Tony Yuen Eng

A comprehensive review of the treatment of Merkel cell carcinoma

Merkel cell carcinoma (MCC) is an uncommon but malignant cutaneous neuroendocrine carcinoma with a high incidence of local recurrence, regional lymph node metastases, and subsequent distant metastases. The etiology of MCC remains unknown. It usually occurs in sun-exposed areas in elderly people, many of whom have a history of other synchronous or metachronous sun-associated skin lesions. The outcome for most patients with MCC is generally poor. Surgery is the mainstay of treatment. The role of adjuvant therapy has been debated. However, data from recent development support a multimodality approach, including surgical excision of primary tumor with adequate margins and sentinel lymph node dissection followed by postoperative radiotherapy in most cases, as current choice of practice with better locoregional control and disease-free survival. Patients with regional nodal involvement or advanced disease should undergo nodal dissection followed by adjuvant radiotherapy and, perhaps, systemic platinum-based chemotherapy in most cases.

Treatment of merkel cell carcinoma

Purpose:The purpose of this study was to evaluate the treatment of Merkel cell carcinoma. Materials and Methods:We reviewed 85 cases of Merkel cell carcinoma. There were 68 males and 17 females. The majority of cases involved head and neck sites (48%), followed by the extremities (38%) and trunk (14%). Sixty-seven percent of the patients had stage I disease that was localized to the skin of origin at presentation. Twenty-five percent and 8% were stage II (nodal metastasis) and stage III (distant metastasis), respectively. Surgical intervention included local or wide local excision ± nodal dissection (68%), radical resection ± nodal dissection (22%), and amputation (4%). Five patients (6%) underwent biopsy only because of metastatic disease or unresectability at presentation. Fifty-one percent received adjuvant therapy consisting of external beam radiation therapy and/or combination chemotherapy. Results:With an average follow-up time of 39.5 months, 12% had persistent disease and 40% had recurrent disease. The median time to recurrence was 8 months with a mean of 10.6 months. Although the addition of adjuvant therapy did not affect survival, the recurrence rate was 32.5% for surgery ± adjuvant radiation therapy ± chemotherapy as compared with 52.7% for surgery-only patients. Although the 40.7% recurrence rate for patients receiving surgery and adjuvant radiation therapy was approximately the same as for patients receiving surgery and adjuvant chemotherapy (40%), the effect of systemic chemotherapy on recurrence is less clear as a result of the small number of patients who received such therapy. Although tumor size and site of presentation were not observed to be statistically significant in overall survival, significant differences were observed based on sex and tumor stage. For females, the median survival time was 96 months (mean, 94.5 months) compared with 63 months (mean, 76.8 months) for males. This difference was significant (P < 0.01). Patients presenting with low-stage (stage I) disease had a significant (P < 0.01) survival benefit when compared with high-stage individuals (stages II and III). The 5-year actuarial survival rates were 68% and 42%, respectively. Conclusion:In this retrospective study, surgery remains the primary modality for Merkel cell carcinoma, and adjuvant radiation therapy ± systemic chemotherapy reduces local recurrence. Female patients and those who present with early-stage disease appear to have a better prognosis.

Multiple patterns of resistance to fluconazole in Candida glabrata isolates from a patient with oropharyngeal candidiasis receiving head and neck radiation

ABSTRACT Candida glabrata has emerged in recent years as a significant cause of systemic fungal infection. We have previously reported on the first three patients receiving radiation for head and neck cancer to develop oropharyngeal candidiasis due to C. glabrata. The goal of this study was to track the development of increased fluconazole resistance in C. glabrata isolates and to evaluate previously described genetic mechanisms associated with this resistance from one of these three patients. The patient was a 52-year-old man with squamous cell carcinoma treated with radiation. At week 7 of his radiation, he developed oropharyngeal candidiasis, which was treated with 200 mg of fluconazole daily for 2 weeks. Serial cultures from this and three subsequent time points yielded C. glabrata. Isolates from these cultures were subjected to antifungal susceptibility testing, DNA karyotyping, and evaluation of the expression of genes previously associated with C. glabrata resistance to fluconazole, CgCDR1, CgCDR2, and CgERG11. Two strains (A and B) of C. glabrata were identified and found to display different patterns of resistance development and gene expression. Strain A developed resistance over a 2-week period and showed no overexpression of these genes. In contrast, strain B first showed resistance 6 weeks after fluconazole therapy was discontinued but showed overexpression of all three genes. In conclusion, development of resistance to fluconazole by C. glabrata is a highly varied process involving multiple molecular mechanisms.

MANAGEMENT OF THE UNKNOWN PRIMARY CARCINOMA: LONG-TERM FOLLOW-UP ON A NEGATIVE PET SCAN AND NEGATIVE PANENDOSCOPY

The unknown primary carcinoma in the head and neck has been estimated to represent up to 7% of all head and neck carcinomas. In an attempt to identify the occult primary tumor the evaluation of this patient population has included a complete head and neck examination, flexible fiberoptic endoscopy, and imaging with CT/MRI. More recently, positron emission tomography (PET) has been advocated as a tool to detect primary tumors.

