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Supplementary Figure 4 - PDF file 1098K, KRT19 inhibition does not down-regulate PTEN protein level through modulation of PTEN stability

Supplementary Figure 6 - PDF file 1339K, Statistical analyses of western blots and RT-PCR data

Supplementary Information - PDF file 163K, Legends to Supplementary data and Materials and Methods

Supplementary Fig. 7A - PDF file 188K, Correlation between KRT19 and HER2 expression in breast cancer patient samples

Purpose: Keratin19 (KRT19) is the smallest known type I intermediate filament and is used as a marker for reverse transcriptase PCR–mediated detection of disseminated tumors. In this study, we investigated the functional analysis of KRT19 in human breast cancer.Experimental Design: Using a short hairpin RNA system, we silenced KRT19 in breast cancer cells. KRT19 silencing was verified by Western blot analysis and immunocytochemistry. We further examined the effect of KRT19 silencing on breast cancer cells by cell proliferation, migration, invasion, colony formation assay, cell-cycle analysis, immunocytochemistry, immunohistochemistry, and mouse xenograft assay.Results: Silencing of KRT19 resulted in increased cell proliferation, migration, invasion, and survival. These effects were mediated by upregulation of Akt signaling as a result of reduced PTEN mRNA expression. Silencing of KRT19 decreased the nuclear import of early growth response-1 (Egr1), a transcriptional factor for PTEN transcription, through reduced association between Egr1 and importin-7. We also confirmed that silencing of KRT19 increased tumor formation in a xenograft model.Conclusions: KRT19 is a potential tumor suppressor that negatively regulates Akt signaling through modulation of Egr1 nuclear localization. Clin Cancer Res; 19(16); 4335–46. ©2013 AACR.

Supplementary Figure 5 - PDF file 2097K, KRT19 regulated nuclear localization of Egr1 transcriptional factor

Supplementary Fig. 3 - PDF file 2033K, KRT19 inhibition induces Akt activity through down-regulation of PTEN expression.

Supplementary Fig. 2 - PDF file 2822K, KRT19 inhibition up-regulates colony formation, cell migration and invasion

Cluster of differentiation 133 (CD133) is a transmembrane glycoprotein that has been reported as a marker of cancer stem cells or cancer-initiating cells in various cancers. However, its contribution to tumorigenesis and differentiation remains to be elucidated. To determine the role of CD133 in colon cancer, we silenced CD133 in human colon cancer cells. Silencing of CD133 results in decreased cell proliferation, survival, migration, invasion, and glucose transport. These effects are mediated by downregulation of the human epidermal growth factor receptor 3 (HER3)/Akt/mTOR signaling pathway, culminating in reduced expression of the glucose transporter GLUT1. We also confirm that the cellular phenotypes of CD133-silenced cells are mediated by GLUT1 downregulation. We conclude that CD133 is a potential tumor initiator that positively regulates GLUT1 expression through modulation of HER3/Akt/mTOR signaling.

SUMMARY: The aim of this study was to clarify the diverse spinal compositions of the branches of the lumbar plexus in terms of their prevalence rates and thicknesses. Thirty lumbar plexuses extracted from Korean adults were used in this study. The nerve fascicles were separated and traced with the aid of a surgical microscope. The thickness of each spinal nerve component was calculated based on the mean of the largest and smallest diameters using digital calipers under the surgical microscope. The most common patterns of the spinal composition of the branches of the lumbar plexus were as follows: The iliohypogastric nerve (IHN) and the ilioinguinal nerve (IIN) arose from the ventral ramus of the first lumbar nerve (L1), the genitofemoral nerve (GFN) arose from the anterior division of the ventral ramus of the second lumbar nerve (L2), and the lateral femoral cutaneous nerve (LFCN) arose from the posterior division of the ventral ramus of theL2, the femoral nerve (FN) arose from the posterior division of the ventral ramus of L2-the fourth lumbar nerve (L4), with the thickest spinal component derived from the third lumbar nerve (L3), and the obturator nerve (OBN) arose from the anterior division of the ventral ramus of L2-L4, with the thickest spinal component derived from L3. However, when L5 constituted the FN and OBN, the thickest spinal components of the FN and OBN was L4. This morphometric study has measured the thicknesses of diverse spinal components that constitute the branches of the lumbar plexus after separating the nerve fascicles. The thicknesses of the various spinal components of these branches can be compared in order to understand which make the main and minor contributions to the lower limb.

