Pei-Jen Lou

Interstitial photodynamic therapy as salvage treatment for recurrent head and neck cancer.

Interstitial photodynamic therapy (IPDT) is a technique for applying photodynamic therapy (PDT) to internal tumours using light delivered via fibres inserted percutaneously. This phase I–II study assessed the safety and efficacy of IPDT for patients with persistent or recurrent head and neck cancer unsuitable for further treatment with surgery, radiotherapy or chemotherapy, recruited for ‘last hope’ salvage treatment. Patients were sensitised with 0.15 mg kg−1 mTHPC (meso-tetrahydroxyphenyl chlorin) 4 days prior to light delivery from fibres inserted directly into the target tumour (20 J per site at 652 nm) under image guidance. In all, 45 patients were treated. Nine achieved a complete response. Five are alive and free of disease 10–60 months later. Symptomatic relief (mainly for bleeding, pain or tumour debulking) was achieved in a further 24. The median survival (Kaplan–Meier) was 16 months for the 33 responders, but only 2 months for the 12 nonresponders. The only serious complication was a carotid blow out 2 weeks after PDT. No loss of function was detected in nerves encased by treated tumours. Interstitial photodynamic therapy provides worthwhile palliation with few complications and occasional long-term survivors for otherwise untreatable advanced head and neck cancers. It is a treatment option worth adding to those available to integrated head and neck oncology teams.

Induction Chemotherapy With Mitomycin, Epirubicin, Cisplatin, Fluorouracil, and Leucovorin Followed by Radiotherapy in the Treatment of Locoregionally Advanced Nasopharyngeal Carcinoma

PURPOSE Survival in advanced nasopharyngeal carcinoma (NPC) is compromised by distant metastasis. Because mitomycin is active against hypoxic and G0 cells, which may help to eradicate micrometastasis, we investigated the effect of mitomycin-containing cisplatin-based induction chemotherapy. PATIENTS AND METHODS Recruited for this study were American Joint Committee on Cancer (AJCC) 1992 staging system stage IV NPC patients with the following adverse features: obvious intracranial invasion, supraclavicular or bilateral neck lymph node metastasis, large neck node (> 6 cm), or elevated serum lactate dehydrogenase (LDH) level. Patients were given three cycles of chemotherapy before radiotherapy. The chemotherapy comprised a 3-week cycle of mitomycin, epirubicin, and cisplatin on day 1 and fluorouracil and leucovorin on day 8 (MEPFL). RESULTS From January 1994 to December 1997, 111 patients were recruited. The median follow-up period was 43 months. The actuarial 5-year overall survival rate was 70% (95% confidence interval [CI], 60% to 80%; n = 111). For patients having completed radiotherapy (n = 100), the 5-year locoregional control rate was 70% (95% CI, 55% to 84%) and the distant metastasis-free rate was 81% (95% CI, 73% to 89%). The 5-year distant metastasis-free rate of N3a and N3b disease of AJCC 1997 staging system were 79% (95% CI, 62% to 95%) and 74% (95% CI, 60% to 89%), respectively. By Cox multivariate analysis, high pretreatment serum LDH level (P = .04) and neck nodal enlargement before radiotherapy (P = .001) were adverse prognostic factors of survival. CONCLUSION The good 5-year survival of N3 disease supports the effectiveness of induction MEPFL in the primary treatment of advanced NPC. Further investigation to incorporate concurrent chemoradiotherapy is warranted.

Reversal of Doxorubicin Resistance in Breast Cancer Cells by Photochemical Internalization

Multiple drug resistance (MDR) is a problem that seriously reduces the efficacy of many chemotherapy agents. One mechanism for MDR is increased acidification of endocytic vesicles and increased cytosol pH, so weak base chemotherapeutic agents, including doxorubicin, are trapped in endocytic vesicles and exhibit a drug resistant phenotype. Treatments that selectively reverse this accumulation may therefore reverse the MDR phenotype. Photochemical internalization (PCI) is a novel technology developed for site‐specific enhancement of the therapeutic efficacy of macromolecules by selective photochemical rupture of endocytic vesicles and consequent release of endocytosed macromolecules into the cytosol. This study evaluates PCI for release of doxorubicin from endocytic vesicles in MDR cells. Two breast cancer cell lines, MCF‐7 and MCF‐7/ADR (the latter resistant to doxorubicin), were selected. They were found equally sensitive to photochemical treatment with the photosensitiser TPPS2a (disulfonated meso‐tetraphenylporphine) and light. On exposure to doxorubicin alone, the IC50 (drug concentration for 50% reduction in colony formation) was 0.1 μM for MCF‐7 and 1 μM for MCF‐7/ADR. After PCI (photochemical treatment followed by doxorubicin), the IC50 concentration was 0.1 μM for both cell lines. Comparable changes were seen with assay of cell viability using 3‐(4,5‐dimethyltiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT). On fluorescence microscopy in MCF‐7/ADR cells, doxorubicin localised in granules identified as lysosomes. After PCI, doxorubicin was released into the cytosol and entered cell nuclei, as was seen in MCF‐7 cells without PCI. In conclusion, PCI reversed the MDR phenotype of doxorubicin resistant breast cancer cells by endo‐lysosomal release of the drug. The technique is a promising new approach to tackling the problem of MDR.

