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BACKGROUND Uveal melanoma exhibits a high incidence of metastases; and, to date, there is no systemic therapy that clearly improves outcomes. The anticytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard of care for metastatic melanoma; however, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined. METHODS To assess ipilimumab in this setting, the authors performed a multicenter, retrospective analysis of 4 hospitals in the United States and Europe. Clinical characteristics, toxicities, and radiographic disease burden, as determined by central, blinded radiology review, were evaluated. RESULTS Thirty-nine patients with uveal melanoma were identified, including 34 patients who received 3 mg/kg ipilimumab and 5 who received 10 mg/kg ipilimumab. Immune-related response criteria and modified World Health Organization criteria were used to assess the response rate (RR) and the combined response plus stable disease (SD) rate after 12 weeks, after 23 weeks, and overall (median follow-up, 50.4 weeks [12.6 months]). At week 12, the RR was 2.6%, and the response plus SD rate was 46.%; at week 23, the RR was 2.6%, and the response plus SD rate was 28.2%. There was 1 complete response and 1 late partial response (at 100 weeks after initial SD) for an immune-related RR of 5.1%. Immune-related adverse events were observed in 28 patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related adverse events were more frequent in patients who received 10 mg/kg ipilimumab than in those who received 3 mg/kg ipilimumab. The median overall survival from the first dose of ipilimumab was 9.6 months (95% confidence interval, 6.3-13.4 months; range, 1.6-41.6 months). Performance status, lactate dehydrogenase level, and an absolute lymphocyte count ≥1000 cells/μL at week 7 were associated significantly with survival. CONCLUSIONS In this multicenter, retrospective analysis of 4 hospitals in the United States and Europe of patients with uveal melanoma, durable responses to ipilimumab and manageable toxicity were observed. Cancer 2013;119:3687–3695. © 2013 American Cancer Society.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) have activity in solid tumors. The authors evaluated an oral EGFR TKI, erlotinib, in patients with previously treated esophageal cancer. METHODS: Thirty patients with measurable, metastatic cancer of the esophageal and gastroesophageal junction received 150 mg erlotinib daily. EGFR-negative tumors (6 patients; 20%) and EGFR-over expressing tumors (24 patients; 80%) were treated. Most patients were men (70%) with adenocarcinoma (57%) and had received previous chemotherapy (97%). RESULTS: Two partial responses were observe d in the EGFR-positive cohort (2 of 24 patients; 8%), and no responses were observed in the EGFR-negative cohort (0 of 6 patients). Reponses were limited to patients who had squamous cell carcinoma (2 of 13 patients; 15%; response duration, 5.5-7 months). The time to tumor progression was longer in patients who had squamous cell carcinoma (3.3 months; range, 1-24 months) compared with patients who had adenocarcinoma (1.6 months; range, 1-6 months; P = .026). Therapy was tolerable with the expected toxicity of skin rash (grade 1-2, 67%; grade 3, 10%). CONCLUSIONS: Erlotinib had limited activity in patients with esophageal cancer, and responses and some protracted stable disease were observed in those with squamous cell carcinoma. Efficacy according to EGFR status could not be assessed given the rarity of EGFR-negative tumors. The current results indicated that further evaluation of this agent in squamous cell carcinoma is warranted. Cancer 2011. © 2010 American Cancer Society.

Melanoma is 1 of several cancers whose incidence has increased in the past several decades.1 In the metastatic setting, therapy is toxic and relatively ineffective.2–4 Most trials have reported objective responses in

BACKGROUND Advanced hepatocellular carcinoma has a poor prognosis. In a Phase II clinical trial, two academic centers assessed irinotecan, a topoisomerase-1 inhibitor with broad spectrum clinical activity, in patients who had advanced hepatocellular cancer. METHODS Patients who had had up to one prior chemotherapy regimen were eligible. Bidimensionally measurable disease, a good performance status, and adequate major organ function were required. At a starting dose of 125 mg/m2, irinotecan was administered weekly for 4 weeks followed by a 2 week break, which constituted 1 treatment cycle. Patients were restaged radiologically after two cycles of therapy. Dose attenuations were made as indicated for toxicity. RESULTS Fourteen patients were enrolled over a 10-week period in 1997. There were ten males and four females. The median age was 58 years (range, 38–74 yrs). The Eastern Cooperative Oncology Group median performance status was 1 (range, 0–1). Two patients had prior chemotherapy (14%), and 1 patient (7%) had had radiation. A total of 30 cycles of therapy were delivered (median, 1; range, 1–6). Considerable toxicity was observed, mostly neutropenia, diarrhea, nausea, vomiting, and fatigue. All patients required at least one dose attenuation for toxicity. One partial response (7%; confidence interval, 0–20%) was noted to last 7 months. One patient had transient stable disease, and all others (86%) had progression of disease as their best response. CONCLUSIONS Irinotecan had modest activity in advanced hepatocellular cancer. Toxicity was substantial, presumably reflecting impaired underlying liver function or poor ability to metabolize and eliminate the drug. The current study indicated that continued new therapy assessment is warranted for this disease. Cancer 2001;91:101–5. © 2001 American Cancer Society.

BACKGROUND Angiosarcomas are rare tumors. Based on a complete response observed in a patient with angiosarcoma of the scalp treated with paclitaxel in a Phase II trial, the authors treated a cohort of patients with angiosarcoma of the scalp or face with paclitaxel as single agent. METHODS The authors identified nine patients with angiosarcoma of the scalp or face treated at Memorial Sloan-Kettering Cancer Center with paclitaxel between January 1992 and December 1998. Various paclitaxel schedules were used over 1, 3, and 24 hours. RESULTS Of the 9 patients, 8 had major responses (4 partial responses and 4 clinical complete responses) and 1 had a minor response, for a major response rate of 89%. The median duration of response was 5 months (range, 2–13 months). Neutropenia and peripheral neuropathy were the most frequent dose-limiting toxicities. No deaths were attributed to therapy. CONCLUSIONS Paclitaxel as a single agent has substantial activity against angiosarcoma of the scalp or face, even in patients previously treated with chemotherapy or radiation therapy. Further investigation is warranted to define the optimal treatment dose and schedule. Cancer 1999;86:2034–7. © 1999 American Cancer Society.

