Histopathological features of complete pathological response predict recurrence-free survival following neoadjuvant targeted therapy for metastatic melanoma.

BACKGROUND: Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse. METHODS: Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes. RESULTS: Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035). CONCLUSIONS: The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.

Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma.

Background: Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. Methods: The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines. Results: Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy-treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated. Conclusions: Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.

Is surviving enough? Coping and impact on activities of daily living among melanoma patients with lymphoedema.

We assessed the impact of lymphoedema (defined as ≥ 10% limb volume change) on quality of life (QOL), ability to perform activities of daily living (ADLs) and coping in 277 melanoma patients. Limb volume was measured prospectively, pre-operatively and every 3-6 months for 18 months post-operatively using a perometer. Three questionnaires were administered to measure QOL, coping and impact on ADLs. Statistical analyses were conducted using longitudinal logistic regression models. At 18 months, the cumulative incidence of lymphoedema was 31% in patients with upper extremity nodal basin treatment and 40% in lower extremity nodal basin treatment patients. Patients with lower extremity lymphoedema reported lower QOL scores than those with upper extremity lymphoedema. Over 18 months, both groups with mild and moderate lymphoedema showed improvement in coping [odds ratio (OR): 6.67, 95% confidence interval (CI): 3.30-13.47] and performance of ADLs (OR: 7.46, CI: 3.38-16.47). Over the course of 18 months, men were found to have poorer coping scores than women (OR: 2.91, CI: 1.35-6.27). Lymphoedema was associated with improvement in coping over time (P = 0.08) and a higher reported interference with ADLs (OR: 2.53, CI: 1.29-4.97). Patient education about lymphoedema at the time of surgical consent may improve self-efficacy and coping ability. Effective management of lymphoedema may improve patient QOL and reduce interference with ADLs.

Safety and feasibility of adjunctive regadenoson injection at peak exercise during exercise myocardial perfusion imaging: The Both Exercise and Regadenoson Stress Test (BERST) trial.

BACKGROUND: The data existing in the literature regarding the safety of using regadenoson with symptom-limited exercise are limited, which motivated the authors to undertake this randomized study. METHODS: We offered patients scheduled to undergo vasodilator stress nuclear myocardial perfusion imaging the opportunity to exercise instead. Patients who failed to reach target heart rate (THR) were randomized to (1) receive regadenoson at peak exercise or (2) stop exercise and receive regadenoson at rest. Patients who reached THR received a standard Tc-99m sestamibi injection with no regadenoson. RESULTS: 200 patients were included (66% male, mean age 52.5 ± 13.6). 125 patients (62%) reached THR with exercise alone. All stress protocols were well tolerated, and there were no significant adverse events. There were no statistically significant differences in the extent of perfusion abnormalities, image quality, or rate of referral to cardiac catheterization within 60 days between the groups. In fully adjusted logistic regression models, beta-blocker use and diabetes remained significant univariate predictors of failure to reach THR (OR 0.21, 95% CI 0.1-0.5, P < .0001, OR 0.34, 95% CI 0.2-0.7, P = .004, respectively). CONCLUSIONS: A protocol combining regadenoson at peak exercise in patients unable to reach THR with exercise is feasible, well-tolerated, and yields comparable imaging results to a standard regadenoson injection at rest. In addition, pharmacologic stress testing may be over-ordered in current clinical practice, as patients referred for such testing were often able to exercise.

Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial.

Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-based intralesional oncolytic immunotherapy approved for the treatment of unresectable melanoma. The present, ongoing study aimed to estimate the treatment effect of neoadjuvant T-VEC on recurrence-free survival (RFS) of patients with advanced resectable melanoma. An open-label, phase 2 trial (NCT02211131) was conducted in 150 patients with resectable stage IIIB-IVM1a melanoma who were randomized to receive T-VEC followed by surgery (arm 1, n = 76) or surgery alone (arm 2, n = 74). The primary endpoint was a 2-year RFS in the intention-to-treat population. Secondary and exploratory endpoints included overall survival (OS), pathological complete response (pCR), safety and biomarker analyses. The 2-year RFS was 29.5% in arm 1 and 16.5% in arm 2 (overall hazard ratio (HR) = 0.75, 80% confidence interval (CI) = 0.58-0.96). The 2-year OS was 88.9% for arm 1 and 77.4% for arm 2 (overall HR = 0.49, 80% CI = 0.30-0.79). The RFS and OS differences between arms persisted at 3 years. In arm 1, 17.1% achieved a pCR. Increased CD8+ density correlated with clinical outcomes in an exploratory analysis. Arm 1 adverse events were consistent with previous reports for T-VEC. The present study met its primary endpoint and estimated a 25% reduction in the risk of disease recurrence for neoadjuvant T-VEC plus surgery versus upfront surgery for patients with resectable stage IIIB-IVM1a melanoma.