Members of the EGFR family are potent mediators of normal cell growth and development. HER2 possesses an active tyrosine kinase domain, but no direct ligand has been identified. To investigate the differential effect of HER2 in breast cell lines, HER2 was overexpressed in MCF-10A, MCF7 and MDA-MB-231 cells. HER2 overexpression promoted proliferation, survival and migration in MCF-10A and MCF-7 cells. No significant differences were seen in proliferation, survival or migration between MDA-MB-231 vec and HER2 cells. The activity of downstream HER2 proteins increased in MCF-10A HER2 and MCF-7 HER2 cells but not in MDA-MB-231 HER2 cells. Exogenously expressed HER2 failed to associate with EGFR or HER3 in MDA-MB-231 cells, while overexpression of HER2 enhanced HER family dimerization in MCF-10A and MCF-7 cells.

The structure and function of the Antarctic marine diatom Chaetoceros neogracile antifreeze protein (Cn-AFP), as well as its expression levels and characteristics of the ice-binding site, were analyzed in the present study. In silico analysis revealed that the Cn-AFP promoter contains both light- and temperature-responsive elements. Northern and Western blot analyses demonstrated that both Cn-AFP transcript and protein expression were strongly and rapidly stimulated by freezing, as well as temperature and high light stress. Immunogold labeling revealed that Cn-AFP is preferentially localized to the intracellular space near the chloroplast membrane. Recombinant Cn-AFP had clear antifreeze activity. Protein-folding simulation was used to predict the putative ice-binding sites in Cn-AFP, and site-directed mutagenesis of the Cn-AFP b-face confirmed their identification.

Purpose: Keratin19 (KRT19) is the smallest known type I intermediate filament and is used as a marker for reverse transcriptase PCR–mediated detection of disseminated tumors. In this study, we investigated the functional analysis of KRT19 in human breast cancer. Experimental Design: Using a short hairpin RNA system, we silenced KRT19 in breast cancer cells. KRT19 silencing was verified by Western blot analysis and immunocytochemistry. We further examined the effect of KRT19 silencing on breast cancer cells by cell proliferation, migration, invasion, colony formation assay, cell-cycle analysis, immunocytochemistry, immunohistochemistry, and mouse xenograft assay. Results: Silencing of KRT19 resulted in increased cell proliferation, migration, invasion, and survival. These effects were mediated by upregulation of Akt signaling as a result of reduced PTEN mRNA expression. Silencing of KRT19 decreased the nuclear import of early growth response-1 (Egr1), a transcriptional factor for PTEN transcription, through reduced association between Egr1 and importin-7. We also confirmed that silencing of KRT19 increased tumor formation in a xenograft model. Conclusions: KRT19 is a potential tumor suppressor that negatively regulates Akt signaling through modulation of Egr1 nuclear localization. Clin Cancer Res; 19(16); 4335–46. ©2013 AACR.

Protein kinase Cδ (PKCδ) plays a significant role in the regulation of growth, apoptosis, and differentiation in a diversity of cell types. We investigated the effect of PKCδ on Notch1 intracellular domain (NICD)-mediated transcription with Notch transcription reporter constructs. The results indicate that co-expression of PKCδ down-regulated NICD-dependent transcription. Co-expression of a dominant negative PKCδ (K376R) variant lacking kinase activity was also able to downregulate NICD-dependent transcription, suggesting that PKCδ exerts its inhibitory effect via a kinase-independent mechanism(s). Interestingly, expression of PKCδ as well as K376R induced NICD up-regulation by inhibiting proteasome-mediated degradation of NICD, indicating that NICD protein quantity is not proportional to its transcriptional activity. When the subcellular distribution of NICD was investigated by both subcellular fractionation and immunocytochemistry, it was found that PKCδ and K376R effectively impaired proper nuclear localization of NICD, possibly via a physical association between NICD and PKCδ, which was confirmed by co-immunoprecipitation experiments. Chromatin immunoprecipitation assays revealed that both PKCδ and K376R inhibit the association of NICD with the promoter region of its target gene, Hes1. Furthermore, silencing of PKCδ resulted in increased NICD nuclear localization and NICD transcriptional activity in MCF-7 cells. PKCδ silencing-induced increase in anti-apoptotic survivin could not rescue apoptosis induced by doxorubicin. The data herein indicate that PKCδ can induce down-regulation of NICD transcriptional activity via a kinase-independent inhibition of NICD nuclear targeting and dissociation of NICD from target gene promoters.

