRα mRNA and protein expression and triggered cell apoptosis by regulating caspase 9/3 pathway and Bcl family proteins. S100A8 and S100A9 also induced apoptosis of imatinib-resistant EoL-1 cells (EoL-1-IR). S100A8 and S100A9 blocked tumor progression of xenografted EoL-1 and EoL-1-IR cells in NOD-SCID mice and evoked apoptosis of eosinophils derived from hypereosinophilic syndrome as well as chronic eosinophilic leukemia. These findings may contribute to a progressive understanding of S100A8 and S100A9 in the pathogenic and therapeutic mechanism of hematological malignancy.

Comparison of the effectiveness of monitoring Cisplatin-induced ototoxicity with extended high-frequency pure-tone audiometry or distortion-product otoacoustic emission.

BACKGROUND AND OBJECTIVES: To compare the effectiveness of monitoring cisplatin-induced ototoxicity in adult patients using extended high-frequency pure-tone audiometry (EHF-PTA) or distortion-product otoacoustic emission (DP-OAE) and to evaluate the concurrence of ototoxicity and nephrotoxicity in cisplatin-treated patients. SUBJECTS AND METHODS: EHF-PTA was measured at frequencies of 0.25, 0.5, 1, 2, 3, 4, 6, 8, 9, 11.2, 12.5, 14, 16, 18, and 20 kHz and DP-OAE at frequencies of 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 kHz in cisplatin-treated patients (n=10). Baseline evaluations were made immediately before chemotherapy and additional tests were performed before each of six cycles of cisplatin treatment. Laboratory tests to monitor nephrotoxicity were included before every cycle of chemotherapy. RESULTS: Four of 10 patients showed threshold changes on EHF-PTA. Five of 10 patients showed reductions in DP-OAE, but one was a false-positive result. The results of EHF-PTA and DP-OAE were consistent in two patients. Only one patient displayed nephrotoxicity on laboratory tests after the third cycle. CONCLUSIONS: In our study, the incidence rate of cisplatin-induced ototoxicity was 40% with EHF-PTA or DP-OAE. Although both EHF-PTA and DP-OAE showed the same sensitivity in detecting ototoxicity, they did not produce the same results in all patients. These two hearing tests could be used to complement one another. Clinicians should use both tests simultaneously in every cycle of chemotherapy to ensure the detection of ototoxicity.

A case of paratesticular leiomyosarcoma successfully treated with orchiectomy and chemotherapy.

A 50-year-old male patient presented with a right scrotal mass that had been growing rapidly for more than one year. A heterogeneous enhancing right scrotal mass (12×9 cm) with para-aortic and peri-caval lymphadenopathies was found on abdominal computed tomography (CT). Right orchiectomy was performed and the gross finding had shown intact testis with a well-defined, huge, whitish solid mass adjacent to the testis. According to pathology, the mass was characterized as a leiomyosarcoma, grade 3 (by National Cancer Instituted [NCI] system). Therefore, the diagnosis was stage III, grade 3 paratesticular leiomyosarcoma. The patient underwent additional systemic chemotherapy using ifosfamide and adriamycin. After nine cycles of chemotherapy, positron emission tomography-CT was performed and no FDP uptake was observed. The patient has been followed up for 12 months after systemic chemotherapy, and he has maintained a complete response. We report here on a rare case of paratesticular leiomyosarcoma treated successfully with orichiectomy and additional systemic chemotherapy.

Multiple myeloma with biclonal gammopathy accompanied by prostate cancer.

We report a rare case of multiple myeloma with biclonal gammopathy (IgG kappa and IgA lambda type) in a 58-year-old man with prostate cancer who presented with lower back pain. Through computed tomography (CT) imaging, an osteolytic lesion at the L3 vertebra and an enhancing lesion of the prostate gland with multiple lymphadenopathies were found. In the whole body positron emission tomography-computed tomography (PET-CT), an additional osteoblastic bone lesion was found in the left ischial bone. A prostate biopsy was performed, and adenocarcinoma was confirmed. Decompression surgery of the L3 vertebra was conducted, and the pathologic result indicated that the lesion was a plasma cell neoplasm. Immunofixation electrophoresis showed the presence of biclonal gammopathy (IgG kappa and IgA lambda). Bone marrow plasma cells (CD138 positive cells) comprised 7.2% of nucleated cells and showed kappa positivity. We started radiation therapy for the L3 vertebra lesion, with a total dose of 3,940 cGy, and androgen deprivation therapy as treatment for the prostate cancer.