Serum enzymes have not proved useful in evaluation of patients with early colon cancer, but certain enzymes such as transpeptidase, phosphohexone isosomerase, or 5'-nucleotidase have been of assistance in following the course of the disease, particularly in patients with metastatic spread to the liver. Attempts have been made to improve the utility of enzyme analysis in colon cancer by examination of enzyme patterns in colon biopsy specimens, feces, and colon washings. These studies, which will be summarized, are of importance in the possible development of diagnostic tools and as probes in the understanding of the etiology of colon cancer. The technical problems in carrying out these assays in humans, as well as the significance of the activity of aryl sulfatase, beta-glucuronidase, beta-glucosidase, lactic dehydrogenase, glucose-6-p-osphate dehydrogenase, and other enzymes will be considered.

BACKGROUND Dose intensification of 5-fluorouracil (5-FU) is complicated by increased toxicity. 5-FU is a fluorine-substituted pyrimidine analog of uracil. In preclinical studies, administration of oral uridine (Ur) has been shown to allow for dose intensification of 5-FU with enhancement of its antitumor activity. Therefore, a Phase I trial was designed aimed at dose intensification of 5-FU as a component of a modified 5-FU-doxorubicin-methotrexate (FAMTX) regimen using oral Ur rescue. METHODS Methotrexate (MTX) was administered to all patients at a fixed dose of 1.5 g/m2. MTX was followed 24 hours later by escalating doses of 5-FU starting at 800 mg/m2 with leucovorin rescue. Cycles of 5-FU and MTX were repeated every 15 days. Every other cycle, patients received doxorubicin (“Adria cycles”) at a dose of 30 mg/m2. Oral Ur was administered at a dose of 8 gm/m2 every 6 hours for 12 doses. In the first phase of the study, patients received Ur only if they developed Grade 3 or 4 hematologic toxicity. In the second phase, all patients received Ur 24 hours after 5-FU on all cycles. RESULTS Without Ur rescue, the maximum tolerated dose (MTD) of 5-FU was 900 mg/m2 on the Adria cycles and 1.1 gm/m2 on the non-Adria cycles. With Ur, the MTD of 5-FU increased to 1.2 gm/m2 on the Adria cycles and to 1.6 gm/m2 on the non-Adria cycles. CONCLUSIONS In this modified FAMTX regimen, oral Ur administration allowed for dose-intensification of 5-FU, with a 33% increase in the MTD of 5-FU on the Adria cycles and a 45% increase in the MTD of 5-FU dose on the non-Adria cycles. Cancer 1997=6;78:1988-95.

BACKGROUND 5-Fluorouracil (5-FU) has shown modest single-agent activity in patients with carcinoid or islet cell tumors. Alpha interferon (alpha-IFN) has also shown modest single agent activity in these diseases, although biologic responses have been far more prevalent than have objective tumor regressions. The combination of alpha-IFN and 5-FU has demonstrated enhanced activity in several gastrointestinal malignancies. METHODS Twenty-one patients with advanced neuro-endocrine tumors (14 with carcinoid tumors, 7 with islet cell carcinomas) were treated with alpha-IFN and 5-FU in a Phase II study. 5-Fluorouracil was administered by intravenous bolus injection at an initial dose of 400 mg/m2/day for 5 consecutive days. After a 1-week break, 5-FU then was administered weekly by intravenous bolus at a dose of 750 mg/m2. Alpha interferon administration was begun on Day 1 of 5-FU at a daily dose of 3 x 10(6) U subcutaneously and continued for the duration of the trial. RESULTS Of the 14 carcinoid patients with carcinoid tumors, 1 experienced a partial response (7%; 95% confidence interval [CI] 0-20%) that lasted for 6 months. Eight of the patients with carcinoid tumors achieved stable disease for a median of 6 months (range, 2-10 months). One of the patients with islet cell tumors (14%; 95% CI 0-39%) achieved a partial response that persisted after 8 months; 4 patients with islet cell tumors had stable disease for a median of 13 months (range, 4-27+ months). Even at this relatively low dose of alpha-IFN, 14 of 21 patients required a dose reduction in the alpha-IFN (13 for fatigue, 1 for ataxia). Three patients experienced myelosuppression of greater than Grade 3, and three patients had diarrhea of greater than Grade 3. One patient experienced dose-limiting hand-foot syndrome. CONCLUSIONS These results suggest that the combination of 5-FU and alpha-IFN does not have any clear superiority over the individual agents alone; 5-FU appears to reduce patient tolerance of alpha-IFN when given on a daily schedule. Further investigations are needed to identify active agents in the treatment of neuroendocrine malignancies.

BACKGROUND: Adenocarcinoma of the proximal stomach is now the most rapidly rising cancer among men in the United States. The development of metastases is the major cause of morbidity and mortality for this aggressive disease. The mechanisms by which tumor cells invade the basement membrane are unknown for this disease. We have identified and established 5 invasive and noninvasive adenocarcinoma cell lines arising from the proximal stomach, which can be used to examine the mechanisms involved in tumor cell invasion. METHODS: The expression of factors associated with tumor cell attachment, proteolysis, and inhibition of proteolysis was determined by reverse transcription of mRNA to cDNA and subsequent amplification by the polymerase chain reaction. In addition, cells were examined for morphologic changes by scanning electron microscopy. RESULTS: Invasive proximal gastric cancer cells express the 72-kD form of collagenase type IV, whereas the noninvasive cells do not. Other factors examined (including the laminin receptor, cathepsin B, cathepsin L, urokinase-type plasminogen activator, and tissue inhibitor metalloproteinases) are expressed by both invasive and noninvasive gastric cancer cells, whereas collagenase type IV 92-kD form is not expressed by any of the cells examined. In addition, scanning electron microscopy revealed that all the invasive cell lines exhibit long cytoplasmic extensions. The noninvasive cells express short cytoplasmic projections and are rounder than the invasive proximal gastric cancer cell lines. CONCLUSIONS: There are distinct phenotypic differences between invasive and noninvasive proximal gastric cancer cell lines both at the level of expression of mRNA for collagenase Type IV 72-kD and at the level of scanning electron microscopy with the expression of cytoplasmic projections. Clinical outcome may be associated with these phenotypic differences.