Cluster of differentiation 24 (CD24) is a small glycosylphosphatidylinositol-linked cell surface molecule that is expressed in a variety of human carcinomas, including breast cancer. To determine the role of CD24 in breast cancer cells, we expressed CD24 in CD24-negative/low and cluster of differentiation 44 (CD44)-positive MDA-MB-231 metastatic breast cancer cells. Forced expression of CD24 resulted in a decrease in c-Raf/mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/mitogen-activated protein kinase signaling and reduced cell proliferation. Apoptosis induced by DNA damage was greatly enhanced in MDA-MB-231 CD24 cells as compared with MDA-MB-231 vec cells. CD24 expression efficiently attenuated DNA damage-induced nuclear factor-kappaB (NF-κB) signaling in MDA-MB-231 cells. However, in CD24-positive and CD44-negative/low MCF-7 cells, knockdown of CD24 did not significantly affect DNA damage-induced apoptosis nor NF-κB signaling. Silencing of CD24 in CD24/CD44-double-positive MDA-MB-468 cells partially rescued DNA damage-induced apoptosis. Transient transfection studies with 293T cells also revealed that CD24 attenuated cell viability and NF-κB signaling only when CD44 was cotransfected. These data indicate that CD24 expression potentiated DNA-induced apoptosis by suppressing antiapoptotic NF-κB signaling in CD44-expressing cells.

In this study, we investigated the underlying mechanism by which phytoestrogens suppress the growth of normal (MCF-10A) and malignant (MDA-MB-231) estrogen receptor α (ERα)-negative breast cells. We hypothesized that phytoestrogen inhibits the proliferation of ERα-negative breast cancer cells. We found that all tested phytoestrogens (genistein, apigenin, and quercetin) suppressed the growth of both MCF-10A and MDA-MB-231 cells, as revealed by proliferation assays. These results were accompanied by an increase in the sub-G0/G1 apoptotic fractions as well as an increase in the cell population in the G2/M phase in both cell types, as revealed by cell cycle analysis. When we assessed the effect of phytoestrogens on the level of intracellular signaling molecules by Western blot analysis, we found that phytoestrogens increased the level of active p53 (phospho-p53) without changing the p53 level in both MCF-10A and MDA-MB-231 cells. Phytoestrogens also induced an increase in p21, a p53 target gene, and a decrease in either Bcl-xL or cyclin B1 in both cell types. In contrast, the protein levels of phosphatase and tensin homolog, cyclin D1, cell division control protein 2 homolog, phospho-cell division control protein 2 homolog, and p27 were not changed after phytoestrogen treatment. Our data indicate that phytoestrogens induce apoptotic cell death of ERα-negative breast cancer cells via p53-dependent pathway and suggest that phytoestrogens may be promising agents in the treatment and prevention of ERα-negative breast cancer.

To dissect the isoform-specific roles of Akt in breast cancer cells, constitutively active Akt isoforms were introduced into MDA-MB-231 cells. Both Akt1 and Akt2 efficiently inhibited the growth of MDA-MB-231 cells. Overexpression of Akt1 down-regulated ERK activity inhibiting Ser 259 phosphorylation of c-Raf and subsequent downstream signaling. Akt2 overexpression up-regulated the cell cycle inhibitor p27. Cycloheximide decay assays showed that Akt2 increased the stability and nuclear localization of p27, thus inhibiting the cyclin E/CDK2 complex. These results suggest that the inhibition of cell proliferation by Akt1 and Akt2 is mediated by isoform-specific mechanisms.

