Seng-jaw Soong

Final Version of 2009 AJCC Melanoma Staging and Classification

PURPOSE To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. METHODS The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria. RESULTS Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level. CONCLUSION Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.

Vidarabine versus Acyclovir Therapy in Herpes Simplex Encephalitis

We randomly assigned 208 patients who underwent brain biopsy for presumptive herpes simplex encephalitis to receive either vidarabine (15 mg per kilogram of body weight per day) or acyclovir (30 mg per kilogram per day) for 10 days. Sixty-nine patients (33 percent) had biopsy-proved disease; 37 received vidarabine, and 32 acyclovir. The mortality in the vidarabine recipients was 54 percent, as compared with 28 percent in the acyclovir recipients (P = 0.008). Six-month mortality varied according to the Glasgow coma score at the onset of therapy. For scores of greater than 10, 7 to 10, and less than or equal to 6, mortality was 42, 46, and 67 percent in the patients treated with vidarabine, as compared with 0, 25, and 25 percent in those treated with acyclovir. A six-month morbidity assessment using an adapted scoring system revealed that 5 of 37 patients receiving vidarabine (14 percent) as compared with 12 of 32 receiving acyclovir (38 percent) were functioning normally (P = 0.021). Eight vidarabine-treated patients (22 percent) and three acyclovir-treated patients (9 percent) had moderate debility. Patients under 30 years of age and with a Glasgow coma score above 10 had the best outcome with acyclovir treatment. We conclude that acyclovir is currently the treatment of choice for biopsy-proved herpes simplex encephalitis.

Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial∗

OBJECTIVE To evaluate the efficacy and safety of ganciclovir therapy in neonates with congenital cytomegalovirus (CMV) disease. STUDY DESIGN Neonates with symptomatic CMV disease involving the central nervous system were randomly assigned to receive 6 weeks of intravenous ganciclovir versus no treatment. The primary end point was improved brainstem-evoked response (BSER) between baseline and 6-month follow-up (or, for patients with normal baseline hearing, normal BSER at both time points). RESULTS From 1991 to 1999, 100 patients were enrolled. Of these, 42 patients had both a baseline and 6-month follow-up BSER audiometric examination and thus were evaluable for the primary end point. Twenty-one (84%) of 25 ganciclovir recipients had improved hearing or maintained normal hearing between baseline and 6 months versus 10 (59%) of 17 control patients (P=.06). None (0%) of 25 ganciclovir recipients had worsening in hearing between baseline and 6 months versus 7 (41%) of 17 control patients (P<.01). A total of 43 patients had a BSER at both baseline and at 1 year or beyond. Five (21%) of 24 ganciclovir recipients had worsening of hearing between baseline and > or =1 year versus 13 (68%) of 19 control patients (P<.01). A total of 89 patients had absolute neutrophil counts determined during the course of the study; 29 (63%) of 46 ganciclovir-treated patients had grade 3 or 4 neutropenia during treatment versus 9 (21%) of 43 control patients (P<.01). CONCLUSIONS Ganciclovir therapy begun in the neonatal period in symptomatically infected infants with CMV infection involving the central nervous system prevents hearing deterioration at 6 months and may prevent hearing deterioration at > or =1 year. Almost two thirds of treated infants have significant neutropenia during therapy.

Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. National Institute of Allergy and Infectious Diseases collaborative antiviral study.

We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex.Abstract We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex. (N Engl J Med 297:289–294, 1977)

A multifactorial analysis of melanoma: prognostic histopathological features comparing Clark's and Breslow's staging methods.