Background Gastric carcinoma is one of the most common malignancies worldwide, with an overall survival of about 10%. Improvement in therapy awaits better understanding of the biologic behavior of this tumor. Establishment of cell lines permits detailed analysis of the biology of gastric cancer. The authors report on the establishment and characterization of five cell lines arising from primary proximal gastric and distal esophageal adenocarcinomas. Methods Cultures of epithelial cells from adenocarcinomas of the proximal stomach or adenocarcinoma of the lower esophagus were established. Gastric cancer cell lines were analyzed for doubling times, anchorage-independent growth, tumorigenic and metastatic potential in nu/nu mice, expression of keratin proteins by indirect immunofluorescence, invasive potential in a Boyden Chamber, and growth factor production by reverse transcription of mRNA in cDNA and subsequent amplification by the polymerase chain reaction. Results Five cell lines were derived from primary gastric adenocarcinomas of the proximal stomach and from Barrett esophagus. All five cell lines were tumorigenic but not metastatic in vivo. None were capable of anchorage independent growth in vitro. Two lines were highly invasive in the Boyden chamber assay, whereas two lines were minimally or noninvasive. All five cell lines expressed RNA transcripts specific for the growth factors TGF beta 1, TGF beta 2, TGF beta 3, TGF alpha, and platelet-derived growth factor A, whereas subsets of cell lines expressed transcripts for aFGF, bFGF, FGF-5, Hst, and platelet-derived growth factor B. Conclusions Five cell lines derived from primary gastric-esophageal adenocarcinomas were established in tissue culture. These cell lines show differences in morphologic features, growth potential, and invasiveness. These newly established gastric cancer cell lines should prove useful for a wide range of studies attempting to decipher the biology of proximal gastric adenocarcinoma.

Background. Chemotherapy has had little impact on the natural history of soft tissue sarcoma, and often is associated with serious toxicity. Edatrexate, an investigational antifolate, is active in patients with lung cancer, and has cytotoxic activity in human sarcoma cell lines. Methods. Edatrexate was administered to 36 patients with measurable, advanced soft tissue sarcoma who had not previously received chemotherapy. The drug was given weekly for 5 weeks, then every other week. The initial dose, 80 mg/m2, was escalated by 10 mg/m2 every 2 weeks in the absence of toxicity. Eleven patients had leiomyosarcoma, 7 had malignant fibrous histiocytoma (MFH), and 5 had liposarcoma; the remainder of cell types included hemangiopericytoma (4), angiosarcoma (3), synovial (2), spindle cell (2), extraosseous chondrosarcoma (1), and fibrosarcoma (1). Results. Thirty-five patients are evaluable. Partial response (PR) was seen in five of the seven patients with MFH; no other major responses occurred. Overall, the response frequency was 14% (two-sided 95% confidence interval, 3% to 26%). Median duration of PR was 6 months (range, 4–18 months). One patient had a minor tumor regression, and six had stable disease. Myelosuppression was generally mild; only three patients had grade 3 hematologic toxicity. Modification of dose or schedule was required in 50% of patients for mucositis. Fatigue was a common toxicity, seen in 66% of patients, but was tolerable in the majority. A rash was seen in 46% of patients; one patient had hepatic toxicity. Conclusions. Overall, the activity of edatrexate in this study, dominated by patients with either visceral or vascular sarcoma, was poor. However, the responses observed in patients with metastatic MFH suggests that further evaluation of edatrexate in patients with soft tissue sarcoma is warranted.

BACKGROUND: Based on evidence of activity in preclinical and Phase I studies, the authors undertook a study of bortezomib, a reversible proteasome inhibitor, for patients with metastatic sarcomas. METHODS: Two arms were opened, each using a Simon two-stage design. Arm A included patients with osteogenic sarcoma, Ewing sarcoma, and rhabdomyosarcoma. Arm B accrued patients with other types of soft tissue sarcomas. Patients were not allowed to have received previous chemotherapy for metastatic disease. The initial dose of bortezomib was a 1.5 mg/m2 intravenous push twice weekly followed by a rest week. The dose was escalated to 1.7 mg/m2 if patients tolerated Cycle 1 well. The dose escalation was eliminated due to toxicity observed in the first six patients. RESULTS: Painful neuropathy, myalgias, and asthenia were the most significant observed toxicities. The most frequent toxicities included fatigue, diarrhea, constipation, and nausea. Pharmacodynamic data from 18 patients with complete data collection did not show consistent differences between patients with or without Grade 2 or Grade 3 neuropathy (toxicity graded according the National Cancer Institute Common Toxicity Criteria). Arm A had low accrual and was closed. One confirmed partial response among 21 evaluable patients was observed on Arm B in a patient with leiomyosarcoma. Due to the inactivity of this agent, the study was closed after the first stage of accrual. CONCLUSIONS: Bortezomib has minimal activity in soft tissue sarcoma as a single agent. If studied further in sarcomas, bortezomib should be investigated in combination with agents with demonstrated preclinical synergy.

Angiosarcomas are rare tumors. Based on a complete response observed in a patient with angiosarcoma of the scalp treated with paclitaxel in a Phase II trial, the authors treated a cohort of patients with angiosarcoma of the scalp or face with paclitaxel as single agent.The authors identified nine patients with angiosarcoma of the scalp or face treated at Memorial Sloan-Kettering Cancer Center with paclitaxel between January 1992 and December 1998. Various paclitaxel schedules were used over 1, 3, and 24 hours.Of the 9 patients, 8 had major responses (4 partial responses and 4 clinical complete responses) and 1 had a minor response, for a major response rate of 89%. The median duration of response was 5 months (range, 2-13 months). Neutropenia and peripheral neuropathy were the most frequent dose-limiting toxicities. No deaths were attributed to therapy.Paclitaxel as a single agent has substantial activity against angiosarcoma of the scalp or face, even in patients previously treated with chemotherapy or radiation therapy. Further investigation is warranted to define the optimal treatment dose and schedule.

