Prognosis after neoadjuvant chemoradiation or chemotherapy for locally advanced gastro-oesophageal junctional adenocarcinoma.

BACKGROUND: Trials typically group cancers of the gastro-oesophageal junction (GOJ) with oesophageal or gastric cancer when studying neoadjuvant chemoradiation and perioperative chemotherapy, so the results may not be fully applicable to GOJ cancer. Because optimal neoadjuvant treatment for GOJ cancer remains controversial, outcomes with neoadjuvant chemoradiation versus chemotherapy for locally advanced GOJ adenocarcinoma were compared retrospectively. METHODS: Data were collected from all patients who underwent neoadjuvant treatment followed by surgery for adenocarcinoma located at the GOJ at a single high-volume institution between 2002 and 2017. Postoperative major complications and mortality were compared between groups using Fisher's exact test. Overall survival (OS) and disease-free survival (DFS) were assessed by log rank test and multivariable Cox regression analyses. Cumulative incidence functions were used to estimate recurrence, and groups were compared using Gray's test. RESULTS: Of 775 patients, 650 had neoadjuvant chemoradiation and 125 had chemotherapy. These groups were comparable in terms of clinical tumour and lymph node categories, although the chemoradiation group had greater proportions of white men, complete pathological response to chemotherapy, and smaller proportions of diffuse cancer, poor differentiation, and neurovascular invasion. Postoperative major complications (20.0 versus 17.6 per cent) and 30-day mortality (1.7 versus 1.6 per cent) were not significantly different between the chemoradiation and chemotherapy groups. After adjustment, type of therapy (chemoradiation versus chemotherapy) was not significantly associated with OS (hazard ratio (HR) 1.26, 95 per cent c.i. 0.96 to 1.67) or DFS (HR 1.27, 0.98 to 1.64). Type of recurrence (local, regional, or distant) did not differ after neoadjuvant chemoradiation versus chemotherapy. CONCLUSION: In patients undergoing surgical resection for locally advanced adenocarcinoma of the GOJ, OS and DFS did not differ significantly between patients who had neoadjuvant chemoradiation compared with chemotherapy.

Treating advanced cancer of the gastro-oesophageal junction (GOJ) poses a challenge given its location in the distal oesophagus and proximal stomach, and whether it should be treated as oesophageal or gastric cancer. Given the indistinct location, it is unclear whether GOJ cancer should be treated with neoadjuvant chemoradiation, which is the treatment of choice for advanced oesophageal cancers, or perioperative chemotherapy, which is the treatment of choice for advanced gastric cancers. Few studies have addressed treatment options specifically for GOJ cancers. This study investigated whether there was a difference in survival between patients with GOJ cancer who were treated with chemoradiation versus chemotherapy.

Nodal and systemic recurrence following observation of a positive sentinel lymph node in melanoma.

BACKGROUND: Two RCTs found no survival benefit for completion lymphadenectomy after positive sentinel lymph node biopsy compared with observation with ultrasound in patients with melanoma. Recurrence patterns and regional control are not well described for patients undergoing observation alone. METHODS: All patients with a positive sentinel node biopsy who did not have immediate completion lymphadenectomy were identified from a single-institution database (1995-2018). First recurrences were classified as node only, local and in-transit (LCIT) only, LCIT and nodal, or systemic. Regional control and factors associated with recurrence survival were analysed. RESULTS: Median follow-up was 33 months. Of 370 patients, 158 (42·7 per cent) had a recurrence. The sites of first recurrence were node only (13·2 per cent), LCIT only (11·9 per cent), LCIT and nodal (3·5 per cent), and systemic (13·8 per cent). The 3-year postrecurrence melanoma-specific survival rate was 73 (95 per cent c.i. 54 to 86) per cent for patients with node-only first recurrence, and 51 (31 to 68) per cent for those with initial systemic recurrence. In multivariable analysis, ulceration in the primary lesion (hazard ratio (HR) 2·53, 95 per cent c.i. 1·27 to 5·04), disease-free interval 12 months or less (HR 2·38, 1·28 to 4·35), and systemic (HR 2·57, 1·16 to 5·65) or LCIT and nodal (HR 2·94, 1·11 to 7·79) first recurrence were associated significantly with decreased postrecurrence survival. Maintenance of regional control required therapeutic lymphadenectomy in 13·0 per cent of patients during follow-up. CONCLUSION: Observation after a positive sentinel lymph node biopsy is associated with good regional control, permits assessment of the time to and pattern of recurrence, and spares lymphadenectomy-related morbidity in patients with melanoma.