Waldenstrom macroglobulinemia with CD5+ expression presented as cryoglobulinemic glomerulonephropathy: a case report.

Waldenstrom macroglobulinemia (WM) is a B-cell lymphoproliferative disorder associated with bone marrow involvement of lymphoplasmacytic lymphoma (LPL) and an IgM monoclonal gammopathy. Generally B-lymphocytes in LPL do not express CD5 that is important for differential diagnosis of B-cell lymphoproliferative disorders. In WM, various renal diseases and type I cryoglobulinemia are well described separately, but cryoglobulinemic glomerulonephropathy is very rarely reported. A 61-yr-old woman complained of generalized edema, cyanosis of the extremities in cold weather, visual disturbance, and pancytopenia. Bone marrow and renal biopsy showed CD5+ expressing B-cells and cryoglobulinemic glomerulonephropathy. With the diagnosis of WM, she received cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy and got complete remission. Here, we report a rare case of WM associated with unusual expression of CD5+ B-lymphocytes and cryoglobulinemic glomerulonephropathy, and emphasize the importance of the clinical features in differentiating CD5+ B-cell lymphoproliferative disorders.

A case of synchronous double primary cancer of the penis and urinary bladder.

Multiple primary cancers are the occurrence of more than two cancers of different origin in an individual. Penile cancer is a rare disease, and finding it combined with other cancers is even rarer. A 64-year-old man with a painful penile mass was referred to us from a primary urological clinic. We performed a biopsy of the penile mass and the histology revealed a well-differentiated squamous cell carcinoma. Abdominal computed tomography showed a localized bladder tumor with inguinal lymphadenopathy. The patient underwent a partial penectomy, transurethral resection of the bladder tumor and inguinal lymph node dissection. The histology of the bladder tumor was high-grade papillary carcinoma, and that of the lymph node was squamous cell carcinoma. The penile and bladder tumors were in stage II (T1N1M0) and stage I (T1N0M0), respectively. We successfully treated the patient with adjuvant radiotherapy and systemic chemotherapy.

[A case of a Korean adult affected by type B Niemann-Pick disease: secondary sea-blue histiocytosis and molecular characterization].

Niemann-Pick disease (NPD) is an inherited metabolic disorder caused by a deficiency of the enzyme acid sphingomyelinase coded by SMPD1 gene. In contrast with type A NPD, a severe neurodegenerative disease of infancy, type B NPD patients have little or no neurodegeneration, and frequently survive into adulthood. Although over 100 mutations have been found within the SMPD1 gene causing NPD, there was only one report about SMPD1 mutation status of a Korean NPD patient. We report a case of a 32-yr-old female, who presented with thrombocytopenia without any neurologic involvement. Hepatosplenomegaly was detected by both physical examination and imaging studies, and a thoracic radiograph examination showed a pattern of interstitial lung disease. Biochemical tests revealed increased liver enzymes, cholesterol, triglyceride, and LDL-cholesterol, and decreased HDL-cholesterol. Sea-blue or foamy vacuolated histiocytes occurred in bone marrow and liver. Sequencing analysis of SMPD1 using genomic DNA from peripheral leukocytes identified a compound heterozygote of two mutations at exon 2: p.E246K and p.A357V. The former is a known mutation in an Italian patient, and the latter has not been reported yet. She has received oral rosuvastatin to treat hyperlipidemia at a dose of 10 mg per day for 4 months. This is the second report in which the mutation of SMPD1 gene was detected in a Korean NPD patient. The active genetic analysis of SMPD1 gene in patients with typical findings of type B NPD would enable us to facilitate diagnosis as well as to accumulate data on molecular characteristics of Korean NPD patients.