Dose intensification of 5-fluorouracil (5-FU) is complicated by increased toxicity. 5-FU is a fluorine-substituted pyrimidine analog of uracil. In preclinical studies, administration of oral uridine (Ur) has been shown to allow for dose intensification of 5-FU with enhancement of its antitumor activity. Therefore, a Phase I trial was designed aimed at dose intensification of 5-FU as a component of a modified 5-FU-doxorubicin-methotrexate (FAMTX) regimen using oral Ur rescue.Methotrexate (MTX) was administered to all patients at a fixed dose of 1.5 g/m2. MTX was followed 24 hours later by escalating doses of 5-FU starting at 800 mg/m2 with leucovorin rescue. Cycles of 5-FU and MTX were repeated every 15 days. Every other cycle, patients received doxorubicin. "Adria cycles") at a dose of 30 mg/m2. Oral Ur was administered at a dose of 8 gm/m2 every 6 hours for 12 doses. In the first phase of the study, patients received Ur only if they developed Grade 3 or 4 hematologic toxicity. In the second phase, all patients received Ur 24 hours after 5-FU on all cycles.Without Ur rescue, the maximum tolerated dose (MTD) of 5-FU was 900 mg/m2 on the Adria cycles and 1.1 gm/m2 on the non-Adria cycles. With Ur, the MTD of 5-FU increased to 1.2 gm/m2 on the Adria cycles and to 1.6 gm/m2 on the non-Adria cycles.In this modified FAMTX regimen, oral Ur administration allowed for dose-intensification of 5-FU, with a 33% increase in the MTD of 5-FU on the Adria cycles and a 45% increase in the MTD of 5-FU dose on the non-Adria cycles.

Adenocarcinoma of the proximal stomach is now the most rapidly rising cancer among men in the United States. The development of metastases is the major cause of morbidity and mortality for this aggressive disease. The mechanisms by which tumor cells invade the basement membrane are unknown for this disease. We have identified and established 5 invasive and noninvasive adenocarcinoma cell lines arising from the proximal stomach, which can be used to examine the mechanisms involved in tumor cell invasion.The expression of factors associated with tumor cell attachment, proteolysis, and inhibition of proteolysis was determined by reverse transcription of mRNA to cDNA and subsequent amplification by the polymerase chain reaction. In addition, cells were examined for morphologic changes by scanning electron microscopy.Invasive proximal gastric cancer cells express the 72-kD form of collagenase type IV, whereas the noninvasive cells do not. Other factors examined (including the laminin receptor, cathepsin B, cathepsin L, urokinase-type plasminogen activator, and tissue inhibitor metalloproteinases) are expressed by both invasive and noninvasive gastric cancer cells, whereas collagenase type IV 92-kD form is not expressed by any of the cells examined. In addition, scanning electron microscopy revealed that all the invasive cell lines exhibit long cytoplasmic extensions. The noninvasive cells express short cytoplasmic projections and are rounder than the invasive proximal gastric cancer cell lines.There are distinct phenotypic differences between invasive and noninvasive proximal gastric cancer cell lines both at the level of expression of mRNA for collagenase Type IV 72-kD and at the level of scanning electron microscopy with the expression of cytoplasmic projections. Clinical outcome may be associated with these phenotypic differences.

Gastric carcinoma is one of the most common malignancies worldwide, with an overall survival of about 10%. Improvement in therapy awaits better understanding of the biologic behavior of this tumor. Establishment of cell lines permits detailed analysis of the biology of gastric cancer. The authors report on the establishment and characterization of five cell lines arising from primary proximal gastric and distal esophageal adenocarcinomas.Cultures of epithelial cells from adenocarcinomas of the proximal stomach or adenocarcinoma of the lower esophagus were established. Gastric cancer cell lines were analyzed for doubling times, anchorage-independent growth, tumorigenic and metastatic potential in nu/nu mice, expression of keratin proteins by indirect immunofluorescence, invasive potential in a Boyden Chamber, and growth factor production by reverse transcription of mRNA in cDNA and subsequent amplification by the polymerase chain reaction.Five cell lines were derived from primary gastric adenocarcinomas of the proximal stomach and from Barrett esophagus. All five cell lines were tumorigenic but not metastatic in vivo. None were capable of anchorage independent growth in vitro. Two lines were highly invasive in the Boyden chamber assay, whereas two lines were minimally or noninvasive. All five cell lines expressed RNA transcripts specific for the growth factors TGF beta 1, TGF beta 2, TGF beta 3, TGF alpha, and platelet-derived growth factor A, whereas subsets of cell lines expressed transcripts for aFGF, bFGF, FGF-5, Hst, and platelet-derived growth factor B.Five cell lines derived from primary gastric-esophageal adenocarcinomas were established in tissue culture. These cell lines show differences in morphologic features, growth potential, and invasiveness. These newly established gastric cancer cell lines should prove useful for a wide range of studies attempting to decipher the biology of proximal gastric adenocarcinoma.

Chemotherapy has had little impact on the natural history of soft tissue sarcoma, and often is associated with serious toxicity. Edatrexate, an investigational antifolate, is active in patients with lung cancer, and has cytotoxic activity in human sarcoma cell lines.Edatrexate was administered to 36 patients with measurable, advanced soft tissue sarcoma who had not previously received chemotherapy. The drug was given weekly for 5 weeks, then every other week. The initial dose, 80 mg/m2, was escalated by 10 mg/m2 every 2 weeks in the absence of toxicity. Eleven patients had leiomyosarcoma, 7 had malignant fibrous histiocytoma (MFH), and 5 had liposarcoma; the remainder of cell types included hemangiopericytoma (4), angiosarcoma (3), synovial (2), spindle cell (2), extraosseous chondrosarcoma (1), and fibrosarcoma (1).Thirty-five patients are evaluable. Partial response (PR) was seen in five of the seven patients with MFH; no other major responses occurred. Overall, the response frequency was 14% (two-sided 95% confidence interval, 3% to 26%). Median duration of PR was 6 months (range, 4-18 months). One patient had a minor tumor regression, and six had stable disease. Myelosuppression was generally mild; only three patients had grade 3 hematologic toxicity. Modification of dose or schedule was required in 50% of patients for mucositis. Fatigue was a common toxicity, seen in 66% of patients, but was tolerable in the majority. A rash was seen in 46% of patients; one patient had hepatic toxicity.Overall, the activity of edatrexate in this study, dominated by patients with either visceral or vascular sarcoma, was poor. However, the responses observed in patients with metastatic MFH suggests that further evaluation of edatrexate in patients with soft tissue sarcoma is warranted.

