The implicated clinical factors for outcomes in 304 patients with salivary duct carcinoma: Multi-institutional retrospective analysis in Japan.

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary malignancy that frequently occurs as the carcinomatous component of carcinoma ex pleomorphic adenoma. We herein examined the clinical factors affecting outcomes in a large cohort of SDC. METHODS: We selected 304 SDC cases and investigated clinical characteristics and the factors affecting outcomes. RESULTS: The median age of the cases examined was 68 years, the most common primary site was the parotid gland (238 cases), and there was a male predominance (M/F = 5:1). Outcomes were significantly worse when the primary tumor site was the minor salivary glands (SG) than when it was the major SG. Outcomes were also significantly worse in pN(+) cases (161 cases) than in pN0 cases, particularly those with a metastatic lymph node number ≥11. The cumulative incidence of relapse and distant metastases was significantly higher in stage IV cases than in stage 0-III cases. CONCLUSIONS: The absolute number of lymph node metastases, higher stages, and the minor SG as the primary tumor site were identified as factors affecting the outcome of SDC.

Acute exacerbation of pulmonary toxoplasmosis during corticosteroid therapy for immune thrombocytopenia: A case report and literature review.

RATIONALE: Pulmonary toxoplasmosis (PT) is an infectious disease that can be fatal if reactivation occurs in the recipients of hematopoietic stem cell transplantation (HSCT) who were previously infected with Toxoplasma gondii. However, whether the toxoplasmosis reactivation is an actual risk factor for patients receiving immunosuppressive therapies without HSCT remains unclear. Therefore, reactivated PT is not typically considered as a differential diagnosis for pneumonia other than in patients with HSCT or human immunodeficiency virus (HIV). PATIENT CONCERNS: A 77-year-old man presented with fever and nonproductive cough for several days. He was hospitalized due to atypical pneumonia that worsened immediately despite antibiotic therapy. Before 4 months, he was diagnosed with immune thrombocytopenia (ITP) and received corticosteroid therapy. Trimethoprim-sulfamethoxazole (ST) was administered to prevent pneumocystis pneumonia resulting from corticosteroid therapy. DIAGNOSIS: The serological and culture test results were negative for all pathogens except T. gondii immunoglobulin G antibody. Polymerase chain reaction, which can detect T. gondii from frozen bronchoalveolar lavage fluid, showed positive results. Therefore, he was diagnosed with PT. INTERVENTION: ST, clindamycin, and azithromycin were administered. Pyrimethamine and sulfadiazine could not be administered because his general condition significantly worsened at the time of polymerase chain reaction (PCR) examination. OUTCOMES: The patient died of acute respiratory distress syndrome despite anti-T. gondii treatment. An autopsy revealed a severe organizing pneumonia and a small area of bronchopneumonia. LESSONS: PT should be considered as a differential diagnosis in patients with pneumonia, particularly in seropositive patients who receive immunosuppressive therapies even for other than HSCT or HIV.

Salivary Duct Carcinoma With Rhabdoid Features-No or Aberrant Expression of E-cadherin and Genetic Changes in CDH1: Immunohistochemical and Genetic Analyses of 17 Cases.

Salivary duct carcinoma is a relatively uncommon malignancy of the salivary glands; however, it frequently occurs as a carcinomatous component of carcinoma ex pleomorphic adenoma. We previously reported salivary duct carcinoma with rhabdoid features (SDCRF) as an extremely rare subtype of salivary duct carcinoma, and that it occurred as a salivary counterpart of pleomorphic lobular carcinoma of the breast (PLCB). We collected new cases of SDCRF for this study, in which we examined a total of 17 cases immunohistochemically and genetically. As it is known that PLCB exhibits loss of or aberrant E-cadherin expression and carries nonsense/missense mutations in or deletion of the CDH1 gene, we examined the CDH1 gene status of our SDCRF cases. All of the examined SDCRF cases involved the diffuse proliferation of large ovoid cells with eosinophilic cytoplasm and eccentric nuclei, which displayed reduced cell-cell adhesion. Most cases were positive for pan-cytokeratin, androgen receptor, gross cystic disease fluid protein-15, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1, and WI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4, whereas they were negative for vimentin. No and decreased/cytoplasmic E-cadherin expression was observed in 11 and 4 of 17 cases, respectively, whereas no and decreased/cytoplasmic ß-catenin expression were observed in 10 and 5 of 17 cases, respectively. Among the 11 cases that could be genetically analyzed, a nonsense mutation (1 case), missense mutations (6 cases), and insertions (1 case) were detected in the CDH1 gene. In conclusion, we propose that SDCRF is the salivary counterpart of PLCB due to its morphology and immunophenotype, and the genetic status of CDH1.