Candida glabrata Oropharyngeal Candidiasis in Patients Receiving Radiation Treatment for Head and Neck Cancer

ABSTRACT Candida glabrata colonization is common in patients receiving radiation treatment for head and neck cancer, but to our knowledge has never been described as the infecting organism with oropharyngeal candidiasis (OPC). This study presents the first three patients described with C. glabrata OPC in this patient population. Patient 1 developed C. glabrata OPC and required fluconazole, 800 mg/day, for clinical resolution. Antifungal susceptibility testing revealed a MIC of fluconazole of >64 μg/ml. Elapsed time from initial culturing to treatment decision was 7 days. Patients 2 and 3 developed C. glabrata OPC. They were patients in a study evaluating OPC infections, and cultures were taken immediately. CHROMagar Candida plates with 0, 8, and 16 μg of fluconazole/ml were employed for these cultures. Lavender colonies, consistent with C. glabrata, grew on the 0- and 8-μg plates but not on the 16-μg plate from patient 2 and grew on all three plates from patient 3. Based on these data, a fluconazole dose of 200 mg/day was chosen for patient 2 and a dose of 400 mg/day was chosen for patient 3, with clinical resolution in both. Elapsed time from initial culturing to treatment decision was 2 days. C. glabrata does cause OPC in head and neck radiation treatment patients, and the use of fluconazole-impregnated chromogenic agar may significantly reduce treatment decision time compared to that with conventional culturing and antifungal susceptibility testing.

Adhesion Molecules in Radiotherapy

Abstract Baluna, R. G., Eng, T. Y. and Thomas, C. R., Jr. Adhesion Molecules in Radiotherapy. Radiat. Res. 166, 819–831 (2006). Recent studies have documented changes in adhesion molecule expression and function after exposure to ionizing radiation. Adhesion molecules mediate cell–cell and cell–matrix interactions and are essential for a variety of physiological and pathological processes including maintenance of normal tissue integrity as well as tumor development and progression. Consequently, modulation of adhesion molecules by radiation may have a role in radiation-induced tumor control and normal tissue damage by interfering with cell signaling, radioresistance, metastasis, angiogenesis, carcinogenesis, immune response, inflammation and fibrosis. In addition, the interactions of radiation with adhesion molecules could have a major impact in developing new strategies to increase the efficacy of radiation therapy. Remarkable progress has been made in recent years to design targeted drug delivery to radiation-up-regulated adhesion molecules. Furthermore, the inhibition of adhesion, migration, invasion and angiogenesis by blocking adhesion receptors may represent a new therapeutic approach to improve tumor control and decrease radiation toxicity. This review is focused on current data concerning the mechanistic interactions of radiation with adhesion molecules and the possible clinical-pathological implications in radiotherapy.

Oropharyngeal candidiasis caused by non-albicans yeast in patients receiving external beam radiotherapy for head-and-neck cancer

PURPOSE To characterize non-albicans Candida oral infections in patients with head-and-neck cancer receiving external beam radiotherapy (EBRT) with or without concurrent chemotherapy. METHODS AND MATERIALS Thirty-seven patients with head-and-neck cancer received EBRT in 2.0-Gy daily fractions to a median dose of 60.4 Gy (range 38-82.8, mean 64.6). They were followed for oropharyngeal candidiasis (OPC) confirmed by positive examination, positive KOH smear, and/or positive swab or swish culture. Samples were identified and plated on chromogenic media to identify non-albicans yeasts. Colonies were plated on Sabouraud dextrose slants for microdilution antifungal susceptibility testing to fluconazole. DNA typing, including karyotyping, restriction fragment length polymorphism analysis, and Southern blot hybridization with the moderately repetitive Ca3 probe, was performed on selected isolates to confirm individual species. RESULTS Of the 37 patients, 10 (27%) developed OPC, and 26 (70.3%) displayed Candida carriage state. The median EBRT dose at time of positive culture was 22.5 Gy and at time of OPC was 28.6 Gy. Of the 6 patients receiving chemotherapy and EBRT, 4 (66%) developed OPC at median dose of 27.6 Gy. Three (8%) of 37 patients were infected with non-albicans Candida, and 3 (30%) of all 10 infections were caused by these organisms. CONCLUSION Non-albicans Candida is emerging as a relatively common cause of OPC in head-and-neck cancer patients. Chromogenic media are helpful to screen these infections. Our data also suggest a greater likelihood of developing OPC in patients receiving concomitant chemotherapy and EBRT.