Adenocarcinoma has an excellent outcome with pemetrexed treatment in Korean patients: a prospective, multicenter trial.

OBJECTIVE: This prospective multicenter study conducted by the Korean Cancer Study Group evaluated the efficacy and safety of pemetrexed in Korean patients with advanced non-small cell lung cancer (NSCLC) who had prior chemotherapy. PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC in whom prior chemotherapy failed received pemetrexed 500 mg/m(2) every 3 weeks with folic acid and vitamin B12 supplementation until disease progression or the development of intolerable toxicity. Eighty-one patients were enrolled. RESULTS: The overall response rate for 78 evaluable patients was 5.1% [95% confidence interval (CI) 1.4-12.6; partial response 4/78, no complete response]. The disease control rate including complete, partial response and stable disease was 46.2% (36/78, 95% CI 34.8-57.8). With a median 8.7 months follow-up, the median time to progression was 3.1 months (95% CI 1.17-5.03) and the median overall survival (OS) was 7.8 months (95% CI 5.19-10.35). The median OS for patients with adenocarcinoma histology was 18.7 months compared to 6.1 months for non-adenocarcinoma. In a multivariate analysis, Eastern Cooperative Oncology Group performance status 0-1 [hazards ratio (HR)=0.331, 95% CI 0.135-0.814] and adenocarcinoma (HR=0.504, 95% CI 0.283-0.899) were independent factors for prolongation of overall survival. CONCLUSIONS: Pemetrexed monotherapy has promising efficacy in patients with advanced NSCLC as a second-line therapy with less hematologic and non-hematologic toxicity, especially in those with adenocarcinoma histology.

Systemic chemotherapy after cranial irradiation in patients with brain metastases from non-small cell lung cancer: a retrospective study.

BACKGROUND: Brain metastases (BMs) are found in about 10% of patients with newly diagnosed non-small cell lung cancer (NSCLC). This retrospective study was conducted to assess the clinical outcomes and prognostic factors of patients who received chemotherapy after cranial irradiation for NSCLC with synchronous BMs. MATERIALS AND METHODS: From January 2000 through July 2007, we reviewed the medical records of patients who received systemic chemotherapy following cranial irradiation for BMs from newly diagnosed NSCLC. RESULTS: A total of 40 patients were included in this review. As the first-line chemotherapy, a total of 114 cycles were administered, for a median number of 2 cycles per patient (range, 0.5-8 cycles). Thirty-four patients (85%) received platinum-based combination regimen and the remaining 6 received chemotherapy with a single agent. Sixteen (40%) patients, 11 of whom had ECOG of 2, only received 1 cycle or less of chemotherapy due to early death, rapid progression, clinical impairment, or toxicity. For 28 patients who were evaluable for response, the extracranial overall response rate was 43%. The median overall survival for all patients was 7 months (range, 0.9-25.3 months) and an estimated 1-year survival rate was 23%. Multivariate analysis revealed that ECOG status (P=0.018) and number of BM (P=0.038) were independent prognostic factors. CONCLUSION: Our results suggest that chemotherapy can be used to increase survival of patients treated with cranial irradiation for newly diagnosed NSCLC with synchronous BM. However, systemic chemotherapy should be carefully considered according to the patient's prognostic condition. Especially, patients with good performance status and limited number of BM may be good candidates for systemic chemotherapy after cranial irradiation.

Unicentric castleman disease is not clearly distinguished from multicentric type: a case report.

Castleman disease (CD) was recently classified as a unicentric hyaline vascular variant, unicentric plasma cell variant, and multicentric plasma cell variant. It is rare that unicentric CD is presented as multiple retroperitoneal lymphadenopathy. The clinical manifestations and prognosis depends on histologic type. We report an unusual case of CD with multiple retroperitoneal lymphadenopathy, which had unicentric hyaline vascular variant histologically but was clinically multicentric. The patient experienced anemia, weight loss, elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), and plasmacytosis in bone marrow without human herpesvirus-8 or HIV. After exploratory laparotomy and lymphadenectomy under presumptive diagnosis of CD, the patient's symptoms recovered, and CRP and ESR decreased. Therefore, we suggest that unicentric CD is not clearly distinguished from multicentric, the type in this report, focusing on the useful role of CRP, ESR, and positron emission tomography/computed tomography in the disease activity of CD.

