Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients.

BACKGROUND: Everolimus, an mTOR inhibitor, is active in refractory lymphomas. However, toxicity with flat dosing limits its usage. Speculatively, pharmacokinetically-targeted dosing could improve tolerability. Therefore, we studied serum-trough dosing with rituximab as maintenance after high-dose cyclophosphamide (HDC) consolidation in lymphoma patients. PATIENTS/METHODS: After HDC, everolimus was dosed to serum trough levels (goal 3-15 ng/mL), with quarterly rituximab infusions for 1 year while maintaining < grade II non-hematologic and < grade III hematologic toxicities. Adult patients in first PR/CR with: mantle cell, transformed, double-hit, or high risk chronic lymphocytic leukemia or in second PR for any relapsed B cell lymphoma were eligible. Prophylaxis was given for encapsulated organisms, HSV and PCP. Serum IgG levels were maintained > 500 mg/dL. RESULTS: 49 patients, median age: 59.0 years enrolled; MCL (26), CLL (10), transformed lymphoma (7), and other histologies (6). During the life of the study, the most frequent everolimus dosing has been 2.5 mg daily or 2.5 mg every other day; at these doses, serum levels are within the therapeutic range and non-hematologic toxicity is rare. At a median follow-up of 27.1 months, three patients remain on active therapy. Two patients withdrew secondary to potentially-attributable adverse events including a bacterial pneumonia and a viral pneumonia; this low rate of discontinuation compares well to other long-term everolimus trials. While a 58 and 76% EFS at 30 months for the entire cohort and MCL cohort, respectively, compares similarly to previously published HDC/rituximab data, longer follow-up is required. CONCLUSIONS: Pharmacokinetically-targeted dosing appears to increase everolimus tolerability. This finding may be applicable to other patient populations.

p53 mutation and locoregional treatment failure in head and neck squamous cell carcinoma.

BACKGROUND: The p53 gene (also known as TP53) may be the most common genetic target involved in the malignant transformation of human cells. Direct sequence analysis has demonstrated that alteration of this gene occurs in approximately 45% of head and neck squamous cell carcinomas. The consequences of p53 mutations in these cancers with respect to tumor behavior and patient survival have not been rigorously determined. PURPOSE: We evaluated the implications of p53 mutations in relation to the control of locoregional disease and overall survival following radiation therapy. METHODS: Data from 110 consecutive patients with invasive disease who were treated with primary radiation therapy (given with curative intent) or with adjuvant radiation therapy (following complete surgical extirpation of gross disease) were included in the analysis. A 1.8-kilobase fragment of the p53 gene encompassing exons 5-9 was amplified from the DNA of stored (frozen) tumor specimens; the amplified DNA was cloned and sequenced by use of standard techniques. Overall survival and locoregional disease-free survival after the completion of radiation therapy were estimated by the Kaplan-Meier method; survival comparisons were made by use of the logrank test or proportional hazards regression models. Reported P values are two-sided. RESULTS: Fortyeight (44%) of the 110 tumors had cells bearing p53 mutations. The risk of locoregional recurrence following either primary or adjuvant radiation therapy was significantly greater (i.e., the time to recurrence was shorter) for patients whose tumors contained mutant p53 genes (univariate model hazard ratio [HR] for p53 mutation versus wild-type = 2.2; 95% confidence interval [CI] = 1.2-4.1; P = .02). The presence of regional lymph node metastases (presence versus absence, HR = 2.0; 95% CI = 1.0-4.2; P = .05) and treatment type (primary radiation therapy versus surgery plus adjuvant radiation therapy, HR = 2.3; 95% CI = 1.2-4.3; P = .01) were also associated with greater risks of locoregional failure. The presence of p53 mutations and lymph node metastases and treatment with primary, as opposed to adjuvant, radiation therapy remained significant risk factors in multivariate regression analysis. No relationship was demonstrated between p53 status and overall survival (mutant versus wild-type, HR = 1.1; 95% CI = 0.6-2.1; P = .66); however, a relationship was shown for tumor stage and overall survival (stages III and IV [more advanced] versus stages I and II [less advanced], HR = 3.3; 95% CI = 1.0-10.8; P = .05). Mutation of the p53 gene was not associated with patient age, sex, tumor stage, primary tumor site, regional lymph node status, degree of tumor cell differentiation, or treatment method. CONCLUSIONS: Mutation of the p53 gene is associated with an increased risk of locoregional failure in patients with invasive head and neck squamous cell carcinoma who are treated with radiation therapy.