An antigen immunologically related to mouse mammary tumor virus (MuMTV) and the major envelope glycoprotein, gp52 of MuMTV, was identified in tissue sections of human male and female mammary carcinomas using the peroxidase-antiperoxidase technique. The specificity of the reaction was established by absorption studies. Positive reactions with the gp52 antiserum were seen in mouse and human mammary carcinomas, but not in normal mammary tissues, mammary tissues with benign diseases and in other primary malignant neoplasms. Almost all (32/36, 89%) male mammary carcinomas were positive for the gp52 related antigen. A lesser proportion of tumors among female patients (14/50, 28%) were positive. The gp52 positive tumors were significantly larger than the gp52 negative tumors in female patients (P less than 0.05). Gp52 positive tumors were also larger than gp52 negative tumors in male patients, but the difference was not statistically significant. Gp52 reactivity was also detected in metastatic mammary carcinoma in axillary lymph nodes of male and female patients. The presence of gp52 related antigen was not apparently related to tumor grade or lymphocytic infiltrate in the primary tumor. The data do not permit a firm conclusion regarding nodal status in men; no correlation of gp52 activity and nodal status in women was evident. These results indicate that mammary carcinomas in men as well as in women have an antigen related immunologically to MuMTV gp52. Other than tumor size, the antigen seems to be unrelated to major prognostic factors. The significance of the antigen with respect to etiologic features and prognosis in breast cancer remains to be determined.

In colon cancer biologic markers have been successfully utilized to follow the course of disease, to evaluate response to therapy, and to predict recurrence. With the exception of occult blood measurements, there has been little success in adopting markers to early diagnosis. The role of CEA in predicting the course of the disease is considered, as well as the utility of combining serum enzyme measurements and carcinoembryonic antigen (CEA) assays for these purposes. Aryl sulfatase B has been correlated to the stage of the disease, and enzymes involved in the metabolism of glycoproteins (sialyltransferase and glucosyltransferase) may be of importance in monitoring colon cancer. Polyamines have been observed in blood and urine of patients with a variety of cancers and their presence during therapy in increased amounts may reflect cancer cell death as well as tumor growth. Their use in diagnosis and chemo-therapeutic monitoring in colon cancer has not yet been established. Another area of possible use of biologic markers is their measurement in colon washings. This is discussed in regard to the assay of CEA and enzymes in colonic lavage.

Flow cytometry studies of the DNA distribution of tumor cells from 92 human breast cancers showed measurable aneuploidy (hyperploidy) in 83 cases (92%). The DNA ploidy values were unimodal in each case, but there was a bimodal distribution for the entire series. One group of tumors had a diploid or near diploid DNA distribution and a second group had ploidy levels from triploid to tetraploid or higher. The tumors with lower DNA ploidy (at or near diploid) tended to be histologically low grade, cytologically more orderly and estrogen-binding positive; those with higher DNA ploidy were more likely to be higher grade, more anaplastic, and estrogen-binding negative.

Serum zinc, copper, and the Cu/Zn ratio were evaluated in 80 patients with breast lesions prior to surgery. There were 37 patients with benign and 43 with malignant breast lesions. There was no evidence of weight loss, impaired appetite, or change in eating pattern in any of the patients. There was a statistically significant difference for the mean SCL and Cu/Zn ratio between controls, age 66-94, and patients with malignant breast lesions. This difference was also observed between the ages of 20-45 and 66-94 among controls, suggesting that this is age related rather than disease related. The range of distribution for SZL and SCL were similar for all groups studied. Neither SZL, SCL, or the Cu/Zn ratio were of value in discriminating between controls and patients with benign or malignant breast lesions. We were unable to demonstrate the value of these parameters as markers of disease activity in patient with benign or malignant breast lesions.

Lactic dehydrogenase (LDH) isoenzymes were measured in the cerebrospinal fluid (CSF) patients suffering a variety of cancer-related neurologic problems. LDH-5 isoenzyme as a percentage of total LDH activity was abnormally elevated (above 10 to 15%) in leptomeningeal infiltration by carcinoma (breast carcinoma, lung carcinoma, and malignant melanoma) but not in other types of CNS metastases. Abnormal LDH isoenzyme patterns were also seen with CSF infections in which a granulocytic pleocytosis was present. In the absence of infection, an elevated LDH isoenzyme 5:1 ratio suggested leptomeningeal tumor and, when used with other CSF markers (beta-glucuronidase and CEA), LDH, isoenzymes aid in early detection of this metastatic neoplastic process. They may also help to differentiate leptomeningeal tumor from other chronic meningitides. Measurement of CSF markers also aids in assessing the effectiveness of treatment since marker levels often vary with the clinical course.

813 patients were prospectively studied to examine the influence of family history and the prior use of exogenous hormones as covariables in the subsequent expression of estrogen receptor protein (ERP) in the primary tumor of patients with breast cancer. Cases were divided by menstrual status: there were 385 pre- and perimenopausal and 428 postmenopausal patients. The influence of prior exposure to estrogen replacement therapy (ERT) in postmenopausal patients or oral contraceptives (OCs) in pre- and perimenopausal patients on tumor ERP was analyzed by controlling for family history: none 1st degree (mother or sister) 2nd degree (grandmother or aunt) or both 1st and 2nd degree relatives. The results showed no influence of the prior use of ERT in postmenopausal women on subsequent tumor ERP. Among pre- and perimenopausal women those with a family history of breast cancer in only a 1st degree relative showed a borderline significant association between prior OC usage and subsequent tumor ERP. The use of OCs was consistently associated with ERP negative tumors (9/9) whereas of 29 patients who had prior OC exposure 17 had ERP negative tumors (P=0.04 Fishers Exact Test). Analysis of the prior exposure to OCs verified with the primary physician care or pharmacist showed that these patients first used OCs at the mean age of 32.2 years had used OCs for a mean duration of 41.9 months and stopped OC use a mean of 79.5 months before being diagnosed as having breast cancer. These results suggest that in a subset of patients with breast cancer and a 1st degree relative who only had breast cancer prior exposure to OCs may influence the subsequent ERP status of the tumor. This is not due to exogenous estrogen saturation of receptors as there was a long latent period between exposure and diagnosis. Alternative hypotheses as to the mechanism of selection of subsequent tumor ERP may be either inhibition of ERP positive preneoplastic or tumor cell clones early in the evolution of the tumor or early selection of a tumor capable of endogenous estrogen synthesis with receptor saturation. (authors modified)

A summary is presented of those organ specific enzyme assays traditionally used in evaluation of the patient with cancer. In addition, the use of certain serum enzymes such as gamma-glutamyl transpeptidase, phosphohexose isomerase or 5'-nucleotidase as aids in following the course of the disease, particularly in patients with metastatic spread to the liver is outlined. Also considered is the utility of enzyme analysis in biopsy tissue, biologic fluids, and washings of body cavities. Newer enzymes are considered which might, in the future, be developed as diagnostic tools or as probes for the understanding of the etiology of cancer.