S100A4, also known as the mts1 gene, has been reported as an invasive and metastatic marker for many types of cancers. S100A4 interacts with various target genes that affect tumor cell metastasis; however, little is known about cellular signaling pathways elicited by S100A4. In the current study, we demonstrate an inhibitory effect of S100A4 on β-catenin signaling in breast cancer cells. By overexpressing S100A4 in MCF-7, MDA-MB-231 and MDA-MB-453 breast cancer cells, we observed the down-regulation of β-catenin expression and β-catenin-dependent TCF/LEF transcriptional activities. The activity of GSK3β, which phosphorylates β-catenin and induces proteasomal degradation of β-catenin, was increased in S100A4-overexpressing cell lines. Blocking Glycogen Synthase Kinase (GSK3β) activity by lithium chloride or Dvl gene overexpression restored β-catenin expression. We also found that increased GSK3β activity was due to decrease in Akt activity resulting from Egr-1-induced phosphatase and tensin homolog (PTEN) expression. S100A4 induced Egr-1 nuclear localization by increasing the association between Egr-1 and importin-7 and this effect was reduced in S100A4 mutants that harbored a defect in nuclear localization signals. Collectively, we verify herein that S100A4 may act as a tumor suppressor in breast cancers by down-regulating the central signaling axis for tumor cell survival.

In breast cancer, the HER2 (human epidermal growth factor receptor 2) receptor tyrosine kinase is associated with extremely poor prognosis and survival. Notch signalling has a key role in cell-fate decisions, especially in cancer-initiating cells. The Notch intracellular domain produced by Notch cleavage is translocated to the nucleus where it activates transcription of target genes. To determine the combinatory effect of HER2 and Notch signalling in breast cancer, we investigated the effect of HER2 on Notch-induced cellular phenomena. We found the down-regulation of Notch-dependent transcriptional activity by HER2 overexpression. Also, the HER2/ERK (extracellular-signal-regulated kinase) signal pathway down-regulated the activity of γ-secretase. When we examined the protein level of Notch target genes in HER2-overexpressing cells, we observed that the level of survivin, downstream of Notch, increased in HER2 cells. We found that activation of ERK resulted in a decrease in XAF1 [XIAP (X-linked inhibitor of apoptosis)-associated factor 1] which reduced the formation of the XIAP–XAF1 E3 ligase complex to ubiquitinate survivin. In addition, Thr34 of survivin was shown to be the most important residue in determining survivin stability upon phosphorylation after HER2/Akt/CDK1 (cyclin-dependent kinase 1)–cyclin B1 signalling. The results of the present study show the combinatorial effects of HER2 and Notch during breast oncogenesis.

Background The clinical implication of Ras/Raf/ERK pathway activity in breast cancer tissue and its association with response to chemotherapy is controversial. We aimed to explore the value of p90RSK phosphorylation, a downstram molecule of the pathway, in predicting chemotherapy response in breast cancer. Methods The expression of phosphorylated p90RSK (phospho-p90RSK) and chemotherapy response was measured in 11 breast cancer cell lines and 21 breast cancer tissues. The predictive value of phospho-p90RSK was validated in core needle biopsy specimens of 112 locally advanced breast cancer patients who received anthracycline and taxane-based neoadjuvant chemotherapy. Results In 11 breast cancer cell lines, the relative expression of phospho-p90RSK was inversely correlated with cell survival after doxorubicin treatment (p = 0.021). Similar association was observed in fresh tissues from 21 breast cancer patients in terms of clinical response. In paraffin-embedded, formalin-fixed tissues from core needle biopsy tissues from 112 patients, positive phospho-p90RSK expression was associated with greater tumor shrinkage and smaller post-chemotherapy tumor size. The association between phospho-p90RSK expression and chemotherapy response was more evident in estrogen receptor(ER)-positive tumors. The expression of phosphor-p90RSK did not show a significant relationship with the incidence of pCR. P90RSK silencing using siRNA did not affect the cancer cell’s response to doxorubicin, and the expression of phospho-p90RSK was highly correlated with other Ras/Raf/ERK pathway activation. Conclusion Our results suggest that phospho-p90RSK expression, which reflects the tumor’s Ras/Raf/ERK/p90RSK pathway activation can be a potential predictive marker for chemotherapy response in ER-positive breast cancer which needs further independent validation.