Phase I-II trial of erythropoietin in the treatment of cisplatin-associated anemia.

BACKGROUND: Cancer patients undergoing chemotherapy with cisplatin-containing regimens often develop anemia. Although the cause is multifactorial, erythropoietin deficiency appears to play an important role. Recombinant human erythropoietin (epoetin) has been reported to be effective in reversing cisplatin-associated anemia in animal studies but not in clinical trials. PURPOSE: This pahse I-II clinical trial was designed to assess the safety and efficacy of treatment with epoetin for anemia associated with cisplatin chemotherapy. METHODS: Twenty-one cancer patients treated with cisplatin and manifesting anemia (hemoglobin level less than 110 g/L) received epoetin at escalating doses (25, 50, 100, or 200 U/kg body weight) intravenously five times a week for 4 weeks. RESULTS: Epoetin was well tolerated, and a maximal tolerated dose was not reached. Two patients experienced hypertension, which responded to standard antihypertensive therapy. No dose-dependent severe toxic effects were seen. The increase in hemoglobin levels from baseline on day 1 of the study was statistically significant after 4 weeks of epoetin therapy in the groups receiving 100 U/kg (mean change +/- SD = 19 +/- 13 g/L; P = .03) or 200 U/kg (mean change = 24 +/- 17 g/L; P = .007). A clinical response--an increase in hemoglobin level greater than 10 g/L--was achieved in 12 patients after 4 weeks of treatment. For these responders, the mean increase in hemoglobin level was 25 +/- 3.3 g/L over the level observed at the same time in the chemotherapy cycle preceding epoetin treatment, and this increase was statistically significant (P = .0001). Neither serum erythropoietin level nor hemoglobin level predicted a patient's response to epoetin. CONCLUSIONS: These preliminary findings suggest that epoetin is effective and well tolerated for the reversal of cisplatin-associated anemia, with the 100-U/kg and 200-U/kg dose levels offering optimal clinical response. IMPLICATIONS: We are conducting a phase III trial to determine the effect of epoetin on transfusion requirements in patients undergoing chemotherapy.

Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.

BACKGROUND: High-risk human papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas (HNSCCs). We investigated, retrospectively, an etiologic role for HPVs in a large series of patients with HNSCC. METHODS: Tumor tissues from 253 patients with newly diagnosed or recurrent HNSCC were tested for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, Southern blot hybridization, and in situ hybridization. The viral E6 coding region was sequenced to confirm the presence of tumor-specific viral isolates. Exons 5-9 of the TP53 gene were sequenced from 166 specimens. The hazard of death from HNSCC in patients with and without HPV-positive tumors was determined by proportional hazards regression analysis. RESULTS: HPV was detected in 62 (25%) of 253 cases (95% confidence interval [CI] = 19%-30%). High-risk, tumorigenic type HPV16 was identified in 90% of the HPV-positive tumors. HPV16 was localized specifically by in situ hybridization within the nuclei of cancer cells in preinvasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade (odds ratio [OR] = 2.4; 95% CI = 1.2- 4.9) and oropharyngeal site (OR = 6.2; 95% CI = 3.1-12.1) independently increased the probability of HPV presence. As compared with HPV-negative oropharyngeal cancers, HPV-positive oropharyngeal cancers were less likely to occur among moderate to heavy drinkers (OR = 0.17; 95% CI = 0.05-0.61) and smokers (OR = 0.16; 95% CI = 0.02-1.4), had a characteristic basaloid morphology (OR = 18.7; 95% CI = 2.1-167), were less likely to have TP53 mutations (OR = 0.06; 95% CI = 0.01-0. 36), and had improved disease-specific survival (hazard ratio [HR] = 0.26; 95% CI = 0.07-0.98). After adjustment for the presence of lymph node disease (HR = 2.3; 95% CI = 1.4- 3.8), heavy alcohol consumption (HR = 2.6; 95% CI = 1.4-4.7), and age greater than 60 years old (HR = 1.4; 95% CI = 0.8-2.3), all patients with HPV-positive tumors had a 59% reduction in risk of death from cancer when compared with HPV-negative HNSCC patients (HR = 0.41; 95% CI = 0.20-0.88). CONCLUSIONS: These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.

