Chen Pm

Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer.

Major causes of head and neck squamous cell carcinoma (HNSCC)-related deaths are cervical node and distant metastasis. We previously demonstrated that overexpression of the DNA double-strand break repair protein Nijmegen breakage syndrome 1 (NBS1) is a prognostic marker of advanced HNSCCs. Epithelial-mesenchymal transition (EMT) was demonstrated to be the major mechanism responsible for mediating invasiveness and metastasis of late-stage cancers. We therefore investigated the role of NBS1 overexpression in mediating EMT and metastasis. NBS1 overexpression was associated with metastasis of HNSCC patients using tissue microarray–immunohistochemistry approach. Induction of EMT was observed in an NBS1-overexpressing HNSCC cell line (FADUNBS), whereas short-interference RNA (siRNA)-mediated repression of endogenous NBS1 reversed the shift of EMT markers. Increased migration/invasiveness of FADUNBS was shown by in vitro and in vivo assays. NBS1 overexpression upregulated the expression of an EMT regulator Snail and its downstream target matrix metalloproteinase-2. EMT phenotypes and increased migration/invasiveness of FADUNBS cells were reversed by siRNA-mediated repression of Snail expression or a phosphatidylinositol 3-kinase-specific inhibitor. In HNSCC samples, co-expression of NBS1/Snail in primary tumors correlated with metastasis and the worst prognosis. These results indicate that NBS1 overexpression induces EMT through the upregulation of Snail expression, and co-expression of NBS1/Snail predicts metastasis in HNSCCs.

Candidemia in cancer patients: Impact of early removal of non-tunneled central venous catheters on outcome

OBJECTIVE To explore the impact of retention of non-tunneled central venous catheters (CVCs) on survival in candidemic cancer patients, where CVCs are commonly used and essential. A second object was to determine whether early CVC removal would benefit a subset of cancer patients. METHODS We retrospectively evaluated 92 cancer patients who had a single, non-tunneled CVC in place. Patients were grouped according to CVC retention or removal; the later group was subdivided into early (CVC removed <or=72h after candidemia onset) and late removal. A Cox regression model was used for determining risk factors of adverse outcome and Kaplan-Meier analyses for comparing in-hospital 3-30 day survival among subgroups. RESULTS Baseline characteristics were comparable between CVC retention (n=20) or removal (n=72) groups. CVC retention was a significant risk factor of poor outcome, independent of other significant prognostic host factors (hazard ratio 7.15, 95% confidence interval 3.51-14.53, p<0.001). Patients of early CVC removal (n=40) had significant better survival than those of late removal (n=32) (p<0.001). CONCLUSION The results suggest that retention of CVCs has a negative impact on survival in candidemic cancer patients, and that early CVC removal should be considered in a subset of cancer patients with candidemia.

Severe anaphylactic reactions in patients receiving oxaliplatin therapy: a rare but potentially fatal complication

GoalsThe most well-known adverse events of oxaliplatin are hematologic toxicity, gastrointestinal tract toxicity, and sensory neuropathy. However, hypersensitivity reaction of oxaliplatin, especially severe anaphylactic reactions (SAR), was less often reported.Materials and methodsThree hundred and three patients with colon cancer treated by oxaliplatin-containing chemotherapy in one institution were analyzed. Patients were considered to have oxaliplatin-induced SAR if they suffered from at least one of the following symptoms after oxaliplatin infusion: symptomatic bronchospasm, allergy-related edema/angioedema, unstable blood pressure, or anaphylaxis. The reported cases in published literatures that met our definition were also reviewed.ResultThere were 4 out of 303 patients suffering from SAR after receiving oxaliplatin infusion, with an estimated incidence of 1.32%. Two of them became unconscious and had hypertensive crisis, and one patient had consciousness loss with hypotension. All four patients needed various level of oxygen support. Twenty-seven cases of oxaliplatin-induced SAR were found from Medline. Among the 31 reported cases, the most frequent SAR symptom was hypotension. However, we reported two unique SAR cases with hypertension crisis. In only four out of ten cases, patients could tolerate rechallenge of oxaliplatin. There is no association between the occurrence of oxaliplatin-induced SAR and metastatic sites.ConclusionOxaliplatin-induced SAR is a rare but potentially fatal complication. Hypertension crisis can be one of the oxaliplatin anaphylactic reactions. Only few patients suffering this complication could tolerate subsequent treatment of oxaliplatin by prolonged infusion time or using a desensitization schedule, thus changing regimen might be a better alternative for them.