Non-toxic phototriggered gene transfection by PAMAM-porphyrin conjugates

Development of controllable and non-toxic gene transfection systems is a core issue in gene therapy. Photochemical internalization, an innovative strategy in cytosolic release, provides us with an opportunity to develop a light-inducible gene delivery system. In this study, a novel photochemical internalization (PCI)-mediated gene delivery system was synthesized by surface modification of polyamidoamine (PAMAM) dendrimers via 5,10,15-tri(4-acetamidophenyl)-20-mono(4-carboxyl-phenyl)porphyrin (TAMCPP) conjugated to the generation 4 PAMAM dendrimer (G4). This water-soluble PAMAM-TAMCPP conjugate was characterized for cell viability, phototoxicity, DNA complexation, and in vitro transfection activity. The results show that TAMCPP conjugation did not increase the cytotoxicity of the PAMAM dendrimer below 20 microM, but significantly induced cell death after suitable irradiation. Under almost non-toxic G4-TAMCPP-mediated PCI treatment, the expression of green fluorescent protein determined by flow cytometry could be markedly enhanced in HeLa cells. Therefore, the G4-TAMCPP conjugate had an inducible and effective gene transfection activity, and showed considerable potential as a bimodal biomaterial for PCI-mediated gene therapy.

Autophagy promotes resistance to photodynamic therapy-induced apoptosis selectively in colorectal cancer stem-like cells

Recent studies have indicated that cancer stem-like cells (CSCs) exhibit a high resistance to current therapeutic strategies, including photodynamic therapy (PDT), leading to the recurrence and progression of colorectal cancer (CRC). In cancer, autophagy acts as both a tumor suppressor and a tumor promoter. However, the role of autophagy in the resistance of CSCs to PDT has not been reported. In this study, CSCs were isolated from colorectal cancer cells using PROM1/CD133 (prominin 1) expression, which is a surface marker commonly found on stem cells of various tissues. We demonstrated that PpIX-mediated PDT induced the formation of autophagosomes in PROM1/CD133+ cells, accompanied by the upregulation of autophagy-related proteins ATG3, ATG5, ATG7, and ATG12. The inhibition of PDT-induced autophagy by pharmacological inhibitors and silencing of the ATG5 gene substantially triggered apoptosis of PROM1/CD133+ cells and decreased the ability of colonosphere formation in vitro and tumorigenicity in vivo. In conclusion, our results revealed a protective role played by autophagy against PDT in CSCs and indicated that targeting autophagy could be used to elevate the PDT sensitivity of CSCs. These findings would aid in the development of novel therapeutic approaches for CSC treatment.

Transnasal endoscopy with narrow-band imaging and Lugol staining to screen patients with head and neck cancer whose condition limits oral intubation with standard endoscope (with video)

BACKGROUND Early detection of esophageal cancer in patients with head and neck cancers may alter treatment planning and improve survival. However, standard endoscopic screening is not feasible for some patients with tumor-related airway compromise or postirradiation trismus. OBJECTIVE To evaluate a novel, sequential approach by integrating ultrathin endoscopy with narrow-band imaging and Lugol chromoendoscopy. DESIGN Cross-sectional study. SETTING Single center in Taiwan. PATIENTS Forty-four consecutive patients with transoral difficulty screened for synchronous or metachronous esophageal cancer. MAIN OUTCOME MEASUREMENTS Sensitivity, specificity, and accuracy in the detection of mucosal high-grade neoplasia or invasive cancer. RESULTS Fifty-four endoscopic interpretations were obtained, and 11 mucosal high-grade neoplasia and 7 invasive cancers were confirmed by histology. The mean examination time was 19.4 minutes (range 7.9-35.2 minutes), and all patients tolerated the procedure well. Sensitivity, specificity, and accuracy (with 95% CI) were 55.6% (95% CI, 33.5%-75.6%), 97.2% (95% CI, 85.8%-99.3%), and 83.3% (95% CI, 71.2%-90.9%), respectively, for standard endoscopy; 88.9% (95% CI, 66.9%-96.6%), 97.2% (95% CI, 85.8%-99.3%), and 94.4% (95% CI, 84.9%-97.9%), respectively, with the adjunct of narrow-band imaging; and 88.9% (95% CI, 66.9%-96.6%), 72.2% (95% CI, 55.9%-84.1%), and 77.8% (95% CI, 64.9%-86.8%), respectively, with the adjunct of Lugol chromoendoscopy. When we integrated all interpretations on the basis of the sequential approach, the estimated probability of false-negative findings was 1.2% (95% CI, 0.1%-4.6%). LIMITATIONS Inherent shortcomings of ultrathin endoscopy, such as its resolution, light source, and lack of magnification. CONCLUSIONS The use of ultrathin endoscopy in a sequential approach for multimodal detection is feasible in patients with transoral difficulty and substantially increases the detection rate of synchronous or metachronous neoplasms.