A metastatic neuroblastoma arose in a posterior mediastinal tumor that had been present for at least 52 years. The diagnosis of neuroblastoma was first made when the patient was 81 years of age from biopsy of a metastatic lesion to the femur and later from biopsy of the mediastinal mass.

The reliability of lipid-bound sialic acid (LSA) as a marker in breast cancer was evaluated in 78 normal subjects, 106 patients with benign breast disease, 64 patients with primary operable breast cancer, and 61 patients with recurrent metastatic breast cancer. LSA levels were determined before and after mastectomy and during chemotherapy in selected patients to determine the value of LSA in monitoring therapy and predicting response. LSA levels greater than 20 mg/dl were not seen in normal subjects but were present in patients with benign breast disease (13%), primary breast cancer (47%) and recurrent metastatic breast cancer (62%). LSA levels decreased after initiation of chemotherapy and remained low in patients clinically disease-free. Recurrences were associated with elevated LSA in patients failing chemotherapy or endocrine ablative surgery. LSA measurements appeared to be of limited value in the detection of breast cancer but serial measurements may be useful in assessing disease progression and identifying patients resistant to therapy. Cancer 50:1815-1819, 1982.

By contract with the National Cancer Institute, the accuracy of diagnostic techniques was assessed in 184 patients suspected of having pancreas cancer. Of 138 patients who were operated upon, 89 were found to have pancreas duct cancer, 30 had cancer of a different site of origin in the head of the pancreas region and in 19 there was no evidence of cancer at operation. All of the 46 patients who were not operated upon, 13 proven to have cancer and 33 patients discharged as free of cancer, were followed in our clinic. The majority of our patients presented with signs and symptoms of biliary obstruction. Computerized transaxial tomography (CTT) gave a "correct" diagnosis in 31 of 33 patients (94%) with proven cancer, there were 2 patients with a false negative report and a false positive diagnosis occurred in 8 of 20 patients (40%) without cancer. Celiac angiography (CA) gave a correct diagnosis in 78 of 94 patients (83%) with cancer, a false negative in 17%, and a false positive in 32%. 76Selenomethionine pancreas scan correctly diagnosed 27 of 36 patients (75%) with cancer, gave a false negative in 25% and a false positive in 31%. Ultrasonography gave a correct diagnosis in 18 of 27 patients with cancer (67%), a false negative in 33% and a false positive in 28%. Endoscopic retrograde cholangiopancreatography diagnosed correctly 8 of 11 cases (73%) of cancer, there were false negative diagnoses in 3 cases (27%) and false positives in 3 of 14 patients (21%). Duodenal aspiration techniques gave a very low percentage of correct diagnoses. Chronic pancreatitis most commonly gave rise to a false positive diagnosis. Serum alkaline phosphatase was elevated in 82% of patients, gave 18% false negatives and 33% false positives. Carcinoembryonic antigen (CEA) was elevated (greater than 2.5 ng/ml) in most of the pancreas cancer patients but also in patients with other cancers and with non-cancerous diseases. In our hands, CTT, CA, alkaline phosphatase, 75Se-methionine and ultrasonography, in descending order, have given the highest percentage of correct diagnoses but false positive and false negative diagnoses prevented any single test from being conclusive.

The administration of CMFVP (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone) results in profound alterations in hormonal profiles of premenopausal women due to a reduction in ovarian and adrenal secretion of estrogens and androgens. Cytotoxic chemotherapy results in ovarian suppression as documented by decreases in estradiol with concomitant elevations in pituitary gonadotrophins, whereas the addition of prednisone to the cytotoxic regimen results in significant decreases in androgen levels due to adrenal suppression. In postmenopausal women, CMFVP also results in significant decreases in estrogens and estrogen precursors due to suppression of adrenal steroid metabolism. Continuous low-dose prednisone administration during cytotoxic chemotherapy appears to be more effective than an intermittent high-dose schedule in achieving and sustaining adrenal suppression. However, complete elimination of adrenal steroidogenesis does not occur in all cases since measurable amounts of adrenal steroids remain in the serum throughout chemohormonal therapy. The administration of tamoxifen plus CMFVP is associated with hyperestrogenemia in younger premenopausal patients which persists until the onset of ovarian suppression.

Analysis of estrogen receptor protein (ERP) was carried out on 784 patients with primary breast carcinomas. Significant relationships were found with the following epidemiologic features; age at diagnosis, menstrual status, race, and use of exogenous hormones (contraceptive and menopausal estrogens). Patients taking either type of hormone at diagnosis had lower median total ERP binding levels. Although the data do not explain how recent hormone usage affects tumor ERP, it seems advisable to discontinue these hormones as early as possible before a breast biopsy because they may cause spuriously low ERP levels. Correlation with pathology variables confirmed most prior observations relating to tumor type, histologic grade, and lymphocytic infiltrate. However, in this large series, infiltrating lobular carcinomas were not ERP-positive more frequently than duct carcinomas to any significant degree. The pattern of progesterone receptors (PRP) did not vary significantly with menstrual status, but in other respects correlations of epidemiologic and pathologic variables were similar for ERP and PRP.