Association of positive transection margins with gastric cancer survival and local recurrence.

PURPOSE: To examine the association between positive resection margins and survival and local recurrence in patients with gastric cancer undergoing resection with curative intent. METHODS: Patients who underwent curative intent resection for gastric carcinoma from 1985 to 2010 were identified from a prospectively maintained database. Positive margins were defined as disease present at the line of luminal transection. Clinicopathological features and outcome of patients undergoing gastrectomy with negative and positive margins were compared. RESULTS: Among 2384 patients undergoing curative intent resection, 108 (4.5 %) had positive margins. Positive margins were associated with higher American Joint Committee on Cancer (AJCC) stage, T stage, N stage, median number of positive nodes, diffuse Lauren type, and poorly differentiated tumors. Treatment of positive margins consisted of: observation (39 %), chemoradiotherapy (26 %), chemotherapy (20 %), repeat resection (10 %), radiotherapy (4 %), and unknown (1 %). Multivariate analysis of the entire cohort demonstrated margin status, T stage, N stage, grade, and perineural invasion to be independent predictors of survival. Margin status was an independent predictor of survival in patients with ≤3 positive nodes or T1-2 disease but was not in patients with >3 positive nodes or T3-4 disease. Local recurrence occurred in 16 % of patients with a positive margin. We identified no factors predictive of local recurrence in patients with positive margins. CONCLUSIONS: Positive resection margin is associated with advanced AJCC stage and aggressive tumor biology but remains an independent predictor of worse survival. The significance of a positive margin in gastric cancer is confined to patients with nontransmural disease and/or limited nodal involvement.

Indications for and efficacy of splenectomy for haematological disorders.

BACKGROUND: Splenectomy is performed for a variety of indications in haematological disorders. This study was undertaken to analyse outcomes, and morbidity and mortality rates associated with this procedure. METHODS: Patients undergoing splenectomy for the treatment or diagnosis of haematological disease were included. Indications for operation, preoperative risk, intraoperative variables and short-term outcomes were evaluated. RESULTS: From January 1997 to December 2010, 381 patients underwent splenectomy for diagnosis or treatment of haematological disease. Some 288 operations were performed by an open approach, 83 laparoscopically, and there were ten conversions. Overall 136 patients (35·7 per cent) experienced complications. Postoperative morbidity was predicted by age more than 65 years (odds ratio (OR) 1·63, 95 per cent confidence interval 1·05 to 2·55), a Karnofsky performance status (KPS) score lower than 60 (OR 2·74, 1·35 to 5·57) and a haemoglobin level of 9 g/dl or less (OR 1·74, 1·09 to 2·77). Twenty-four patients (6·3 per cent) died within 30 days of surgery. Postoperative mortality was predicted by a KPS score lower than 60 (OR 16·20, 6·10 to 42·92) and a platelet count of 50,000/µl or less (OR 3·34, 1·25 to 8·86). The objective of the operation was achieved in 309 patients (81·1 per cent). The success rate varied for each indication: diagnosis (106 of 110 patients, 96·4 per cent), thrombocytopenia (76 of 115, 66·1 per cent), anaemia (10 of 16, 63 per cent), to allow further treatment (46 of 59, 78 per cent) and primary treatment (16 of 18, 89 per cent). CONCLUSION: Splenectomy is an effective procedure in the diagnosis and treatment of haematological disease in selected patients.

Tobacco use is associated with increased recurrence and death from gastric cancer.