Clinical outcomes of photodynamic therapy for head-and-neck cancer

Head-and-neck cancers not only carry poor prognoses, but also reduced quality of life for the patients. Disease control is often achieved at the expense of substantial functional loss and disfigurement. Photodynamic therapy (PDT) is particularly well suited to the treatment of head-and-neck-tumors because it has little effect on underlying functional structures and has an excellent cosmetic outcome. Studies in the past decades have shown that PDT is of similar efficacy as traditional measures in the treatment of early-stage head-and-neck cancers with an overall response rate of 85%–100%, with up to 75% of the complete responses sustained at 2 years after PDT. For advanced head-and-neck cancers, studies were also conducted to evaluate the palliative effects of PDT. Overall, a 58%–70% palliative benefit can be observed in these patients. Using interstitial PDT, the median survival of the patients with recurrent unresectable head-and-neck cancers can be improved to 14 months (cf. 226 days by using surface illumination PDT). PDT is thus a therapeutic option that may prove a useful addition to the armamentarium of the integrated head and neck oncology team.

Transcutaneous ultrasound for evaluation of vocal fold movement in patients with thyroid disease

BACKGROUND Preoperative evaluation of recurrent laryngeal nerve function is important in the context of thyroid surgery. Transcutaneous ultrasound may be useful to visualize vocal fold movement when evaluating thyroid disease. METHODS A 7-18 MHz linear array transducer was placed transversely on the midline of the thyroid cartilage at the anterior neck of patients with thyroid disease. The gray-scale technique was used, with the scan setting for the thyroid gland. RESULTS Between August 2008 and March 2010, 705 patients, including 672 patients with normal vocal fold movement and 33 patients with vocal fold paralysis were enrolled. They included 159 male and 546 female patients. Their ages ranged from 10 to 88 years. Vocal fold movement could be seen by ultrasound in 614 (87%) patients, including 589 (88%) patients with normal vocal fold movement and 25 (76%) patients with vocal fold paralysis (p=0.06). The mean age of patients with visible and invisible vocal fold movement was 46.6 and 57.9 years old, respectively (p=0.001). Ultrasound was able to see vocal fold movement in 533 (98%) female patients but only in 81 (51%) male patients (p=0.001). Among the patients with vocal fold paralysis, ultrasound revealed palsied vocal folds in 17 of 18 (94%) female patients but in only 8 of 15 (53%) male patients (p=0.01). CONCLUSION Transcutaneous ultrasound represents an alternative tool to evaluate vocal fold movement for more than 85% of patients with thyroid disease, including more than 90% of female patients and about half of male patients.

G-Quadruplex Stabilizer 3,6-Bis(1-Methyl-4-Vinylpyridinium)Carbazole Diiodide Induces Accelerated Senescence and Inhibits Tumorigenic Properties in Cancer Cells

Carbazole derivatives that stabilized G-quadruplex DNA structure formed by human telomeric sequence have been designed and synthesized. Among them, 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide (BMVC) showed an increase in G-quadruplex melting temperature by 13°C and has a potent inhibitory effect on telomerase activity. Treatment of H1299 cancer cells with 0.5 μmol/L BMVC did not cause acute toxicity and affect DNA replication; however, the BMVC-treated cells ceased to divide after a lag period. Hallmarks of senescence, including morphologic changes, detection of senescence-associated β-galactosidase activity, and decreased bromodeoxyuridine incorporation, were detected in BMVC-treated cancer cells. The BMVC-induced senescence phenotype is accompanied by progressive telomere shortening and detection of the DNA damage foci, indicating that BMVC caused telomere uncapping after long-term treatments. Unlike other telomerase inhibitors, the BMVC-treated cancer cells showed a fast telomere shortening rate and a lag period of growth before entering senescence. Interestingly, BMVC also suppressed the tumor-related properties of cancer cells, including cell migration, colony-forming ability, and anchorage-independent growth, indicating that the cellular effects of BMVC were not limited to telomeres. Consistent with the observations from cellular experiments, the tumorigenic potential of cancer cells was also reduced in mouse xenografts after BMVC treatments. Thus, BMVC repressed tumor progression through both telomere-dependent and telomere-independent pathways. (Mol Cancer Res 2008;6(6):955–64)

Lymphoepithelial Carcinoma versus Large Cell Undifferentiated Carcinoma of the Major Salivary Glands

Undifferentiated carcinomas of the major salivary glands are rare malignant neoplasms of the head and neck region, and patients with these lesions have a poor prognosis. Patients with lymphoepithelial carcinoma (LEC), a specific subtype of undifferentiated carcinoma, however, have a better prognosis, and LEC seems to differ from large cell undifferentiated carcinoma (LCUC) clinically.