Neurologically asymptomatic cerebral oligometastatic prostate carcinoma metastasis identified on [Ga]Ga-THP-PSMA PET/CT.

BACKGROUND: Brain metastases from prostate cancer are rare and usually only occur in the context of widespread systemic disease. This is the first case report of a solitary brain oligometastasis, in a neurologically intact prostate cancer patient with no other systemic disease, detected using [68Ga]Ga-THP-PSMA PET/CT and only the second one using a PSMA-based radiopharmaceutical. CASE PRESENTATION: We report the case of a prostate cancer patient presenting 5 years after robot-assisted laparoscopic prostatectomy with biochemical recurrence, no neurological symptoms, and in the absence of metastatic lesions in the body on conventional imaging. A solitary cerebral metastasis was detected using [68Ga]Ga-THP-PSMA PET/CT, surgically resected, leading to a drop in serum PSA and a good recovery. CONCLUSION: In this case, [68Ga]Ga-THP-PSMA PET/CT resulted in a major change in clinical management and avoided additional morbidity associated with delayed diagnosis and treatment. This report demonstrates the importance of considering the presence of metastatic disease outside the conventional locations of prostate cancer spread, as well as the importance of ensuring comprehensive [68Ga]Ga-PSMA PET/CT coverage from vertex to upper thighs.

Correction to: Neurologically asymptomatic cerebral oligometastatic prostate carcinoma metastasis identified on [Ga]Ga-THP-PSMA PET/CT.

An amendment to this paper has been published and can be accessed via the original article.

Phase II trial of imatinib mesylate in patients with metastatic melanoma.

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

Role of computed tomography in the staging of patients with local-regional metastases of melanoma.

PURPOSE: To determine the value of computed tomographic (CT) scans in the staging of asymptomatic melanoma patients who presented with or developed local-regional disease as the first site of recurrence and had both a normal chest radiograph and serum lactate dehydrogenase (LDH) level. PATIENTS AND METHODS: The records of 99 patients with local-regional disease were reviewed. Of these, 89 met the study criteria and are the subjects of this analysis. Radiologic findings were categorized into the following four groups: (1) true-positive (TP), when the scan identified either regional or distant disease that was not appreciated on physical examination; (2) false-positive (FP), when the scan showed a radiologic abnormality that either did not change for at least 6 months or was proven to be histologically benign; (3) false-negative (FN), when a patient had symptoms suggestive of or suspicious for metastases and was subsequently found to have metastases, but all imaging studies were nondiagnostic; and (4) true-negative (TN), when all imaging studies were negative for metastases in an asymptomatic patient. RESULTS: Findings on CT scan were TP for six patients (7%), FP for 20 (22%), and TN for 63 (71%). Of the six patients with TP findings, CT of the chest identified disease that was not visible on chest radiograph in only one and CT of the abdomen or pelvis showed metastases in five. CT or magnetic resonance imaging (MRI) of the brain showed no evidence of brain metastases in any patient, although it showed asymptomatic skull metastases in one patient. The most common FP findings were hypodense hepatic lesions and noncalcified lung nodules. CONCLUSION: TP findings are observed in approximately 7% of patients with local-regional disease, which indicates a low yield but definite usefulness of CT scans in this subset of patients. Because FP are more common than TP findings, histologic diagnosis of recurrence is advisable. CT scan or MRI of the brain is not necessary in asymptomatic patients. CT of the chest adds little to a chest radiograph. In light of today's more cost-conscious health-care environment, our results are of practical importance.

Prognostic value of size of lymph node metastases in patients with cutaneous melanoma.