Clinical outcomes of patients with liver cirrhosis who underwent curative surgery for gastric cancer: a retrospective multi-center study.

We investigated early postoperative morbidity, mortality, and long-term outcomes in patients with liver cirrhosis (LC) who had undergone curative surgery for gastric cancer. The medical records of patients with LC who had undergone radical gastrectomy for gastric adenocarcinoma between January 1996 and September 2006 were retrospectively reviewed. A total of 57 patients were enrolled in this study. Forty-six patients (81%) were classified into Child's class A. In 22 patients (39%) postoperative complications developed, the most common being ascites (23%), followed by wound infection and hepatic encephalopathy. Postoperative ascites occurred more frequently in patients with Child's class B or C than in those with class A (63.6% vs 13%, P = 0.001). Massive ascites developed in 4 patients, 3 of whom had Child's class B and underwent D2 lymph node (LN) dissection, and 1 of whom had Child's class C and a D1 LN dissection. Postoperative mortality occurred in 5 patients (9%), with a significantly higher mortality rate for patients with Child's class B or C than for those with class A (27.2% vs 4.3%, P = 0.045). With a median follow-up of 32 months, the estimated 5-year survival rate for all patients was 54%. Regardless of the tumor depth, overall survival was longer for patients with Child's class A than for those with Child's class B or C. These results demonstrated that radical gastrectomy with extended LN dissection is feasible in patients with compensated LC. For patients with moderate to severe hepatic dysfunction, however, D1 or less extensive LN dissection may be the more reasonable surgical procedure.

Bilateral breast cancer: differential diagnosis using histological and biological parameters.

BACKGROUND: Contralateral breast cancer is either a metastatic lesion or the second primary cancer. From biological and therapeutic viewpoints, it is important to differentiate metastatic lesions from second primary cancer in bilateral breast cancer. METHODS: Based on Chaudary's histological criteria, we analysed the tumors in 14 and 27 patients with synchronous and metachronous bilateral breast cancers with full histological and biological evaluations. The Nottingham combined histological grade and immunohistochemistry (IHC) for the estrogen receptor, progesterone receptor and cerbB-2 were used. RESULTS: The median age of the patients at first diagnosis was 41 years (range, 26-68 years) and the median time interval between first and second tumors was 34 months (range; 7-209 months) in metachronous cancers. The histopathological type was found in 93% of synchronous cancers and 59% of metachronous cancers (P = 0.02). The concordance rates of T stage and TNM stage were 71 and 64% respectively in synchronous cancers, while they were 24 and 32% respectively in metachronous cancers (P = 0.03). For progesterone receptor status, the concordance rates were 86 and 52% in synchronous and metachronous cancers respectively (P = 0.03). In addition, there was no statistically significant difference in terms of N stage, histological grade, intraductal component, estrogen receptor status, or cerbB-2 expression. CONCLUSION: In spite of the limitation of Chaudary's criteria and the number of patients involved, the combination of histopathological type, T stage and TNM stage shows that synchronous cancers are closer to same clonal lesions (metastatic lesions) than metachronous cancers and that a biomarker, such as progesterone receptor status, plays a role in addition to the histological parameters in differentiating metastatic cancers from second primary cancers.

Protein-kinase-C-mediated beta-catenin phosphorylation negatively regulates the Wnt/beta-catenin pathway.