BACKGROUND: Tobacco use increases the risk of developing gastric cancer. We examined the hypothesis that gastric cancer developing in patients with a history of tobacco use may be associated with increased risk of cancer-specific death after curative surgical resection. METHODS: From the Memorial Sloan-Kettering Cancer Center Gastric Cancer prospective surgical database, we collected baseline demographic data and tumor characteristics from all patients who had undergone curative resection for gastric cancer between 1995 and 2009 and who had not received pre- or postoperative chemo- or radiotherapy. A smoking history was defined as >100 cigarettes' lifetime use. The primary end point was gastric cancer disease-specific survival (DSS); secondary end points were 5-year disease-free survival (DFS) and overall survival (OS). Gastric cancer-specific hazard was modeled by Cox regression. RESULTS: A total of 699 eligible patients were identified with a median age of 70 years (range 25-96 years); 410 (59%) were current or previous smokers. Smoking was associated with gastroesophageal junction/cardia tumors and white non-Hispanic ethnicity. Multivariate analysis included the following variables: tumor stage, age, performance status, diabetes mellitus, gender, and tumor location. In this analysis, the hazard ratio for gastric cancer DSS in smokers was 1.43 (95% confidence interval 1.08-1.91, P=0.01). Smoking was also an independent significant risk factor for worse 5-year DFS (hazard ratio 1.46, P=0.007) and OS (hazard ratio 1.48, P=0.003). Among 516 patients for whom tobacco pack-year usage was available, both heavy (≥20 pack-years) and light (<20 pack-years) tobacco use was significantly associated with DSS, DFS, and OS. CONCLUSIONS: Smoking history appears to be an independent risk factor for death from gastric cancer in patients who have undergone curative surgical resection.

The role of sentinel lymph node biopsy in the management of head and neck desmoplastic melanoma.

BACKGROUND: Desmoplastic melanoma (DM), a variant of spindle cell melanoma, has a higher propensity for local recurrence and a lower incidence of nodal metastasis. In this retrospective review, we evaluated the risk for regional nodal metastases and the need for sentinel lymph node biopsy (SLNB) in patients with head and neck DM. METHODS: We identified 103 patients with DM from an institutional database of patients with head and neck melanomas treated between 1985 and 2009. Forty-seven patients had their primary treatment at Memorial Sloan-Kettering Cancer Center, and 56 patients were treated for recurrent or metastatic disease. RESULTS: Of the 47 study patients, 27 were men and 20 were women with a median age of 71 years. All patients underwent wide excision, and 21 (44 %) underwent SLNB. None of the patients who underwent SLNB had positive nodes. The mean Breslow thickness for the 45 reported patients was 6.1 mm, with 84 % of tumors >2 mm in thickness and 55 % >4 mm. All known Clark thickness levels (n = 40) were IV or V. The overall survival was 73 %, with disease-specific survival of 84 %, local recurrence-free survival of 75 %, and neck recurrence-free survival of 97 % at 5 years. CONCLUSIONS: Although DM is diagnosed at higher Breslow thickness and Clark level, neck metastases are rare and prognosis is favorable compared to conventional melanoma. The low incidence of lymphovascular invasion, high frequency of histopathologically negative sentinel lymph nodes, and low neck recurrence rates indicate that staging of neck disease by SLNB is not necessary in patients with pure DM of the head and neck.

Recurrence and survival after pathologic complete response to preoperative therapy followed by surgery for gastric or gastrooesophageal adenocarcinoma.