We identified two S/T-P-S/T domains (2122-2124, 2126-2128) inducing Notch intracellular domain (NICD) nuclear localization. The GFP-NICD (1963-2145) fusion protein deletion mutant without classical NLS was localized in the nucleus like the full length GFP-NICD. However, quadruple substitution mutant (T2122A T2124A S2126A T2128A) showed increased cytoplasmic localization. GSK-3β enhanced nuclear localization and transcriptional activity of WT NICD but not of quadruple substitution mutant. In vitro kinase assays revealed that GSK-3β phosphorylated S and T residues in NICD S/T-P-S/T domains. These results suggest that the novel S/T-P-S/T domain, phosphorylated by GSK-3β is also involved in the nuclear localization of NICD as well as classical NLS.

To determine the role of CD24 in breast cancer cells, we knocked down CD24 in MCF-7 human breast cancer cells by retroviral delivery of shRNA. MCF-7 cells with knocked down CD24 (MCF-7 hCD24 shRNA) exhibited decreased cell proliferation and cell adhesion as compared to control MCF-7 mCD24 shRNA cells. Decreased proliferation of MCF-7 hCD24 shRNA cells resulted from the inhibition of cell cycle progression from G1 to S phase. The specific inhibition of MEK/ERK signaling by CD24 ablation might be responsible for the inhibition of cell proliferation. Phosphorylation of Src/FAK and TGF-β1-mediated epithelial to mesenchymal transition was also down-regulated in MCF-7 hCD24 shRNA cells. Reduced Src/FAK activity was caused by a decrease in integrin β1 bound with CD24 and subsequent destabilization of integrin β1. Our results suggest that down-regulation of Raf/MEK/ERK signaling via Src/FAK may be dependent on integrin β1 function and that this mechanism is largely responsible for the CD24 ablation-induced decreases in cell proliferation and epithelial to mesenchymal transition.

Aim of the study We performed this study to investigate the anti-cancer activity of Pharbitis nil (PN) ethanol extract which has been used for herbal medicinal treatment against diseases in East Asia. Materials and methods We analyzed the effects of PN extract on proliferation of breast cancer cell lines, MCF-7 control vector (vec) and MCF-7 human epidermal growth factor receptor 2 (HER2) cells engineered to overexpress oncogenic HER2 via retroviral infection. We performed the proliferation assay to measure the growth rate of the cells. FACS analysis was used to analyze the cell cycle. Western blot analysis was used to investigate the effect of PN on the level and activation of intracellular molecules. Results We found that PN extract inhibited the proliferation of both MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with the increase of sub G0/G1 apoptotic fractions. When we check the efficiency of PN on the level of intracellular signaling molecules, we found that PN extract induced the inhibition of phosphorylation of HER2 and its downstream effectors, Akt and extracellular signal-regulated kinases (ERK). Active forms of both Akt and ERK were gradually decreased in PN-treated MCF-7 vec and MCF-7 HER2 cells suggesting that the growth suppressive activity of PN is related to signaling pathway. The level of cyclin D also diminished in PN-treated both cells suggesting that PN may inhibit the growth of MCF-7 vec and MCF-7 HER2 cells by perturbing cell cycle progression. It should be noted that PN decreased the growth rate of both MCF-7 vec and MCF-7 HER2 cells without changing the level and activation of p53. Conclusion PN extract suppressed the proliferation rate of HER-2 overexpressing MCF-7 breast cancer cells inducing apoptotic cell death in vitro . Our data demonstrates that PN extracts contain useful anti-tumor activity especially against HER2 overexpressing breast cancer.