Flow cytometry analysis of cell cycle distribution was carried out on acridine-orange-stained cell suspensions freshly prepared from carcinoma of the breast of 90 women, and compared with control, benign breast specimens from 10 women. There was a significantly greater proportion of cells in S (9.1% +/- 5.8) and G2 + M (8.0 +/- 6.0) phases of the cycle in breast cancer specimens than in the S (1.5% +/- 0.6) and G2 + M (2.5 +/- 0.9) phases of the cycle in benign, control specimens of breast tissue. Great variation was noted among the breast cancers, with medullary carcinomas having the highest percentage of cells in S + G2 + M, and papillary, tubular, colloid and well-differentiated duct carcinomas having the lowest. Tumors from premenopausal women classified as estrogen receptor negative had significantly more cells in S + G2 + M than did tumors from postmenopausal women that were estrogen-receptor positive.

During therapeutic trials with E. coli L-asparaginase in 131 children and 143 adults with neoplastic disease the following signs of toxicity have been observed: fever, nausea and vomiting, weight loss, somnolence, lethargy, confusion, hypolipidemia, hyperlipidemia, hypoproteinemia, abnormal liver function tests, fatty metamorphosis of the liver, pancreatitis (in rare instances), azotemia, granulocytopenia, lymphopenia, thrombocytopenia, and hypersensitivity reactions. While these effects have been moderately severe and reversible in most instances, some patients have shown dangerous degrees of toxicity. This has been the case most frequently in adult patients receiving a dose of 5000 IU/kg/day.

Eleven specimens of breast lesions obtained from 10 male patients were analyzed for estrogen receptor protein (ERP). Three patients (ages 49, 77, 82 years) had infiltrating duct carcinomas with no axillary metastases. ERP in each of these was positive. Eight specimens with gynecomastia, one of which was obtained from the 77-year-old patient with carcinoma in the same breast, were also analyzed. Of these ERP was positive in a 59-year-old man who had cirrhosis of the liver; two patients with borderline ERP had hepatitis and testicular seminoma, respectively. No relationship between histopathologic features of the lesions and ERP results was found and it is too early to relate these ERP studies to prognosis in these patients. Review of available literature, including our cases, reveals that six of eight male breast carcinomas were ERP-positive.

The reliability of lipid-bound sialic acid (LSA) as a marker in breast cancer was evaluated in 78 normal subjects, 106 patients with benign breast disease, 64 patients with primary operable breast cancer, and 61 patients with recurrent metastatic breast cancer. LSA levels were determined before and after mastectomy and during chemotherapy in selected patients to determine the value of LSA in monitoring therapy and predicting response. LSA levels greater than 20 mg/dl were not seen in normal subjects but were present in patients with benign breast disease (13%), primary breast cancer (47%) and recurrent metastatic breast cancer (62%). LSA levels decreased after initiation of chemotherapy and remained low in patients clinically disease-free. Recurrences were associated with elevated LSA in patients failing chemotherapy or endocrine ablative surgery. LSA measurements appeared to be of limited value in the detection of breast cancer but serial measurements may be useful in assessing disease progression and identifying patients resistant to therapy.

The effect of CMF adjuvant therapy (cyclophosphamide, methotrexate, and 5-fluorouracil) on endocrine function was investigated in breast cancer patients. CMF therapy resulted in suppression of ovarian function in some premenopausal patients but pituitary function and adrenal function were unaffected. There was an inverse relation between age and duration of treatment required to induce ovarian suppression. Although amenorrhea was achieved within 2-4 months in patients aged 40 years or older, younger women required larger cumulative doses of cytotoxic drugs to induce ovarian dysfunction. Patients younger than 30 years of age continued to menstruate with no major alteration in hormonal levels resulting from the cytotoxic drugs. CMF therapy had no significant effect on hormonal levels in postmenopausal patients indicating that in this group therapeutic response is not mediated via the endocrine system.

Eleven specimens of breast lesions obtained from 10 male patients were analyzed for estrogen receptor protein (ERP). Three patients (ages 49, 77, 82 years) had infiltrating duct carcinomas with no axillary metastases. ERP in each of these was positive. Eight specimens with gynecomastia, one of which was obtained from the 77-year-old patient with carcinoma in the same breast, were also analyzed. Of these ERP was positive in a 59-year-old man who had cirrhosis of the liver; two patients with borderline ERP had hepatitis and testicular seminoma, respectively. No relationship between histopathologic features of the lesions and ERP results was found and it is too early to relate these ERP studies to prognosis in these patients. Review of available literature, including our cases, reveals that six of eight male breast carcinomas were ERP-positive.

A summary is presented of those organ specific enzyme assays traditionally used in evaluation of the patient with cancer. In addition, the use of certain serum enzymes such as gamma-glutamyl transpeptidase, phosphohexose isomerase or 5'-nucleotidase as aids in following the course of the disease, particularly in patients with metastatic spread to the liver is outlined. Also considered is the utility of enzyme analysis in biopsy tissue, biologic fluids, and washings of body cavities. Newer enzymes are considered which might, in the future, be developed as diagnostic tools or as probes for the understanding of the etiology of cancer.

Flow cytometry analysis of cell cycle distribution was carried out on acridine-orange-stained cell suspensions freshly prepared from carcinoma of the breast of 90 women, and compared with control, benign breast specimens from 10 women. There was a significantly greater proportion of cells in S (9.1% +/- 5.8) and G2 + M (8.0 +/- 6.0) phases of the cycle in breast cancer specimens than in the S (1.5% +/- 0.6) and G2 + M (2.5 +/- 0.9) phases of the cycle in benign, control specimens of breast tissue. Great variation was noted among the breast cancers, with medullary carcinomas having the highest percentage of cells in S + G2 + M, and papillary, tubular, colloid and well-differentiated duct carcinomas having the lowest. Tumors from premenopausal women classified as estrogen receptor negative had significantly more cells in S + G2 + M than did tumors from postmenopausal women that were estrogen-receptor positive.

We have studied 29 patients from whom two or more spatially and temporally separate samples of breast carcinoma were obtained for ERP analysis. Differences in ERP were obtained in 24% of all cases studied. The greatest degree of variation was found when comparing a primary tumor with a subsequent metastasis (38%). Among eight patients with ERP negative (-) primary tumors, six had ERP (-) and two ERP positive (+) metastases. Among 11 patients with ERP (+) primaries eight had ERP (+) and three ERP (-) metastases. Variations were found in 20% of multiple nonsimultaneous metastases from individual patients. The difference in average interval between cases that did not show variation (9.6 months) and those that did vary (19.3 months) suggests that variation may be more likely to occur with later metastases. However, there was considerable overlap in the range of intervals. These findings underscore the need to biopsy readily accessible recurrences rather than to rely on the results of prior specimens. There was no apparent consistent relationship of these variations to age, site of specimen, interval between specimens or the histologic features of the tissues submitted for analysis. Two patients with an ERP (+) primary tumor had ERP (-) metastases after interval therapy. Similar variations were observed in patients who did not have interval therapy. The data do not perimit any definite conclusions as to the effect of chemotherapy or radiation on the ERP properties of mammary carcinoma.