BACKGROUND: To characterise recurrence patterns and survival following pathologic complete response (pCR) in patients who received preoperative therapy for localised gastric or gastrooesophageal junction (GEJ) adenocarcinoma. METHODS: A retrospective review of a prospective database identified patients with pCR after preoperative chemotherapy for gastric or preoperative chemoradiation for GEJ (Siewert II/III) adenocarcinoma. Recurrence patterns, overall survival, recurrence-free survival, and disease-specific survival were analysed. RESULTS: From 1985 to 2009, 714 patients received preoperative therapy for localised gastric/GEJ adenocarcinoma, and 609 (85%) underwent a subsequent R0 resection. There were 60 patients (8.4%) with a pCR. Median follow-up was 46 months. Recurrence at 5 years was significantly lower for pCR vs non-pCR patients (27% and 51%, respectively, P=0.01). The probability of recurrence for patients with pCR was similar to non-pCR patients with pathologic stage I or II disease. Although the overall pattern of local/regional (LR) vs distant recurrence was comparable (43% LR vs 57% distant) between pCR and non-pCR groups, there was a significantly higher incidence of central nervous system (CNS) first recurrences in pCR patients (36 vs 4%, P=0.01). CONCLUSION: Patients with gastric or GEJ adenocarcinoma who achieve a pCR following preoperative therapy still have a significant risk of recurrence and cancer-specific death following resection. One third of the recurrences in the pCR group were symptomatic CNS recurrences. Increased awareness of the risk of CNS metastases and selective brain imaging in patients who achieve a pCR following preoperative therapy for gastric/GEJ adenocarcinoma is warranted.

Cloning and characterization of a cDNA for murine macrophage inflammatory protein (MIP), a novel monokine with inflammatory and chemokinetic properties.

In the course of studies on cachectin/TNF being conducted in our laboratory, a novel macrophage product has been detected and characterized. Termed macrophage inflammatory protein or MIP, this protein appears to be an endogenous mediator of the inflammatory events induced by endotoxin. A cDNA cloned probe for this protein has been isolated from a lambda gt10 phage library prepared from poly(A)+ RNA obtained of endotoxin-induced RAW264.7 cells. The sequence codes for a 92 amino acid-long polypeptide, of which 69 amino acids correspond to the mature product. The sequence predicts a molecular weight of 7,889 and structural analysis of the protein indicates a characteristic signal sequence alpha-helix and a hydrophobic core. Sequence data also confirm no sequence similarity to any other protein listed in the Dayhoff data base.

Resolution of the two components of macrophage inflammatory protein 1, and cloning and characterization of one of those components, macrophage inflammatory protein 1 beta.

A number of macrophage-derived mediators have been implicated in the vascular changes of inflammation. We recently reported the isolation of a novel monokine, macrophage inflammatory protein 1 (MIP-1), which causes local inflammatory responses in vivo, and induces superoxide production by neutrophils in vitro. Purified native MIP-1 comprises two peptides with very similar physical characteristics. We report here the resolution of MIP-1 into component peptides by SDS-hydroxylapatite chromatography, and compare the NH2-terminal sequences of the two peptides, now referred to as MIP-1 alpha and MIP-1 beta. A synthetic oligonucleotide probe pool corresponding to the NH2-terminal amino acid sequence of MIP-1 beta was used to isolate a cDNA clone containing its coding sequence. The sequence codes for a 109 amino acid-long polypeptide, of which 69 amino acids correspond to the mature product. Comparison of this MIP-1 beta cDNA with our previously cloned MIP-1 alpha sequence reveals that the MIP-1 peptides, members of a growing family of potential inflammatory mediators, are distinct but highly homologous (58.9% sequence identity) products of different genes.

Phase II trial of neoadjuvant temozolomide in resectable melanoma patients.

BACKGROUND: We treated melanoma patients with temozolomide (TMZ) in the neoadjuvant setting and collected cryopreserved tumor samples before and after treatment. The primary objective was to determine whether the response proportion was higher than previously reported in widely metastatic patients. A secondary objective was to test the feasibility of obtaining adequate tissue before and after treatment for genetic testing. MATERIALS AND METHODS: Chemotherapy-naive melanoma patients who were candidates for surgical resection were eligible. TMZ was administered orally at 75 mg/m(2)/day for 6 weeks of every 8-week cycle. Cycles were repeated until complete response (CR), progression, or stable disease (SD) for two cycles. RESULTS: Of 19 assessable patients, 2 had CRs and 1 had partial response. Four patients had SD; 12 progressed. Tumor O-6-methylguanine-DNA methyltransferase (MGMT) promoter was unmethylated in all nine patients analyzed including from the two CR patients. Pretreatment tumor microarray results were obtained in 16 of 19 patients. CONCLUSIONS: The response proportion to TMZ in the neoadjuvant setting was 16%, not different than in the metastatic setting. Responses were seen even in tumors with a methylated MGMT promoter. Pretreatment cryopreserved tumor adequate for microarray analysis could be obtained in most, but not all, patients. Post-treatment tumor was unavailable in complete responders.