Danshen is widely used in traditional Chinese medicine, often in combination with other herbs. To check the effect of Danshen on the proliferation of breast cancer cells, Danshen extract was used to treat MCF-7 and MCF-7 HER2 cells, the latter of which overexpresses HER2. HER2 is a receptor tyrosine kinase, and is involved in signal transduction pathways leading to tumor cell proliferation. MTT and cell proliferation assays revealed that Danshen strongly inhibited the proliferation of both MCF-7 vec cells and MCF-7 HER2 cells. Flow cytometry analyses indicated that Danshen induced cell cycle delay in the G1 phase. HER2 expression was shown to confer resistance to Danshen-induced inhibition of proliferation and cell cycle delay, suggesting that HER2 is responsible for the resistance to Danshen. Danshen treatment induced the down-regulation of Akt phosphorylation and an increase in p27 in MCF-7 vec and MCF-7 HER2 cells. Nevertheless, MCF-7 HER2 cells were more resistant to the Danshen-induced inhibition of Akt phosphorylation and p27 up-regulation.

MMTV-neu transgenic mice overexpressing NEU in their mammary glands develop tumor after 6 months of age. To find a novel protein biomarker using this mouse model, we identified and characterized the proteins that were differently expressed between primary mammary epithelial cells from 2 months old MMTV-neu heterozygote mice and wild type (WT) littermates using two-dimensional digest (ChemDigest™/Trypsin)-LC-MS/MS. The differentially expressed proteins were selected and analyzed using DAVID Bioinformatics resource. The proteins involved in anti-apoptosis, purine metabolism, ribosome and proteasome functions were upregulated, whereas cell adhesion-related proteins were downregulated in PMECs from MMTV-neu mice when compared with WT PMECs. The results indicate that several functional units are coregulated by HER2/NEU. We hypothesize that these changes in the cellular proteome may be responsible for early onset of HER2/NEU-driven tumorigenesis. © 2009 IUBMB IUBMB Life, 62(1):41–50, 2010

We performed a phase II study of combination chemotherapy with S-1 plus gemcitabine for treating chemo-naïve patients with unresectable pancreatic cancer to evaluate the efficacy and toxicity.Patients with histologically confirmed unresectable pancreatic cancer were eligible. The treatment consisted of S-1 (40 mg/m(2) p.o. b.i.d. from D1 to 14) and gemcitabine (1,250 mg/m(2) on D1 and 8), repeated every 3 weeks.Thirty-two patients were enrolled between March 2005 and December 2007. No complete response was observed and a partial response was observed in 14 patients (44.0%), stable disease in eight patients (25.0%), and progressive disease in eight patients (25.0%). The median time to progression was 4.92 months (95% CI: 4.16-5.67 months), and the median overall survival was 7.89 months (95% CI: 5.96-9.82 months). The survival duration was significantly longer for the patients with a good performance status compared with that of the patients with a poor performance status. The major toxicities were grade 3-4 neutropenia (9, 28.1%), grade 3/4 thrombocytopenia (5, 15.6%), and grade 3 diarrhea (5, 15.6%).The combination chemotherapy of S-1 and gemcitabine showed promising antitumor activity and manageable toxicities, and especially for the good performance status patients with unresectable pancreatic cancer.

A 63-year-old female diagnosed with relapsed multiple myeloma visited our hospital complaining of a persistent cough. Since July 2006, she had been taking 100 mg thalidomide daily and gradually developed shortness of breath and a persistent dry cough. A chest X-ray and computed tomography showed ground glass opacities in both lungs. An open lung biopsy of the right middle lobe under general anesthesia revealed chronic peribronchial inflammation, mild interstitial fibrosis, and intra-alveolar macrophage infiltration, with some hemosiderin features, compatible with non-specific interstitial pneumonia (NSIP). After discontinuing the thalidomide, the patient's symptoms did not deteriorate, although the radiographs did not improve. The patient is alive and well with regular outpatient follow-up without progression of the NSIP.