Multi-Lineage BCR-ABL Expression in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Is Associated With Improved Prognosis but No Specific Molecular Features.

BACKGROUND: Recently, various blood cell lineages expressing the BCR-ABL fusion gene in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have been reported. However, the biological and clinical significance of these BCR-ABL lineages has not been established; therefore, we aimed to clarify the impacts of these different BCR-ABL-expressing lineages. PATIENTS: Multi-lineage BCR-ABL expression (multi-Ph) was defined as BCR-ABL expression outside of the B-lineage compartment, as determined by fluorescence in situ hybridization (FISH) in peripheral blood neutrophils and bone marrow clots, and flow cytometry-sorted polymerase chain reaction (PCR). We analyzed IKZF1 deletion patterns by PCR, examined gene expression profiles using RNA sequencing, and compared treatment outcomes across different BCR-ABL-expressing lineages. RESULTS: Among the 21 multi-Ph patients in our 59-patient cohort (36%), BCR-ABL expression was detected at the multipotential progenitor level. However, no IKZF1 deletion patterns or gene expression profiles were identified that were specific for multi-Ph. However, multi-Ph patients were found to have better survival rates than patients with uni-lineage BCR-ABL expression [event-free survival (EFS): 74 vs. 33%, P = 0.01; overall survival (OS): 79 vs. 44% at 4 years, P = 0.01]. In multivariate analyses, multi-Ph was identified as a good prognostic factor for both EFS and OS. CONCLUSION: We confirmed that more than one-third of Ph+ALL patients could be classified as mutli-Ph. Although no specific molecular characteristics were identified for multi-Ph, this phenotype was associated with better treatment outcomes.

Pulmonary Barotrauma Following Nasal High-Flow Therapy in a Patient with Bronchiolitis Obliterans Syndrome.

BACKGROUND Pulmonary barotrauma is considered as complication of the use of positive-pressure ventilations. Nasal high-flow therapy is increasingly being used as an alternative to them. Nasal high-flow therapy rarely causes pulmonary barotrauma probably because airway pressures are lower when compared with invasive mechanical ventilation. Bronchiolitis obliterans syndrome after allogenic hematopoietic stem cell transplantation is triggered by an alloimmune response in the bronchioles and causes obstruction of the bronchioles. However, the threshold of additional positive pressure has not been determined in a patient with bronchiolitis obliterans syndrome. CASE REPORT A 14-year-old female patient with acute myeloid leukemia at high risk of recurrence received an allogeneic hematopoietic stem cell transplantation from an unrelated bone marrow donor. After engraftment, she developed acute graft-versus-host disease, followed by chronic graft-versus-host disease. Ten months post-transplantation, she developed bronchiolitis obliterans syndrome. She continued to receive nasal supplemental oxygen therapy for persistent dyspnea due to bronchiolitis obliterans syndrome. At month +25, hypercapnia was noted. Therefore, we carefully initiated nasal high-flow therapy for dyspnea and adjusted the oxygen dose to maintain 90% SpO2 to avoid life-threatening apnea. The flow rate was as low as 14 to 20 L/min to avoid the risk of barotrauma and the deterioration of air trapping. Unfortunately, she died of respiratory failure at month +31 post-transplantation. A lung autopsy revealed pulmonary barotrauma. CONCLUSIONS Nasal high-flow therapy, even at low flow rates, may cause fatal pulmonary barotrauma in bronchiolitis obliterans syndrome.

Hypereosinophilia and Multisite Vasculopathy of Fibromuscular Dysplasia: A Case Report.

The impact of blood disorders on fibromuscular dysplasia is unknown, and cardiovascular surgery results are also unclear. Furthermore, there are only a few case reports about the association between fibromuscular dysplasia and blood disorders. We report a case of a coronary bypass surgery and an aortic root replacement for a patient who is hypereosinophilic with multisite vasculopathy of fibromuscular dysplasia, including that of the coronary artery and saphenous vein, which was diagnosed by a histopathologic examination after an autopsy was performed 5 months after surgery. The outcome of cardiovascular surgery can be unfavorable for fibromuscular dysplasia. Blood disorders may also have an impact on the outcome.

An Unusual Presentation of Nasopharyngeal Carcinoma as Lemierre Syndrome.