Fatal Fulminant Hepatitis B after Withdrawal of Prophylactic Lamivudine in Hematopoietic Stem Cell Transplantation Patients

Hepatitis B virus (HBV) reactivation can give rise to acute hepatitis and even fatal fulminant hepatitis in patients receiving immunosuppressive or cytostatic treatment. Recently, the prophylactic use of lamivudine for HBV reactivation in HBV surface antigen-positive chronic-disease patients undergoing hematopoietic stem cell transplantation (HSCT) has been reported. However, the appropriate duration for this prophylactic therapy is unclear. Here, we report 2 cases of fatal fulminant hepatitis B reactivation in HSCT patients after lamivudine withdrawal. One patient with non-Hodgkin’s lymphoma completed 6 courses of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone) and autologous peripheral blood SCT (PBSCT). Lamivudine was discontinued 3 months after transplantation. The second patient had acute myeloid leukemia. He received induction chemotherapy and postremission allogeneic PBSCT as late intensified consolidation therapy. Lamivudine treatment was discontinued 10 months after transplantation. In both patients, HBV reactivation 2 to 3 months following lamivudine cessation led to fatal fulminant hepatitis. We suggest that the duration of prophylactic use of lamivudine in chronic HBV carriers receiving HSCT be prolonged until the patient’s immune system has been reconstituted.

2-Methoxyestradiol attenuates phosphatidylinositol 3-kinase/Akt pathway-mediated metastasis of gastric cancer

The major obstacle for the treatment of gastric cancer is recurrence and metastasis; yet, its molecular mechanism is largely unknown. 2‐methoxyestradiol (2‐ME), a metabolite of the estradiol‐17β, has recently been demonstrated to have multifactorial effects against tumor proliferation and angiogenesis; how these effects are interrelated and act cooperatively is the key question to be elucidated. Akt activation was shown to promote cancer cell invasiveness, and inhibition of Akt phosphorylation by 2‐ME was also noted. We herein investigated the significance of PI3K/Akt activation in gastric cancer metastasis and the anti‐metastatic effect of 2‐ME through attenuation of Akt activity. Immunohistochemistry of PI3K, phosphorylated Akt (p‐Akt) and phosphorylated Erk (p‐Erk) was performed in tumors from 56 gastric cancer patients, and a significant correlation between PI3K/p‐Akt and tumor stage/prognosis was demonstrated (p < 0.05). An in vitro study of 7 gastric cancer cell lines showed a remarkable correlation between PI3K and p‐Akt. PI3K/p‐Akt overexpression was associated with invasiveness/migration; in contrast, phosphorylation of Erk was not shown to be correlated with invasiveness. In addition, metastatic gastric cancer clones expressed a higher level of PI3K/p‐Akt. The anti‐metastatic effect of a low dose of 2‐ME and inactivation of Akt was demonstrated. 2‐ME also exhibited an ability to inhibit gastric cancer cell proliferation and induce G2/M cell cycle arrest at a higher concentration than that required for inhibition of migration. We conclude that the activation of PI3K/Akt pathway is involved in the late‐stage progression and metastasis of gastric cancer, and attenuation of p‐Akt by 2‐ME suppresses metastasis.

Impact of bloodstream infections on outcome and the influence of prophylactic oral antibiotic regimens in allogeneic hematopoietic SCT recipients.

This study aimed to determine the impact of blood stream infections (BSIs) on outcome of allogeneic hematopoietic SCT (HSCT), and to examine the influence of old (non-levofloxacin-containing) and new (levofloxacin-based) prophylactic antibiotic protocols on the pattern of BSIs. We retrospectively enrolled 246 allogeneic HSCT recipients between January 1999 and June 2006, dividing patients into BSI (within 6 months post-HSCT, n=61) and non-BSI groups (n=185). We found that Gram-negative bacteria (GNB) predominated BSI pathogens (54%). Multivariate analyses showed that patients with a BSI, compared with those without, had a significantly greater 6-month mortality (hazard ratio, 1.75; 95% confidence interval, 1.09–2.82; P=0.021) and a significantly increased length of hospital (LOH) stay (70.8 vs 55.2 days, P=0.014). Moreover, recipients of old and new protocols did not have a significantly different 6-month mortality and time-to-occurrence of BSIs. However, there were significantly more resistant GNB to third-generation cephalosporins and carbapenem in recipients of levofloxacin-based prophylaxis. Our data suggest that BSIs occur substantially and impact negatively on the outcome and LOH stay after allogeneic HSCT despite antibiotic prophylaxis. Levofloxacin-based prophylaxis, albeit providing similar efficacy to non-levofloxacin-containing regimens, may be associated with increased antimicrobial resistance.

Epidermal growth factor receptor R521K polymorphism shows favorable outcomes in KRAS wild-type colorectal cancer patients treated with cetuximab-based chemotherapy.