Treatment of recurrent merkel cell carcinoma: An analysis of 46 cases

This report describes the course of recurrent Merkel cell carcinoma and defines possible treatment strategies for recurrent disease as seen in a long-term multisite retrospective analysis. Merkel cell carcinoma is a highly aggressive neuroendocrine skin cancer. Surgery and radiation therapy have been demonstrated ability to control this disease; however, recurrence is common. Systemic chemotherapy has, as yet, no presently defined role in primary treatment, and few conclusions can be reached regarding optimal treatment of disease recurrence. Forty-six patients were identified over the last 15 years in a retrospective analysis of patient records from several hospitals in the San Antonio, TX area. Hospital charts as well as outpatient treatment records were reviewed. Almost all patients developing recurrent disease did so within the first 2 years after primary treatment. Patients presenting distant disease had a median survival of 12 months, faring worse than those who display local or nodal disease. For patients with nodal or local recurrence, the mean survival after combination therapy (chemotherapy, radiation ± surgery) was 36.5 months as compared with 17.5 months for those treated with a single modality (surgery or radiation or chemotherapy). The overall survival rate for the 46 patients with recurrence was 37%. Multimodality therapy has shown the best results for recurrent Merkel cell carcinoma thus far, and should be used if tolerated by the patient. Aggressive salvage surgery for local or nodal recurrence is encouraged, because this disease has a tendency to become more destructive upon recurrence. Adjuvant radiation therapy should also be used, if the patient has not exceeded their dose limitations. Disseminated disease, whether primary or recurrent, warrants further investigation in terms of optimal treatment.

Retrospective study of the treatment of urethral cancer.

Urethral cancer is rare, encompassing less than 1% of all malignancies. Optimal management, at present, often relies on the limited experience gained from the study of retrospective cases. Therefore, it is imperative to share all available information regarding urethral cancer treatment via reportage of pertinent cases, thus enabling more complete comprehension and decision-making options by both clinicians and researchers. A retrospective review of 18 consecutive patients with primary urethral cancer was performed. An analysis was performed of clinical stage, treatment modality, and outcome. Overall patient survival rate for this retrospective was 44%, with a mean follow-up of 63.5 months. Seven of 10 patients with low-stage diagnosis remained disease free. Comparatively, only one of eight patients with high-stage cancer had no apparent disease. Patients with advanced cancer treated with surgery alone had a shorter disease-free survival (23.3 months) versus those treated with combination chemo/radiation therapy (45.2 months). The major characteristic with prognostic impact was statistically found to be low (T1-2, N0, M0) versus high (T3-4, N1, M1) stage, as assessed by Mann-Whitney U test (z = 2.83, p = 0.0023). Clinical staging afforded the strongest prognostic indication of survival. Patients with low-stage disease exhibited increased survival with single-modality therapy. However, patients with advanced cancer benefited from combined treatment using chemotherapy and radiation therapy.

Fertility in men after treatment for stage 1 and 2A seminoma

The purpose of this article is to assess the long-term fertility and attitudes towards fecundity in men after radical inguinal orchiectomy and radiation therapy (RT) for seminoma, and also to assess how often sperm cryopreservation is being offered to patients with seminoma prior to treatment. A retrospective review was conducted at 3 institutions (Wilford Hall Air Force Medical Center, Brooke Army Medical Center, and Fitzsimmons Army Medical Center) to identify patients who had undergone treatment of stage 1 or 2A seminoma during the period from 1975 to 1997. Seventy-three of 212 (34%) patients meeting the selection criteria of stage 1 or 2A seminoma provided information for this analysis. This was thought to be a good response rate, given that many of the patients had changed duty stations or had separated from the military by the time this study started. We performed a review of RT and tumor board records of 73 patients who were treated for testicular seminoma at selected treatment facilities from 1975 to 1997. Patients completed questionnaires and phone interviews that focused on prior fertility, the desire to father (more) children, other fertility-affecting factors (varicocele, cryptorchidism, infection, and erectile dysfunction), and incidence of physician counseling with regard to cryopreservation. All patients were asked to obtain a current semen analysis (SA). Eleven (15%) patients reported that they had tried to father children since completion of their RT. Seven of 11 (64%) successfully achieved pregnancy within a mean time of 3.5 years since RT (range: 1 month to 5 years). Of the 4 couples that were not successful, 1 had severe female factor infertility problems and a second had organic erectile dysfunction. A third had a past surgical history remarkable for vasectomy with subsequent vasectomy reversal. Nine patients provided SA. Mean sperm count and motility were 24.2 Mil/mL (range: 5–81 Mil/mL) and 63.1% (range: 30–90%), respectively (normal SA values: count = 20–250 Mil/mL, motility >50%, and volume = 1.5–5.0 mL). No patients were azoospermic. Overall mean time interval from radiation therapy was 7.9 years. Radiation dose and time since RT did not correlate with either SA results or conception. Only 16 of 73 (22%) men had been offered pretreatment sperm cryopreservation by their counseling physician. It is concluded that (1) patients who are treated for early stage seminoma by orchiectomy and RT have greater than a 50% chance of regaining normal semen parameters, and all regain at least some spermatogenesis; 2) recovery of spermatogenesis is not related to therapeutic radiation dose with the use of modern shielding and RT portals; (3) the majority of treated patients who desire children can conceive; and (4) sperm cryopreservation remains an underutilized option for seminoma patients.