BACKGROUND Clinical presentation of nasopharyngeal carcinoma (NPC) is correlated with the extent of primary and nodal disease. Hence, depending on the anatomical structures affected, the clinical presentation varies accordingly, ranging from non-specific symptoms of epistaxis, unilateral nasal obstruction, and auditory complaints, to cranial nerve palsies. Nodal metastasis in the neck is a frequent clinical finding in nasopharyngeal carcinoma. CASE REPORT A female was admitted to the hospital because of fever and trismus with painful swelling in the right neck. Computed tomography (CT) revealed a mass in the nasopharynx with heterogeneous enhancement and multiple swollen lymph nodes in the corresponding neck. Initial biopsies of nasopharyngeal mass and lymph node of the neck revealed nonspecific lymphoid hyperplasia; we administered antibiotics with the provisional diagnosis of bacterial infection, including Lemierre syndrome that is typically defined by the constellation of septic internal jugular vein thrombophlebitis, pulmonary and other septic emboli, and sterile site bacterial infection. However, the patient was refractory to antibiotics over a month of treatments. The third biopsy of the throat lesion revealed NPC and bacterial cultures using the biopsy specimen were negative. She received intensity-modulated radiation therapy and chemotherapy for NPC stage II (TNM staging: T2N1M0). She never developed Lemierre syndrome-like symptoms after chemoradiotherapy. CONCLUSIONS We report a unique case of NPC presenting with Lemierre syndrome-like symptoms, including prior sore throat, trismus, painful swollen neck, and high fever. Since these symptoms have not been reported in NPC, we included NPC as a differential diagnosis.

[Gastric tuberculosis in an elderly patient:a case report].

A woman in her 70s presented to our hospital with epigastric pain, back pain, and weight loss. Esophagogastroduodenoscopy was performed, and numerous protuberances, which were suspected to be submucosal tumors, were found at the gastric corpus. The patient was diagnosed with gastric tuberculosis based on the biopsy results of these protuberances. Histopathological analysis demonstrated non-caseating epithelioid granuloma. A positive culture for Mycobacterium tuberculosis was also obtained on gastric juice analysis and confirmed using polymerase chain reaction assay. In the rapidly aging population in Japan, our findings emphasize on the importance of differentiating gastrointestinal tuberculosis, including gastric tuberculosis, from other diseases. This case may provide information about the development of gastric tuberculosis.

Characterization of V-set and immunoglobulin domain containing 1 exerting a tumor suppressor function in gastric, lung, and esophageal cancer cells.

V-set and immunoglobulin domain containing 1 (VSIG1) is a newly discovered member of the immunoglobulin superfamily of proteins, expressed in normal stomach and testis. In cancers, however, the clinical and biological roles of VSIG1 remain unknown. Here we investigated VSIG1 expression in 11 cancers and assessed the prognostic roles of VSIG1 in patients with gastric cancer (GC) (n = 362) and non-small-cell lung cancer (n = 650). V-set and immunoglobulin domain containing 1 was downregulated in 60.5% of GC specimens, and high VSIG1 expression was identified as an independent favorable prognostic factor for overall survival in GC patients (hazard ratio, 0.58; 95% confidence interval, 0.35-0.96). Among lung adenocarcinomas (n = 428), VSIG1 was significantly and inversely associated with thyroid transcription factor 1 expression and was frequently expressed in the invasive mucinous subtype (17 of 19, 89.5%). In addition, VSIG1 was expressed in a subset of pancreatic, ovarian, and prostate cancers. The variant 2 VSIG1 transcript was the dominant form in these tissues and cancer cells. Introduction of VSIG1 significantly reduced the proliferative ability of MKN1 and MKN28 GC cells and H1299 lung cancer cells and downregulated cell migration of these cells, as well as of KYSE150, an esophageal cancer cell line. Cell invasion of MKN1, MKN28, and KYSE150 cells was also reduced by VSIG1 introduction. In vitro characterization revealed that VSIG1 forms homodimers through homophilic cis-interactions but not through homophilic trans-interactions. These results suggest that VSIG1 possesses tumor suppressive functions that are translated into favorable prognosis of VSIG1-expressing GC patients.

Salivary duct carcinoma with rhabdoid features: a salivary counterpart of pleomorphic lobular carcinoma of the breast.