Analysis of estrogen receptor protein (ERP) was carried out on 784 patients with primary breast carcinomas. Significant relationships were found with the following epidemiologic features; age at diagnosis, menstrual status, race, and use of exogenous hormones (contraceptive and menopausal estrogens). Patients taking either type of hormone at diagnosis had lower median total ERP binding levels. Although the data do not explain how recent hormone usage affects tumor ERP, it seems advisable to discontinue these hormones as early as possible before a breast biopsy because they may cause spuriously low ERP levels. Correlation with pathology variables confirmed most prior observations relating to tumor type, histologic grade, and lymphocytic infiltrate. However, in this large series, infiltrating lobular carcinomas were not ERP-positive more frequently than duct carcinomas to any significant degree. The pattern of progesterone receptors (PRP) did not vary significantly with menstrual status, but in other respects correlations of epidemiologic and pathologic variables were similar for ERP and PRP.

Serum enzymes have not proved useful in evaluation of patients with early colon cancer, but certain enzymes such as transpeptidase, phosphohexone isosomerase, or 5'-nucleotidase have been of assistance in following the course of the disease, particularly in patients with metastatic spread to the liver. Attempts have been made to improve the utility of enzyme analysis in colon cancer by examination of enzyme patterns in colon biopsy specimens, feces, and colon washings. These studies, which will be summarized, are of importance in the possible development of diagnostic tools and as probes in the understanding of the etiology of colon cancer. The technical problems in carrying out these assays in humans, as well as the significance of the activity of aryl sulfatase, beta-glucuronidase, beta-glucosidase, lactic dehydrogenase, glucose-6-p-osphate dehydrogenase, and other enzymes will be considered.

By contract with the National Cancer Institute, the accuracy of diagnostic techniques was assessed in 184 patients suspected of having pancreas cancer. Of 138 patients who were operated upon, 89 were found to have pancreas duct cancer, 30 had cancer of a different site of origin in the head of the pancreas region and in 19 there was no evidence of cancer at operation. All of the 46 patients who were not operated upon, 13 proven to have cancer and 33 patients discharged as free of cancer, were followed in our clinic. The majority of our patients presented with signs and symptoms of biliary obstruction. Computerized transaxial tomography (CTT) gave a "correct" diagnosis in 31 of 33 patients (94%) with proven cancer, there were 2 patients with a false negative report and a false positive diagnosis occurred in 8 of 20 patients (40%) without cancer. Celiac angiography (CA) gave a correct diagnosis in 78 of 94 patients (83%) with cancer, a false negative in 17%, and a false positive in 32%. 76Selenomethionine pancreas scan correctly diagnosed 27 of 36 patients (75%) with cancer, gave a false negative in 25% and a false positive in 31%. Ultrasonography gave a correct diagnosis in 18 of 27 patients with cancer (67%), a false negative in 33% and a false positive in 28%. Endoscopic retrograde cholangiopancreatography diagnosed correctly 8 of 11 cases (73%) of cancer, there were false negative diagnoses in 3 cases (27%) and false positives in 3 of 14 patients (21%). Duodenal aspiration techniques gave a very low percentage of correct diagnoses. Chronic pancreatitis most commonly gave rise to a false positive diagnosis. Serum alkaline phosphatase was elevated in 82% of patients, gave 18% false negatives and 33% false positives. Carcinoembryonic antigen (CEA) was elevated (greater than 2.5 ng/ml) in most of the pancreas cancer patients but also in patients with other cancers and with non-cancerous diseases. In our hands, CTT, CA, alkaline phosphatase, 75Se-methionine and ultrasonography, in descending order, have given the highest percentage of correct diagnoses but false positive and false negative diagnoses prevented any single test from being conclusive.

An antigen immunologically related to mouse mammary tumor virus (MuMTV) and the major envelope glycoprotein, gp52 of MuMTV, was identified in tissue sections of human male and female mammary carcinomas using the peroxidase-antiperoxidase technique. The specificity of the reaction was established by absorption studies. Positive reactions with the gp52 antiserum were seen in mouse and human mammary carcinomas, but not in normal mammary tissues, mammary tissues with benign diseases and in other primary malignant neoplasms. Almost all (32/36, 89%) male mammary carcinomas were positive for the gp52 related antigen. A lesser proportion of tumors among female patients (14/50, 28%) were positive. The gp52 positive tumors were significantly larger than the gp52 negative tumors in female patients (P less than 0.05). Gp52 positive tumors were also larger than gp52 negative tumors in male patients, but the difference was not statistically significant. Gp52 reactivity was also detected in metastatic mammary carcinoma in axillary lymph nodes of male and female patients. The presence of gp52 related antigen was not apparently related to tumor grade or lymphocytic infiltrate in the primary tumor. The data do not permit a firm conclusion regarding nodal status in men; no correlation of gp52 activity and nodal status in women was evident. These results indicate that mammary carcinomas in men as well as in women have an antigen related immunologically to MuMTV gp52. Other than tumor size, the antigen seems to be unrelated to major prognostic factors. The significance of the antigen with respect to etiologic features and prognosis in breast cancer remains to be determined.

Flow cytometry studies of the DNA distribution of tumor cells from 92 human breast cancers showed measurable aneuploidy (hyperploidy) in 83 cases (92%). The DNA ploidy values were unimodal in each case, but there was a bimodal distribution for the entire series. One group of tumors had a diploid or near diploid DNA distribution and a second group had ploidy levels from triploid to tetraploid or higher. The tumors with lower DNA ploidy (at or near diploid) tended to be histologically low grade, cytologically more orderly and estrogen-binding positive; those with higher DNA ploidy were more likely to be higher grade, more anaplastic, and estrogen-binding negative.