A multifactorial analysis was used to identify the dominant prognostic variables affecting survival from a computerized data base of 339 melanoma patients treated at this institution during the past 17 years. Five of the 13 parameters examined simultaneously were found to independently influence five year survival rates: 1) pathological stage (I vs II, p = 0.0014), 2) lesion ulceration (present vs absent, p = 0.006), 3) surgical treatment (wide excision vs wide excision plus lymphadenectomy, p = 0.024), 4) melanoma thickness (p = 0.032), and 5) location (upper extremity vs lower extremity vs trunk vs head and neck, p = 0.038). Additional factors considered that had either indirect or no influence on survival rates were clinical stage of disease, age, sex, level of invasion, pigmentation, lymphocyte infiltration, growth pattern, and regression. Most of these latter variables derived their prognostic value from correlation with melanoma thickness, except sex which correlated with location (extremity lesions were more frequent on females, trunk lesions on males). This statistical analysis enabled us to derive a mathematical equation for predicting an individual patients probability of five year survival. Three categories of risk were delineated by measuring tumor thickness (Breslow microstaging) in Stage I patients: 1) thin melanomas (<0.76 mm) were associated with localized disease and a 100% cure rate: 2) intermediate thickness melanomas (0.76–4.00 mm) had an increasing risk (up to 80%) of harboring regional and/or distant metastases and 3) thick melanomas (≤4.00 mm) had a 80% risk of occult distant metastases at the time of initial presentation. The level of invasion (Clarks microstaging) correlated with survival, but was less predictive than measuring tumor thickness. Within each of Clarks Level II, III and IV groups, there were gradations of thickness with statistically different survival rates. Both microstaging methods (Breslow and Clark) were less predictive factors in patients with lymph node or distant metastases. Clinical trials evaluating alternative surgical treatments or adjunctive therapy modalities for melanoma patients should incorporate these parameters into their assessment, especially in Stage I (localized) disease where tumor thickness and the anatomical site of the primary melanoma are dominant prognostic factors.

Herpes Simplex Encephalitis: Vidarabine Therapy and Diagnostic Problems

To learn more about the treatment of herpes simplex encephalitis with vidarabine, we conducted an uncontrolled study of 132 patients referred to 22 hospitals because of suspected disease. All had a brain biopsy and were started on vidarabine, but only 75 were diagnosed by isolation of virus from a brain-biopsy specimen. Cumulative mortality in the latter group was 39 per cent at one year. Other than therapy, levels of consciousness and age were the major variables that influenced outcome. Of 23 patients under 30 years of age who were lethargic at the initiation of therapy, two died and 16 returned to normal. Of 26 patients over 30 years of age who were lethargic at the outset, nine died and 10 returned to normal. Semicoma and coma were associated with worse outcomes, especially in older patients. Our data suggest that outcome is improved with treatment; they provide more support for the use of brain biopsy to diagnose the infection and indicate a need for better therapy.

A new American Joint Committee on Cancer staging system for cutaneous melanoma.

The Melanoma Staging Committee of the AJCC has proposed major revisions of the melanoma TNM and stage grouping criteria. The committee members represent most of the major cooperative groups and cancer centers worldwide with a special interest in melanoma; the committee also collectively has had clinical experience with over 40,000 patients. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include 1) melanoma thickness and ulceration, but not level of invasion, to be used in the T classification; 2) the number of metastatic lymph nodes, rather than their gross dimensions, the delineation of microscopic versus macroscopic lymph node metastases, and presence of ulceration of the primary melanoma to be used in the N classification; 3) the site of distant metastases and the presence of elevated serum LDH, to be used in the M classification; 4) an upstaging of all patients with Stage I,II, and III disease when a primary melanoma is ulcerated; 5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into Stage III disease; and 6) a new convention for defining clinical and pathologic staging so as to take into account the new staging information gained from intraoperative lymphatic mapping and sentinel lymph node biopsy. The AJC Melanoma Staging Committee invites comments and suggestions regarding this proposed staging system before a final recommendation is made.

Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm)

BACKGROUND: Ten- to 15-year survival results were analyzed from a prospective multi-institutional randomized surgical trial that involved 740 stages I and II melanoma patients with intermediate thickness melanomas (1.0 to 4.0 mm) and compared elective (immediate) lymph node dissection (ELND) with clinical observation of the lymph nodes as well as prognostic factors that independently predict outcomes. METHODS: Eligible patients were stratified according to tumor thickness, anatomical site, and ulceration, and then prerandomized to either ELND or nodal observation. By using Cox stepwise multivariate regression analysis, the independent predictors of outcome were tumor thickness (P < .001), the presence of tumor ulceration (P < .001), trunk site (P = .003), and patient age more than 60 years (P = .01). RESULTS: Overall 10-year survival was not significantly different for patients who received ELND or nodal observation (77% vs. 73%; P = .12). Among the prospectively stratified subgroups of patients, 10-year survival rates favored those patients with ELND, with a 30% reduction in mortality rate for the 543 patients with nonulcerated melanomas (84% vs. 77%; P = .03), a 30% reduction in mortality rate for the 446 patients with tumor thickness of 1.0 to 2.0 mm (86% vs. 80%; P = .03), and a 27% reduction in mortality rate for 385 patients with limb melanomas (84% vs. 78%; P = .05). Of these subgroups, the presence or absence of ulceration should be the key factor for making treatment recommendations with regard to ELND for patients with intermediate thickness melanomas. CONCLUSIONS: These long-term survival rates from patients treated at 77 institutions demonstrate that ulceration and tumor thickness are dominant predictive factors that should be used in the staging of stages I and II melanomas, and confer a survival advantage for these subgroups of prospectively defined melanoma patients.

Adenine Arabinoside Therapy of Biopsy-Proved Herpes Simplex Encephalitis

We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex.Abstract We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex. (N Engl J Med 297:289–294, 1977)

A multifactorial analysis of melanoma. III. Prognostic factors in melanoma patients with lymph node metastases (stage II)

Twelve prognostic features of melanoma were examined in a series of 185 patients with nodal metastases (Stage II), who underwent surgical treatment at our institution during the past 20 years. Forty-four per cent of the patients presented with synchronous nodal metastases (substage IIA), 44% of the patients had delayed nodal metastases (substage IIB), and 12% of the patients had nodal metastases from an unknown primary site (substage IIC). The patients with IIB (delayed) metastases had a better overall survival rate than patients with IIA (synchronous) metastases, when calculated from the time of diagnosis. These differences could be explained on the basis of tumor burden at the time of initial diagnosis (microscopic for IIB patients versus macroscopic for IIA patients). Once nodal metastases became evident in IIB patients, their survival rates were the same as for substage IIA patients, when calculated from the onset of nodal metastases. The survival rates for both subgroups was 28% at five years and 15% for ten years. Substage IIC patients (unknown 1st site) had better five-year survival rates (39%), but the sample size was small and the differences were not statistically significant. A multifactorial analysis was used to identify the dominant prognostic variables from among 12 clinical and pathologic parameters. Only two factors were found to independently influence survival rates: 1) the number of metastatic nodes (p = 0.005), and the presence or absence of ulceration (p = 0.0019). Additional factors considered that had either indirect or no influence on survival rates (p > 0.10) were: anatomic location, age, sex, remission duration, substage of disease, tumor thickness, level of invasion, pigmentation, and lymphocyte infiltration. All combinations of nodal metastases were analyzed from survival differences. The combination that showed the greatest differences was one versus two to four versus more than four nodes. Their five-year survival rates were 58%, 27% and 10%, respectively (p < 0.001). Ulceration of the primary cutaneous melanoma was associated with a <15% five-year survival rate, while nonulcerative melanomas had a 30% five-year survival rate (p < 0.001). The combination of ulceration and multiple metastatic nodes had a profound adverse effect on survival rates. While tumor thickness was the most important factor in predicting the risk of nodal metastases in Stage I patients (p < 10-8), it had no predictive value on the patients clinical course once nodal metastases had occurred (p = 0.507). The number of metastatic nodes and the presence of ulceration are important factors to account for when comparing surgical results, and when analyzing the efficacy of adjunctive systemic treatments.