The prognostic impact of isolated tumor cells in lymph nodes of T2N0 gastric cancer: comparison of American and Japanese gastric cancer patients.

BACKGROUND: The clinical significance of immunohistochemically detected isolated tumor cells (ITC) in lymph nodes of gastric cancer patients is controversial. This study examined the prognostic impact of ITC on patients with early-stage gastric cancer in two large volume centers in the United States and Japan. METHODS: Fifty-seven patients with T2N0M0 gastric carcinoma who underwent gastric resection between January 1987 and January 1997 at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York and 107 patients resected at National Cancer Center Hospital (NCCH) in Tokyo between January 1984 and December 1990 were studied. The sections were newly prepared from each lymph node for immunohistochemical staining for cytokeratin. Lymph nodes and original specimens from MSKCC were examined by pathologists in NCCH. The prognostic significance of the presence of ITC in lymph nodes was investigated in patients of both institutions. RESULTS: ITC were identified in 30 of 57 patients (52.6%) at MSKCC and in 38 of 107 patients (35.5%) at NCCH. In both institutions, there was no significant difference in the prognosis of the studied patients with or without ITC (P= .22, .86 respectively). CONCLUSIONS: The presence of ITC detected by immunohistochemistry in the regional lymph nodes did not affect the prognosis of American and Japanese patients with T2N0M0 gastric carcinoma who underwent gastrectomy with D2 lymph node dissection.

Initial experience with hand-assisted laparoscopic distal pancreatectomy.

BACKGROUND: Hand-assisted laparoscopic distal pancreatectomy, with or without splenectomy, is gradually gaining acceptance, although its ultimate benefit is yet to be confirmed. This study aimed to report our initial experience with hand-assisted laparoscopic distal pancreatectomy. METHODS: A retrospective review of a prospectively collected database including 17 patients during the period 2002-2004 was conducted. The median age was 60 years (range, 29-85 years), and the female-to-male ratio was 13:4. The preoperative diagnoses included benign and malignant conditions. Besides two to three ports, a hand port was placed in the upper midline to aid in dissection. The pancreas was divided with a stapler in all the patients, and drains were placed in 10 patients (70%). RESULTS: One patient was found to be unresectable because of celiac artery involvement, and 2 of the remaining 16 patients underwent conversion to an open procedure. The median operating time was 196 min (range, 128-235 min). The mean tumor size was 4 cm (range, 2-7 cm), and the estimated blood loss was 125 ml (range, 50-1,250 ml). The median time to resumption of a regular diet was 3.5 days (range, 2-9 days), and the time to conversion to oral pain medications was 3 days (range, 2-9 days). The length of hospital stay was 5.5 days (range, 4-18 days), with a majority of the patients (11 patients, 78%) staying less than 7 days. There were no mortalities. The overall postoperative morbidity rate was 25%, and the morbidities consisted of pancreatic leak/fistula (2 patients, 14%) and fever (1 patient). The margins were negative in 10 (76%) of the relevant 13 patients. At a median follow-up period of 3.8 months (range, 5-14 months), 11 (84%) of 13 patients had no evidence of disease recurrence. CONCLUSIONS: The minimally invasive approach to pancreatic disease is safe and technically feasible. Further large studies with longer follow-up periods are necessary to determine the role of laparoscopic surgery in the management of pancreatic disease.

Phase I evaluation of a combination of monoclonal antibody R24 and interleukin 2 in patients with metastatic melanoma.