PURPOSE: To determine the prognostic significance of the size of the lymph node mass as measured by physical examination (PE) and of the size of the largest node measured by pathologic analysis (path) in patients with cutaneous melanoma and nodal metastases. PATIENTS AND METHODS: The medical records of all patients with nodal metastases seen at The University of Texas M.D. Anderson Cancer Center from January 1, 1973 to December 31, 1989 were reviewed. Patient eligibility criteria included the following: (1) availability of data describing the nodal size either by PE or by path and the number of positive nodes; (2) no history of preoperative chemotherapy or radiotherapy; and (3) no history or presence of in-transit, satellite, local, or distant metastases. Eleven variables, including largest diameter of the nodal mass by PE and diameter of the largest node by path, were examined as potential prognostic factors for disease-free survival (DFS) and overall survival (OS). RESULTS: Of 800 patients evaluated, 442 met the eligibility criteria and are the subjects of this study. In the univariate analysis, size of the nodal mass by PE was marginally significant for survival as a continuous variable (P = .045), but not as a categorical variable using a cutoff size of < or = 3 or more than 3 cm as indicated by the American Joint Committee on Cancer (AJCC) staging system (P = .61). Size of the largest node by path was not significant for survival. In the multivariate analysis, only the number of positive nodes (P < .001), age (P < .001), and tumor thickness (P < .001) were significant for survival. CONCLUSION: Size of the nodal mass by PE and size of the largest node by path are not useful prognostic factors for survival and should be eliminated from the current staging system. More powerful and well-established prognostic factors, such as the number of positive nodes, should be considered for inclusion in staging.

Evaluation of tyrosinase mRNA as a tumor marker in the blood of melanoma patients.

PURPOSE: The value of tyrosinase messenger RNA (mRNA) detection in the peripheral blood by reverse-transcription polymerase chain reaction (RT-PCR) as a melanoma marker remains controversial. The purpose of this study was to compare the sensitivities of two different blood processing techniques for tyrosinase mRNA detection and evaluate its potential clinical value. METHODS: A total of 50 patients with progressive stage IV melanoma was studied. Two blood processing methods were used: RNA extraction from the whole blood and RNA extraction from density gradient-isolated peripheral-blood mononuclear cells (PBMC). The RNA samples were tested with a sensitive nested-primer RT-PCR assay. RT-PCR results were also correlated with serum lactate dehydrogenase (LDH), treatment status, and presence of visceral versus nonvisceral metastases. RESULTS: Thirteen (26%) of the density gradient and five (10%) of the whole blood processed samples were PCR positive (P = .011). Serum LDH levels were found to be significantly higher in PCR-positive PBMC-processed patients (P = .015). There was no significant difference in the detection rates between visceral versus nonvisceral metastases or between prior treatment versus no prior treatment. CONCLUSION: Using a density gradient method to process the blood samples resulted in a higher detection rate of tyrosinase mRNA than extracting the RNA from the whole blood. However, the relatively low sensitivity in patients with disseminated and progressive disease compared with other reports suggests that tyrosinase mRNA may be of limited value in the management of malignant melanoma.

Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma.

PURPOSE: To determine the patterns of recurrence and causes of regional nodal basin failure in stage I or II melanoma patients who had a histologically negative sentinel lymph node (SLN) and whose regional nodal basins were not dissected following lymphatic mapping and SLN biopsy. PATIENTS AND METHODS: The records of 344 patients with primary cutaneous melanoma who underwent lymphatic mapping and SLN biopsy between 1991 and 1995 at The University of Texas M.D. Anderson Cancer Center were reviewed. Of 322 patients who underwent successful lymphatic mapping procedures, 270 had histologically negative SLNs; mapped nodal basins were observed without further surgical intervention in 243 of these 270 patients. Recurrence patterns were analyzed from this cohort and a histologic reevaluation of all previously identified SLNs on which a biopsy had been taken was performed in patients who developed recurrent disease. RESULTS: Of 243 patients with a histologically negative SLN, 27 (11%) developed local, in-transit, regional nodal, and/or distant metastases after a median follow-up time of 35 months. Ten patients (4.1%) developed a nodal recurrence in the previously mapped basin, either solely or as a component of the first site of recurrence. Detailed analysis of the SLNs in these 10 patients demonstrated evidence of occult metastases in 80% by serial sectioning or immunohistochemical staining. CONCLUSION: Regional nodal failures in melanoma patients following a negative SLN biopsy are infrequent and to date have most commonly occurred because conventional histologic evaluation was unable to identify occult metastatic disease. These data provide further evidence that lymphatic mapping and SLN biopsy accurately reflect the status of the regional nodal basin. Specialized pathologic techniques are necessary to reduce further the already low false-negative rates and to improve disease staging.

Sentinel lymph node biopsy for melanoma: controversy despite widespread agreement.