Normally, the Wnt/beta-catenin pathway controls developmental processes and homeostasis, but abnormal activation of this pathway is a frequent event during the development of cancer. The key mechanism in regulation of the Wnt/beta-catenin pathway is the amino-terminal phosphorylation of beta-catenin, marking it for proteasomal degradation. Here we present small-molecule-based identification of protein kinase C (PKC)-mediated beta-catenin phosphorylation as a novel mechanism regulating the Wnt/beta-catenin pathway. We used a cell-based chemical screen to identify A23187, which inhibits the Wnt/beta-catenin pathway. PKC was activated by A23187 treatment and subsequently phosphorylated N-terminal serine (Ser) residues of beta-catenin, which promoted beta-catenin degradation. Moreover, the depletion of PKCalpha inhibited the phosphorylation and degradation of beta-catenin. Therefore, our findings suggest that the PKC pathway negatively regulates the beta-catenin level outside of the Wnt/beta-catenin pathway.

Expression of glucocorticoid receptor mRNAs in glucocorticoid-resistant nasal polyps.

Glucocorticoids (GCs) are the most effective group of medications available to treat inflammation. Although most patients with inflammation respond to GC, a small group of patients exhibit persistent GC-resistance with prolonged inflammation. Previously, it was proposed that the GC-resistance is caused by low amount of human GC receptor (hGRalpha) and/or excessive presence of a GC receptor isoform, hGRbeta that was generated from alternative splicing of the hGR message. We have tested this hypothesis by investigating correlation between the expression pattern of hGR mRNAs in patients with inflammatory nasal polyps and the effectiveness of GC treatment.? We have performed reverse transcription PCR analysis of mRNAs coding each hGRalpha and hGRbeta in nasal tissues.? hGRalpha mRNA was more expressed in patients with nasal polyps than in normal subjects. However, the elevated hGRalphamRNA expression was decreased after GC treatment. Compared with hGRalpha mRNA expression, level of hGRbeta mRNA expression was very low in all groups. In patients, hGRbetamRNA was expressed at a similar level regardless of GC efficacy, indicating that there is no correlation between the GC sensitivity and the expression level of hGRbeta mRNA. Thus, persistent GC-resistance is not associated with low expression of hGRa or over- expression of hGRbeta.

Growth inhibitory effects of trastuzumab and chemotherapeutic drugs in gastric cancer cell lines.

The various treatments for advanced gastric cancer have limitations and induce only marginal survival benefit. HER-2/neu protein is overexpressed in several types of human cancers and its amplification is associated with poor prognosis. Recombinant humanized anti-HER-2/neu antibody (trastuzumab) not only inhibits the proliferation of HER-2/neu overexpressing tumor cells but also augments the cytotoxicity of concomitant chemotherapeutic agents in metastatic breast cancer. In this study, we evaluated the growth inhibitory effects of trastuzumab in gastric cancer cells. HER-2/neu protein was evaluated by immunohistochemical analysis in seven gastric cancer cell lines. MTT assay was performed to evaluate the growth inhibitory effects of trastuzumab and three chemotherapeutic agents, doxorubicin, cisplatin and paclitaxel, both alone and in combinations. The changes of cell cycle after trastuzumab treatment were analyzed by flow cytometry. Four of the cell lines, YCC-2 with strong positivity of HER-2/neu expression, NCI-N87 with moderate positivity, YCC-3 with weak positivity, and SK-BR-3 as a positive control, were selected. After in vitro MTT assay for 1-day and 5 consecutive days' treatment of trastuzumab at various concentrations, growth inhibition was not observed in any cancer cell lines. However, there was variable dose-dependent sensitivity to doxorubicin, cisplatin and paclitaxel. YCC-2 and SK-BR-3 cancer cells were more sensitive to three chemotherapeutic drugs, constantly (P<0.05). The combination of 5 consecutive days' treatment of trastuzumab with 1-day doxorubicin treatment showed significant growth inhibition only in YCC-2 and NCI-N87 gastric cancer cells. After 1-day trastuzumab treatment, the S-phase fraction was decreased by 52 and 70% in YCC-2 and SK-BR-3, respectively. In conclusion, the expressions of HER-2/neu protein in gastric cancer cells are variable, and concomitant treatments of trastuzumab with doxorubicin increase cytotoxicity. This suggests that trastuzumab-based biologic therapy with chemotherapeutic agents can be applied in gastric cancer treatment.