A combination of recombinant human interleukin 2 (rhIL-2) and mouse monoclonal antibody R24 (recognizing the ganglioside GD3) was evaluated in patients with metastatic melanoma in a phase I trial. rhIL-2 was given at a constant daily dose of 1 x 10(6) units/m2 i.v. over 6 h on days 1-5 and 8-12. R24 was given on days 8-12 at four dose levels (1, 3, 8, and 12 mg/m2 daily). Twenty patients were evaluable for toxicity and response, five at each dose level. The toxicity of the combination was not overlapping and generally mild. There was a rebound peripheral blood T-lymphocytosis at the end of treatment increasing with the dose of R24. The median lymphocyte count on day 12 of treatment was 3108 +/- 554/ml in patients treated at R24 doses of 8 and 12 mg/m2 versus 2239 +/- 672/ml at doses of 1 and 3 mg/m2. This evidence and other data suggested that R24 enhanced IL-2-mediated T-cell activation in vivo. Two patients demonstrated increases in R24-mediated antibody-dependent cellular cytotoxicity for GD3-expressing cells during treatment. rhIL-2 appeared to accelerate the development of human anti-mouse antibody; three patients developed human anti-mouse antibody by the fifth day of R24 treatment, earlier than observed in prior studies using R24 alone and one patient during the first week of rhIL-2 alone, prior to R24 treatment. One patient had a partial response in soft tissue sites lasting 6 months and two patients had minor responses. This clinical trial extends the previous observation that R24 enhances lymphocyte proliferation in vitro.

A phase I toxicity, pharmacology, and dosimetry trial of monoclonal antibody OKB7 in patients with non-Hodgkin's lymphoma: effects of tumor burden and antigen expression.

Eighteen patients with relapsed non-Hodgkin's lymphoma (NHL) were infused with escalating doses of monoclonal antibody (mAb) OKB7, trace-labeled with iodine-131 (131I), in order to study toxicity, pharmacology, antibody localization, and dosimetry of radioiodine. OKB7 is a noncytotoxic mouse immunoglobulin G2b (IgG2b) mAb reactive with B cells and most B-cell NHL. Three patients each were treated at six dose levels ranging from 0.1 mg to 40 mg. All patients had radionuclide imaging and counting daily, had serial blood sampling to study pharmacokinetics, human antimouse antibody (HAMA), and circulating antigen, and had a biopsy of accessible lymphoma to determine delivery of isotope to tumors and assess the effect of tumor antigen expression on mAb delivery. Bone marrow biopsies were also done in the majority of patients. There was no toxicity. Serum clearance showed a median early phase half-life of 1.9 hours and a later phase half-life of 21.7 hours. Median total body clearance half-life was 22 hours. Pharmacokinetics were not dose-related. HAMA was detected in five patients. Circulating blocking antigen was detected in the serum of four patients, but at levels that were of pharmacologic consequence only in one. Biopsied tumor tissue from five patients did not express OKB7 antigen. No significant uptake of antibody was seen in these tumor sites. Mean total uptake of isotope into lymphoma measured in biopsies correlated linearly over the 400-fold increase in injected mAb dose. However, the percent of injected dose found per gram of tumor was unrelated to dose, but correlated inversely with tumor burden. In two patients with minimal tumor burden, 1.0 mg and 5.0 mg doses of OKB7 resulted in tumor to body radioisotope dose ratios of 22 and 7, which would theoretically permit tolerable delivery of 4,400 and 1,400 rads to these tumors, respectively, if OKB7 were conjugated with higher doses of 131I.

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.

Liver resection for colorectal metastases.