AIM: To analyse the clinicopathological features and immunohistochemical characteristics of nine cases of salivary duct carcinoma (SDC) with rhabdoid features (SDCRF), representing a new, extremely rare type of salivary gland malignancy. METHODS AND RESULTS: We analysed 2511 cases of salivary gland tumour, clinicopathologically and immunohistochemically. The incidence of SDCRF was 0.4%. Eight patients were male. The age of patients ranged from 36 years to 85 years (mean, 61 years). SDC arose from the parotid glands and submandibular gland in six and three cases, respectively. Seven cases appeared as a carcinoma component of carcinoma ex pleomorphic adenoma cases. Six patients died of disease. Histologically, diffuse proliferations of non-coherent large ovoid or polygonal carcinoma cells with eosinophilic cytoplasm and eccentric nuclei were observed in all cases; such cytological characteristics were defined as 'rhabdoid features'. Immunohistochemically, all cases were positive for cytokeratin, gross cystic disease fluid protein-15, androgen receptor, and SMARCB1, seven cases were positive for HER2, and two cases were positive for epidermal growth factor receptor. However, all cases were negative for vimentin and myoepithelial markers. Eight cases showed no or aberrant expression of E-cadherin and ß-catenin. The results suggest that SDCRF is an extremely rare subtype of SDC, and not a sarcomatoid variant of SDC. SDCRF is histologically unique, and is positive for SDC markers but negative for vimentin, unlike rhabdoid-type carcinomas arising from other organs. CONCLUSIONS: The morphogenesis of SDCRF is related to no or aberrant expression of cell-cell adhesion molecules. Therefore, SDCRF could be a salivary counterpart to pleomorphic lobular breast carcinoma.

Nab-paclitaxel+gemcitabine therapy for adenosquamous carcinoma of the pancreas: an autopsy case.

A male patient aged over 60 years presented with abdominal pain. A solid lesion measuring 7cm was detected in the pancreatic body and tail, along with periaortic lymphadenopathy. Endoscopic ultrasound-guided fine-needle aspiration suggested squamous cell carcinoma. Nab-paclitaxel+gemcitabine therapy was effective;however, tumor progression was noted after the completion of the fourth course, and the patient died from the primary cancer 7 months after the initial consultation. Autopsy led to a definitive diagnosis of adenosquamous carcinoma of the pancreas. Non-resected adenosquamous carcinoma of the pancreas treated by chemotherapy is rare. Here, we report such an example in the present case study.

Effective Treatment with Intravitreal Injection of Bevacizumab for Exudative Retinal Detachment Secondary to Choroidal Metastasis of Non-Small Cell Lung Carcinoma.

BACKGROUND: Visual disturbance caused by cancer metastasis from other organs is one of the largest challenges to cancer patients' quality of life (QOL). Lung cancer is the most frequent primary site of choroidal metastasis in men, but improvement of visual disturbance has not always been emphasized in lung cancers. Recently intravitreal bevacizumab is a newer modality being tried for local control of choroidal metastases. CASE REPORT: A 68-year-old man was admitted the hospital with complaint of visual disturbance in his left eye. He was diagnosed with lung adenocarcinoma cT2N0M1b (OSS, OTH) stage IV. The ophthalmologic evaluation showed exudative fluid, which caused retinal detachment under the retina. Fluorescence angiography showed granular hyperfluorescence with leakage consistent with a tumor. He received radiotherapy for bone metastasis and systematic chemotherapy with carboplatin, pemetrexed, and bevacizumab, as well as intravitreal injection of bevacizumab 1.25 mg to improve the visual disturbance. His visual symptom and retinal detachment improved until he died. An autopsy revealed that the metastatic lesion in his left eye was totally cured macroscopically and microscopically. CONCLUSIONS: We report a case of exudative retinal detachment secondary to a metastatic choroidal tumor from lung adenocarcinoma, which was treated with chemotherapy and intravitreal injection of bevacizumab. Although he finally died of lung cancer, he maintained his visual QOL and autopsy revealed complete cure of the choroidal metastasis.

[Pneumothorax Secondary to Pulmonary Metastasis of Angiosarcoma of the Scalp;Report of a Case].

Angiosarcoma has been reported as a rare case, having high potential of hematogeneous lung metastasis and then developing to pneumothorax with ease. The patient was a 74-year-old man afflicted with a malignant hemangio endothelioma (MHE) of the scalp. His MHE of the scalp was resected and skin grafting was made, then, he was administered docetaxel hydrate intravenously as adjuvant setting. Three years after, he complainted left chest pain and dyspnea, so his chest Xp was checked up and showed left pneumothorax. Chest computed tomography revealed multiple thin walled cavities of right and left lung and bullae with slightly thick walled cavity at apex legion of the left lung. We resected bullae with tumor of the left apex legion under video assisted thoracic surgery. After operation, He was administerd ricombinant interleukin-2 intravenously in order to control lung metastasis of the scalp, but his condition deteriorated and 6 months after pneumothorax he died. The average survival time from the 1st pneumothorax episode was only 4.7 months. He kept a good activities of daily living without reccurrence of pneumothorax by operation, so we thought that the operaion for pneumothorax with MHE was one option for therapy.