Strongyloides stercoralis is an intestinal nematode that is a parasite to humans. The infecting filariform larvae of S. stercoralis enters the host body via the bloodstream, passes through the lungs, penetrates the alveoli, and then ascends the airway to transit down the esophagus into the small bowel. The infection can persist for decades without causing major symptoms and can elicit eosinophilia of varying magnitudes. Of note, this infection can also develop into a disseminated, often fatal, disease (hyperinfection) in patients receiving immunosuppressive corticosteroids. A 65-year-old man who was receiving corticosteroid therapy for the treatment of spinal stenosis was admitted to the emergency room with complaints of abdominal pain and severe dyspnea. We detected many S. stercoralis larvae in the sputum and in the bronchoalveolar-lavage sample collected by bronchoscopy. Here, we report a fatal case of strongyloidiasis with acute respiratory failure and intestinal perforation. In addition, we provide a brief review of the relevant medical literature.

Recurrent syncope as a complication of recurrent neck malignancy is an uncommon but well documented association. The syncope is presumed to occur when a tumor mass invades the baroreceptor within the carotid sinus or when it disrupts the afferent nerve fibers of the glossopharyngeal nerve. A 59-year-old man presented with recurrent syncope and headache. He had a wide local excision including tonsillectomy and modified left radical neck dissection for tonsilar cancer 4 years ago. A computed tomography scan revealed ill-defined lesions in left parapharyngeal, carotid space and right upper jugular region. After clinical evaluation, cardiac pacemaker was placed, but he still suffered from the syncope. Then, he received the chemotherapy with docetaxel and cisplatin. The last hypotension event occurred on day 10 of the chemotherapy. Six months after 3 cycles of chemotherapy, he remained in complete remission and resolution of syncope. We report a case in which syncope was associated with a recurrence of tonsilar cancer and successfully treated with chemotherapy.

Pure red cell aplasia (PRCA) is a rare hematologic disorder characterized by anemia, reticulocytopenia in the blood and isolated severe erythroblastopenia with no abnormalities of the granulopoiesis and mega- karyopoiesis in the bone marrow. Acquired PRCA has been reported in association with various auto- immune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, mixed connective tissue disease and Sjogren's syndrome. We report here on a case of PRCA associated with Hashimoto disease (without any other autoimmune disease) which, to the best of our knowledge, has not been pre- viously reported in Korean and English literatures. Our patient was treated with levothyroxine alone with- out other immunosuppressive agents and her hemoglobin concentration and hematocrit values returned

Purpose: We performed a pilot study on defining duration of docetaxel and cisplatin combination chemotherapy in patients with advanced non-small cell lung cancer to evaluate its efficacy. Patients and Methods: Sixteen chemonaive patients with biopsy proven, unresectable (stage IIIB or IV) non-small cell lung cancer (NSCLC) were enrolled between January 2003 and December 2004. Treatment consisted of docetaxel (75 mg/m/day) and cisplatin (70 mg/m/day) every 3 week up to 4 cycles. The outcome was compared with that of a historical control group of 42 patients treated from January 1998 until December 2001, who were treated with mitomycin-C, vinorelbine, cisplatin for unresectable stage IIIB or IV NSCLC. Results: Median age was 68 (age range 43∼72). Among 16 patients, 5 patients were stage IIIB and 11 were stage IV. Fourteen patients had performance status of 0-1 and, 2 had performace status 2 respectively. Two patients were lost due to refusal of receiving chemotherapy. By intention-totreat-analysis, overall response rate was 44% (C.I.: 0.19∼0.68). No complete response was noted. Median time to progression (TTP) was 144 days. Overall survival (OS) was 285 days. There is no difference in TTP & OS between docetaxel, cispatin (DP) group and mitomycin, vinorelbine, cisplatin (MVP) group statistically. Neutropenia was the most common grade III or IV toxicity; (two patients had Grade III toxicity and five Grade IV toxicity). Five patients developed febrile neutropenia, and three of neutropenia patients died due to pneumonia or septic shock. The most common non-hematologic toxicity was infection. Two of 3 patients with infection required admission. Conclusion: These findings suggested that four cycles of docetaxel and cisplatin might be as effective as MVP continous therapy for advanced NSCLC. (J Lung Cancer 2007;6(1):8 󰠏 14)