PURPOSE: More than 50,000 patients in the United States will present each year with liver metastases from colorectal cancers. The current study was performed to determine if liver resection for colorectal metastases is safe and effective and to evaluate predictors of outcome. MATERIALS AND METHODS: Data for 456 consecutive resections performed between July 1985 and December 1991 in a tertiary referral center were analyzed. RESULTS: The perioperative mortality rate was 2.8%, with a mortality rate of 4.6% for resections that involved a lobectomy or more. The median hospital stay was 12 days and only 9% of patients were admitted to the intensive care unit. The 5-year survival rate is 38%, with a median survival duration of 46 months. By univariate analysis, nodal status of the primary lesion, short disease-free interval before detection of liver metastases, carcinoembryonic antigen (CEA) level greater than 200 ng/mL, multiple liver tumors, extrahepatic disease, large tumors, or positive resection margin was predictive of poorer outcome. Sex, age greater than 70 years, site of primary tumor, or perioperative transfusion was not predictive of outcome. By multivariate analysis, positive margin, size greater than 10 cm, disease-free interval less than 12 months, multiple tumors, and extrahepatic disease were independent predictors of poorer outcome. Short disease-free interval or multiple tumors were nevertheless associated with a 5-year survival rate greater than 24%. CONCLUSION: Liver resection for colorectal metastases is safe and effective therapy and currently represents the only potentially curative therapy for metastatic colorectal cancer. The only absolute contraindication to resection is extrahepatic disease. A randomized trial to examine efficacy of surgical resection cannot ethically be performed. Liver resection should be considered standard therapy for all fit patients with colorectal metastases isolated to the liver.

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.

Association between molecular detection of GAGE and survival in patients with malignant melanoma: a retrospective cohort study.

We used GAGE as a molecular marker to identify melanoma cells with metastatic potential in the peripheral blood and the bone marrow. One hundred thirty-three patients with malignant melanoma (21 clinical stage II, 74 stage III, and 38 stage IV) had a single marrow and/or blood sample drawn immediately prior to surgical resection. Simultaneous bone marrow and blood samples (85 patients), marrow-only samples (35 patients), and blood-only samples (13 patients) were examined for the presence of GAGE expression using reverse transcription-PCR. GAGE expression was associated with adverse overall patient survival, measured from the time of sampling (P = 0.01). When data were stratified for clinical stage, median survival was statistically longer among GAGE-negative patients in the stage III cohort only (P = 0.01). In a multivariate model, only GAGE positivity in blood and/or marrow and clinical stage were significant prognostic variables. It was the detection of GAGE in blood but not marrow that was associated with poor survival. The detection of blood GAGE by reverse transcription-PCR has significant adverse implications for overall survival of patients with malignant melanoma in this cohort, and it warrants further investigation.

Prognostic significance of peripheral blood and bone marrow tyrosinase messenger RNA in malignant melanoma.

The objectives of this study were to evaluate the prognostic significance of reverse transcription PCR (RT-PCR) detection of tyrosinase mRNA in the peripheral blood (PB) and bone marrow (BM) of patients with stage II-IV malignant melanoma (MM). Seventy-three PB samples and 109 BM aspirates from 123 assessable patients with stage II-IV MM were analyzed for tyrosinase mRNA using nested RT-PCR. Twenty-five controls without MM were also evaluated. The RT-PCR results were correlated with overall survival (OS) and clinical stage. Overall, 23 of the 123 patients with MM (19%) had tyrosinase mRNA in their blood and/or BM. RT-PCR positivity was present in the PB of 9 of 73 patients (12%), whereas 18 of 109 (16.5%) had tyrosinase mRNA in their BM. All controls were tyrosinase PCR negative. There was no correlation between RT-PCR results and clinical stage. Within stage II, BM PCR-positive patients had a shorter median survival (24 months) than BM PCR-negative individuals (median not reached), with a P approaching significance (P = 0.06). There was a statistically significant correlation between blood PCR positivity and decreased overall survival (P = 0.03) in all patients. Blood PCR positivity was associated with a significantly decreased OS in stage II and III (P = 0.01 and 0.02, respectively) and was not a predictor of OS in stage IV. In multivariate analysis, blood RT-PCR for tyrosinase mRNA was found to be an independent predictor of survival (P = 0.03; risk ratio, 2.87). RT-PCR can specifically detect tyrosinase mRNA in the PB and BM of patients with MM. Blood RT-PCR is an independent predictor of overall survival in stage II-III MM. Additional studies are needed to define the potential role of this assay in the management of patients with advanced melanoma.