Carcinoma of unknown primary site treated with Carboplatin + Paclitaxel + bevacizumab + erlotinib and its maintenance chemotherapy.

About 3% of all cancer patients suffer from carcinoma of unknown primary site (CUP). In spite of its rarity, we will encounter them. While CUPs manifest a wide variety of clinical presentations, they have often resulted in poor prognosis. Although platinum/taxane combination chemotherapy, e.g. carboplatin (CBDCA) + paclitaxel (PTX) is widely used for patients suffering from CUP, the response rate is only about 30-40% and the median overall survival (OS) is only 9 months, which means that improvement is needed. Among the new regimens, the combination of CBDCA, PTX, bevacizumab (BEV) and erlotinib is thought to be highly promising. Herein, we report a case with CUP treated with this regimen and his maintenance therapy. Our patient was a 75-year-old man who was admitted with a left neck lump. CT revealed systemic massive lymphadenopathy. In spite of various investigations for primary origin, he was diagnosed with CUP and treated with CBDCA + PTX + BEV + erlotinib (AUC 6 + 175 mg/m(2) + 15 mg/kg + 150 mg). Since the evaluation of the efficacy indicated partial response, maintenance chemotherapy (BEV and erlotinib) was performed. Chemotherapy was continued for 9 months until the patient was in a progressive disease state with meningeal dissemination. He died 12 months after the initiation of chemotherapy, which is a longer period than the previously reported OS. Of note, according to our case, CBDCA + PTX + BEV + erlotinib and its maintenance chemotherapy are feasible and well tolerated for CUP.

TNK2 gene amplification is a novel predictor of a poor prognosis in patients with gastric cancer.

BACKGROUNDS AND OBJECTIVES: We previously examined the amplification status of 10 kinase genes (PIK3CA, EPHB3, TNK2, PTK7, EGFR, MET, ERBB2, HCK, SRC, and AURKA) in gastric cancer (GC). This study aimed to determine the prognostic significance of these gene amplifications in GC. METHODS: A survival analysis was performed for GC patients. Since TNK2 amplification was identified as a prognostic marker in the analysis, we also examined the functional effect of TNK2 overexpression on gastric cells. RESULTS: A Kaplan-Meier analysis showed that the prognosis of patients with GC exhibiting TNK2 or AURKA amplification was significantly poorer than the prognosis of patients with GC without TNK2 or AURKA amplification. A further multivariate analysis revealed that TNK2 amplification was an independent predictor of a poor survival outcome among patients with GC (hazard ratio, 3.668; 95% confidence interval, 1.513-7.968; P = 0.0056). TNK2-overexpressing GC cells showed an increase in cell migration and non-anchored cell growth. Finally, microarray and pathway analyses revealed the aberrant regulation of some cancer-related pathways in TNK2-overexpressing GC cells. CONCLUSIONS: These results suggested that TNK2 amplification is an independent predictor of a poor prognosis in patients with GC and leads to an increase in the malignant potential of GC cells.

Granulocyte colony-stimulating factor-producing carcinoma of unknown primary site.

Granulocyte colony-stimulating factor (G-CSF)-producing nonhematopoietic malignancies have been reported in various organs and are associated with a poor clinical outcome. Moreover, carcinoma of unknown primary site (CUP) is an uncommon malignancy that occurs in about 2-6% of cancer patients. CUP also has a poor prognosis due to its missing profile. Since both G-CSF-producing carcinoma and CUP are rare, G-CSF-producing CUP (GCSF-CUP) is considered to have an even poorer prognosis and is seldom encountered. Herein, we report the case of a GCSF-CUP patient. A 75-year-old man was admitted to our hospital complaining of cervical lymphadenopathy. Multiple bulky lymph nodes without a primary site were revealed by image analysis. His complete blood count showed leukocytosis, and his blood chemistry panel indicated highly elevated levels of G-CSF. Although the patient was treated with combination chemotherapy of carboplatin, paclitaxel, bevacizumab and erlotinib, he died of intestinal perforation due to tumor invasion 23 days after the start of the therapy. An autopsy confirmed that the tumor was positive for anti-G-CSF antibody, but the primary site was still not detected.