Although sentinel lymph node (SLN) biopsy for melanoma has been adopted throughout the United States and abroad as a standard method of determining the pathologic status of the regional lymph nodes, some controversy still exists regarding the validity and utility of this procedure. SLN biopsy is a minimally invasive procedure, performed on an outpatient basis at the time of wide local excision of the melanoma, with little morbidity. Numerous studies have documented the accuracy of this procedure for identifying nodal metastases. There are four major reasons to perform SLN biopsy. First, SLN biopsy improves the accuracy of staging and provides valuable prognostic information for patients and physicians to guide subsequent treatment decisions. Second, SLN biopsy facilitates early therapeutic lymph node dissection for those patients with nodal metastases. Third, SLN biopsy identifies patients who are candidates for adjuvant therapy with interferon alfa-2b. Fourth, SLN biopsy identifies homogeneous patient populations for entry onto clinical trials of novel adjuvant therapy agents. Overall, the benefit of accurate nodal staging obtained by SLN biopsy far outweighs the risks and has important implications for patient management.

Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients.

PURPOSE: To compare the effect of pathologic sentinel lymph node (SLN) status with that of other known prognostic factors on recurrence and survival in patients with stage I or II cutaneous melanoma. PATIENTS AND METHODS: We reviewed the records of 612 patients with primary cutaneous melanoma who underwent lymphatic mapping and SLN biopsy between January 1991 and May 1995 to determine the effects of tumor thickness, ulceration, Clark level, location, sex, and SLN pathologic status on disease-free and disease-specific survival. RESULTS: In the 580 patients in whom lymphatic mapping and SLN biopsy were successful, the SLN was positive by conventional histology in 85 patients (15%) but negative in 495 patients (85%). SLN status was the most significant prognostic factor with respect to disease-free and disease-specific survival by univariate and multiple covariate analyses. Although tumor thickness and ulceration influenced survival in SLN-negative patients, they provided no additional prognostic information in SLN-positive patients. CONCLUSION: Lymphatic mapping and SLN biopsy is highly accurate in staging nodal basins at risk for regional metastases in primary melanoma patients and identifies those who may benefit from earlier lymphadenectomy. Furthermore, pathologic status of the SLN in these patients with clinically negative nodes is the most important prognostic factor for recurrence. The information from SLN biopsy is particularly helpful in establishing stratification criteria for future adjuvant trials.

Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system.

PURPOSE: To critically review the accuracy of the current American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma and propose a more useful staging system. METHODS: Retrospective evaluation of the published data as well as a reanalysis of the University of Alabama and Sydney Melanoma Unit (UAB/SMU) data bases (n = 4,568) for patients with primary melanoma was performed to examine specifically the impact of level of invasion and ulceration on the prognostic value of tumor thickness. In addition, an overlay graphic technique was used to compare the Kaplan-Meier survival curves of patients with local recurrences, satellites, in-transit metastases, and nodal metastases reported in the literature. RESULTS: Tumor thickness and ulceration remained the most powerful prognostic indicators in patients with stage I and II disease. Level of invasion provided statistically significant prognostic information only in the subgroup of patients with tumor thickness < or = 1 mm, but the absolute 10-year survival differences were small and inconsistent (level II, 95%; level III, 85%; level IV, 89%). The best statistical fit for tumor thickness cutoffs was at 1 versus 2 versus 4 mm. The overlay graphic technique showed that patients who developed satellite lesions or local recurrence had prognoses similar to those of patients with stage III disease. The most important prognostic factor for patients with nodal metastases was number of involved nodes rather than size. CONCLUSION: Our analysis showed that the current AJCC staging system has many inaccuracies that should be modified to conform to published data. On the basis of our analysis and review of the literature, we propose a new and more accurate staging system.

Sentinel lymph node biopsy is accurate after neoadjuvant chemotherapy for breast cancer.