The R521K polymorphism of epidermal growth factor receptor has attenuated affinity in ligand binding and proto‐oncogene induction, which may affect the efficacy of cetuximab. We analyzed the effect of this polymorphism on the outcome of 112 patients with KRAS wild‐type metastatic colorectal carcinoma treated with first‐line cetuximab plus FOLFOX‐4. The associations of this polymorphism with vascular endothelial growth factor (VEGF) expression and clinicopathologic characteristics were also examined. The results showed that the frequencies of the G/G, G/A, and A/A genotypes were 32.1% (n = 36), 42.9% (n = 48), and 25.0% (n = 28), respectively. A marked decrease in VEGF expression levels (66.7% vs 28.9%, P < 0.01) was observed in patients with 521A allele variants (Arg/Lys or Lys/Lys), which were associated with a decreased tumor size (55.6% vs 31.6%, P = 0.02), good histological differentiation (63.9% vs 85.5%, P = 0.01), decreased lymphovascular invasion (69.4% vs 39.5%, P < 0.01), and a higher response rate to cetuximab plus FOLFOX treatment (55.6% vs 78.9%, P = 0.01). In addition, this polymorphism was associated with a longer progression‐free period (P = 0.001) and overall survival (P = 0.001). By multivariate analysis, this polymorphism was also identified as an independent prognostic factor. These data suggest that the R521K polymorphism of epidermal growth factor receptor, by reducing its activation and a consequential downregulation of its target genes, including VEGF, could be a key determinant of an increased response to cetuximab‐based chemotherapy and a longer survival for KRAS wild‐type colorectal carcinoma patients. (Cancer Sci 2012; 103: 791–796)

High incidence of oral squamous cell carcinoma independent of HPV infection after allogeneic hematopoietic SCT in Taiwan

Hematopoietic SCT (HSCT) is a well-recognized therapeutic procedure to prolong life and cure patients with life-threatening hematological malignancies; however, the risk of developing secondary carcinoma may increase in long-term survivors. The objective of this study was to determine the incidence and risk factors for secondary squamous carcinoma after HSCT. Between 1984 and 2004, 170 allogeneic HSCT recipients aged >15 years, who had survived for >5 years were enrolled. Demographic data and the characteristics of secondary carcinoma were collected and analyzed for the determination of the incidence and risk of developing secondary carcinoma. Eight patients developed secondary carcinoma, including five oral squamous cell carcinomas, one esophageal, one gastric and one ovarian carcinoma, but no cutaneous carcinomas were detected at a median follow-up of 14.1 years (range, 5.1–23.3 years) after HSCT. The accrual 10-year cumulative incidence of secondary carcinoma was 2.89%. In univariate and multivariate analyses, chronic GVHD and age >40 years at the time of HSCT were both significant risk factors independently associated with the development of secondary carcinoma. Thus, the occurrence of secondary carcinoma is one of the late complications in patients undergoing HSCT. Oral squamous cell carcinoma was more common in our patients after HSCT, indicating the need for lifelong surveillance of the oral cavity. Moreover, because of the relatively long latency in developing secondary carcinoma, extended follow-up is required for a thorough understanding of the incidence and characteristics of secondary carcinoma after HSCT.

Nonmyeloablative allogeneic bone marrow transplantation for orbital granulocytic sarcoma associated with t(8;21)(q22;q22) in acute myeloid leukemia.

We report a nonmyeloablative allogeneic bone marrow transplant (allo-BMT) from an HLA-matched unrelated donor in a case of acute myeloid leukemia (AML), M2 with t(8;21)(q22;q22) and the presence of orbital granulocytic sarcoma (GS), who had residual tumor after conventional chemotherapy. The course of BMT was well tolerated, with no major procedure-related toxicity. The residual orbital GS regressed completely 4 months after BMT. She is currently 19 months post BMT, disease-free. To our knowledge, this is the first reported pediatric patient with AML, GS and t(8;21)(q22;q22) who received a nonmyeloablative allo-BMT.Bone Marrow Transplantation (2002) 29, 67–70. doi:10.1038/sj.bmt.1703316

Successful pregnancy following very high-dose total body irradiation (1575 cGy) and bone marrow transplantation in a woman with acute myeloid leukemia

A 22-year-old woman had a normal full-term delivery 6 years after a successful allogeneic bone marrow transplantation (BMT) for acute myeloid leukemia (AML). Conditioning therapy consisted of cyclophosphamide (120 mg/kg) and total body irradiation (TBI) to a total of 1575 cGy in seven fractions (225 cGy × 7, at a dose rate of 3.5 cGy/min). Graft-versus-host disease prophylaxis was with methotrexate and cyclosporin A. Grade I acute GVHD developed after BMT but there was no chronic GVHD. She became amenorrhoeic after BMT and serial gonadal testing indicated hypergonadotrophic hypogonadism. She became pregnant and delivered a full-term, healthy baby 6 years after BMT. Successful pregnancy after TBI of more than 1200 cGy is extremely rare. This case, to the best of our knowledge, is the second patient who received a higher dose of TBI (1575 cGy) to have a successful pregnancy. This and previous reports indicate that normal pregnancy is possible after BMT with TBI in excess of 1200 cGy.