Chromogenic in situ hybridization (CISH) to detect HER2 gene amplification in breast and gastric cancer: comparison with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).

The chromogenic in situ hybridization (CISH) assay, designed to detect the amplification of the HER2 gene in formalin-fixed, paraffin-embedded (FFPE) breast cancer (BC) and gastric cancer (GC) tissue specimens, was evaluated in 125 FFPE BC cases and 198 FFPE GC cases for which the HER2 status had been predetermined using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). In the 125 BC cases and the 198 gastric cases, we found a very good concordance (98.4% and 99.0%, respectively) between CISH and FISH. In particular, we evaluated the polysomy cases, as these cases often have ambiguous treatment options in clinical practice. The polysomy of chromosome 17 was defined as the presence of three or more CEP17 signals in at least 10% of the tumor cells. In the 50 BC cases and 54 GC cases displaying chromosome 17 polysomy, the concordance between FISH and CISH was 98.0% and 98.1%, respectively. These results indicate that CISH could provide an accurate and practical alternative to FISH for the clinical diagnosis of HER2 gene amplification in FFPE BC and FFPE GC samples.

Detection of kinase amplifications in gastric cancer archives using fluorescence in situ hybridization.

To test the feasibility of using bacterial artificial chromosomes (BAC) containing kinases for pathological diagnosis using fluorescence in situ hybridization (FISH), 10 BAC probes containing a gene amplified in 5% or more of a pilot cohort were selected from a previous survey using arbitrarily selected BAC clones harboring 100 kinases. In this report, we describe the prevalence and association with the clinicopathological profile of these selected 10 BAC probes in 365 gastric cancer tissues. FISH analyses using these 10 BAC probes containing loci encoding EGFR, ERBB2(HER2), EPHB3, PIK3CA, MET, PTK7, ACK1, STK15, SRC, and HCK showed detectable amplifications in paraffin-embedded tissue in 2.83% to 13.6% of the gastric cancer tissues. Considerable numbers of the cases showed the co-amplification of two or more of the probes that were tested. BAC probes located within a genome neighborhood, such as PIK3CA, EPHB3, and ACK1 at 3q26-29 or HCK, SRC, and STK15 at 20q11-13.1, were often co-amplified in the same cases, but non-random co-amplifications of genes at distant genomic loci were also observed. These findings provide basic information regarding the creation of a strategy for personalizing gastric cancer therapy, especially when using multiple kinase inhibitors.

The CRKL gene encoding an adaptor protein is amplified, overexpressed, and a possible therapeutic target in gastric cancer.

BACKGROUND: Genomic DNA amplification is a genetic factor involved in cancer, and some oncogenes, such as ERBB2, are highly amplified in gastric cancer. We searched for the possible amplification of other genes in gastric cancer. METHODS AND RESULTS: A genome-wide single nucleotide polymorphism microarray analysis was performed using three cell lines of differentiated gastric cancers, and 22 genes (including ERBB2) in five highly amplified chromosome regions (with a copy number of more than 6) were identified. Particular attention was paid to the CRKL gene, the product of which is an adaptor protein containing Src homology 2 and 3 (SH2/SH3) domains. An extremely high CRKL copy number was confirmed in the MKN74 gastric cancer cell line using fluorescence in situ hybridization (FISH), and a high level of CRKL expression was also observed in the cells. The RNA-interference-mediated knockdown of CRKL in MKN74 disclosed the ability of CRKL to upregulate gastric cell proliferation. An immunohistochemical analysis revealed that CRKL protein was overexpressed in 24.4% (88/360) of the primary gastric cancers that were analyzed. The CRKL copy number was also examined in 360 primary gastric cancers using a FISH analysis, and CRKL amplification was found to be associated with CRKL overexpression. Finally, we showed that MKN74 cells with CRKL amplification were responsive to the dual Src/BCR-ABL kinase inhibitor BMS354825, likely via the inhibition of CRKL phosphorylation, and that the proliferation of MKN74 cells was suppressed by treatment with a CRKL-targeting peptide. CONCLUSION: These results suggested that CRKL protein is overexpressed in a subset of gastric cancers and is associated with CRKL amplification in gastric cancer. Furthermore, our results suggested that CRKL protein has the ability to regulate gastric cell proliferation and has the potential to serve as a molecular therapy target for gastric cancer.