PURPOSE: Sentinel lymph node (SLN) biopsy has proved to be an accurate method for detecting nodal micrometastases in previously untreated patients with early-stage breast cancer. We investigated the accuracy of this technique for patients with more advanced breast cancer after neoadjuvant chemotherapy. PATIENTS AND METHODS: Patients with stage II or III breast cancer who had undergone doxorubicin-based neoadjuvant chemotherapy before breast surgery were eligible. Intraoperative lymphatic mapping was performed with peritumoral injections of blue dye alone or in combination with technetium-labeled sulfur colloid. All patients were offered axillary lymph node dissection. Negative sentinel and axillary nodes were subjected to additional processing with serial step sectioning and immunohistochemical staining with an anticytokeratin antibody to detect micrometastases. RESULTS: Fifty-one patients underwent SLN biopsy after neoadjuvant chemotherapy from 1994 to 1999. The SLN identification rate improved from 64.7% to 94.1%. Twenty-two (51.2%) of the 43 successfully mapped patients had positive SLNs, and in 10 of those 22 patients (45.5%), the SLN was the only positive node. Three patients had false-negative SLN biopsy; that is, the sentinel node was negative, but at least one nonsentinel node contained metastases. Additional processing revealed occult micrometastases in four patients (three in sentinel nodes and one in a nonsentinel node). CONCLUSION: SLN biopsy is accurate after neoadjuvant chemotherapy. The SLN identification improved with experience. False-negative findings occurred at a low rate throughout the series. This technique is a potential way to guide the axillary treatment of patients who are clinically node negative after neoadjuvant chemotherapy.

Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy.

PURPOSE: To assess patient and tumor characteristics associated with a complete pathologic response (pCR) in both the breast and axillary lymph node specimens and the outcome of patients found to have a pCR after neoadjuvant chemotherapy for locally advanced breast cancer (LABC). PATIENTS AND METHODS: Three hundred seventy-two LABC patients received treatment in two prospective neoadjuvant trials using four cycles of doxorubicin-containing chemotherapy. Patients had a total mastectomy with axillary dissection or segmental mastectomy and axillary dissection followed by four or more cycles of additional chemotherapy. Patients then received irradiation treatment of the chest-wall or breast and regional lymphatics. Median follow-up was 58 months (range, 8 to 99 months). RESULTS: The initial nodal status, age, and stage distribution of patients with a pCR were not significantly different from those of patients with less than a pCR (P>.05). Patients with a pCR had initial tumors that were more likely to be estrogen receptor (ER)-negative (P<.01), and anaplastic (P = .01) but of smaller size (P<.01) than those of patients with less than a pCR. Upon multivariate analysis, the effects of ER status and nuclear grade were independent of initial tumor size. Sixteen percent of the patients in this study (n = 60) had a pathologic complete primary tumor response. Twelve percent of patients (n = 43) had no microscopic evidence of invasive cancer in their breast and axillary specimens. A pathologic complete primary tumor response was predictive of a complete axillary lymph node response (P<.01 ). The 5-year overall and disease-free survival rates were significantly higher in the group who had a pCR (89% and 87%, respectively) than in the group who had less than a pCR (64% and 58%, respectively; P<.01). CONCLUSION: Neoadjuvant chemotherapy has the capacity to completely clear the breast and axillary lymph nodes of invasive tumor before surgery. Patients with LABC who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival rate. However, a pCR does not entirely eliminate recurrence. Further efforts should focus on elucidating the molecular mechanisms associated with this response.

Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system.

PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION: The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.

Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma.

PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (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 staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. CONCLUSION: This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.

Active immunotherapy with ultraviolet B-irradiated autologous whole melanoma cells plus DETOX in patients with metastatic melanoma.

Our objective was to determine the clinical activity, toxicity, and immunological effects of active immunotherapy using UVB-irradiated (UVR) autologous tumor (AT) cells plus adjuvant DETOX in metastatic melanoma patients. Eligibility included nonanergic patients fully recovered after resection of 5 or more grams of metastatic melanoma. Treatment consisted of intradermal injections of 10(7) UVR-AT plus 0.25 ml of DETOX every 2 weeks x 6, then monthly. Peripheral blood mononuclear cells (PBMCs) were harvested for cytotoxicity assays, and skin testing was performed for delayed-type hypersensitivity (DTH) determinations before the first, fourth, seventh, and subsequent treatments. Forty-two patients were treated, 18 in the adjuvant setting and 24 with measurable disease. Among the latter group, there were two durable responses in soft-tissue sites and in a bone metastasis. Treatment was well tolerated. Thirty-five patients were assessable for immunological parameters; 10 of these patients, including the 2 responders, demonstrated early induction of PBMC cytotoxicity against AT cells that persisted up to 10 months on treatment before falling to background levels. In five of seven patients, the fall-off heralded progressive disease. Late induction of a weak DTH reaction to AT cells was observed in eight patients. Active immunotherapy with UVR-AT + DETOX had modest but definite clinical activity in advanced melanoma. The induction of both PBMC cytotoxicity and DTH reactivity to AT cells supported a specific systemic immune effect of treatment, although the former more closely followed disease course in this study.