Tumor-suppressive pathways in pancreatic carcinoma.

During tumorigenesis, positive selection is exerted upon those tumor cells that alter rate-limiting regulatory pathways. A corollary of this principle is that mutation of one gene abrogates the need for alteration of another gene in the same pathway and also that the coexistence in a single tumor of mutations in different genes implies their involvement in distinct tumor-suppressive pathways. We studied 42 pancreatic adenocarcinomas for genetic alterations in the K-ras oncogene and the p16, p53, and DPC4 tumor suppressor genes. All of them had the K-ras gene mutated. Thirty-eight % of the tumors had four altered genes, another 38% had three altered genes, 15% had two altered genes, and 8% of the tumors had one altered gene. Interestingly, we noted a high concordance of DPC4 and p16 inactivations (P = 0.007), suggesting that the genetic inactivation of p16 increases the selective advantage of subsequent mutation in DPC4. No statistically significant association was identified between the alteration of these cancer genes and pathological or clinical parameters. This type of multigenic analysis in human tumors may serve to substantiate experimental tumor models and thus increase our understanding of the truly physiologically relevant tumor-suppressive pathways that are abrogated during human tumorigenesis.

Preoperative chemoradiation followed by transhiatal esophagectomy for carcinoma of the esophagus: final report.

PURPOSE: In 1990 we published the results of an intensive 3-week preoperative chemoradiation regimen for locoregional esophageal cancer that suggested improved survival compared with historical controls. We now report the long-term results at a median follow-up of 78.7 months. PATIENTS AND METHODS: Forty-three patients with locoregional squamous cell carcinoma or adenocarcinoma of the esophagus or cardia were treated with fluorouracil (5-FU), cisplatin, and bolus vinblastine concurrent with radiation administered over 21 days. Transhiatal esophagectomy was performed on day 42. RESULTS: Forty-one patients (95%) completed the preoperative treatment, and 36 (84%) had a potentially curative resection. Ten of 41 (24%) had no tumor in the resected esophagus and nodal tissues (path-negative group). The median survival duration of all 43 patients registered on study was 29 months; 34% were alive at 5 years. By histology, median survival durations were 32 months for 21 adenocarcinoma patients and 23 months for 22 squamous cell patients, with corresponding 5-year survival rates of 34% and 31%, respectively. Analysis of the 36 patients who underwent a potentially curative resection demonstrated median survival durations of 32 and 44 months and 5-year survival rates of 36% and 43%, respectively, for adenocarcinoma and squamous cell histologies. Path-negative (complete response [CR]) patients had a median survival duration of 70 months and 60% were alive at 5 years, while those patients with residual tumor in the resected esophagus had a median survival duration of 26 months and 32% were alive at 5 years (P = .114 by the log-rank test and P = .04 by the Wilcoxon test). CONCLUSION: The results of this regimen appear improved over those reported with surgery alone, with an approximate doubling of the 5-year survival rate. Thirty-two percent of patients with residual tumor in the esophageal specimen are long-term survivors, which suggests a benefit from esophagectomy. A randomized trial is in progress to compare this preoperative regimen with immediate surgery.

Phase I and pharmacologic study of sequences of paclitaxel and cyclophosphamide supported by granulocyte colony-stimulating factor in women with previously treated metastatic breast cancer.

PURPOSE: Pacltaxel is active in metastatic breast cancer, but limited information is available on combinations of this agent with other cytotoxic agents. Study aims were to determine the maximum-tolerated doses (MTDs) of paclitaxel (24-hour infusion) and cyclophosphamide (1-hour infusion) administered every 21 days with granulocyte colony-stimulating factor (G-CSF, filgrastim) to determine the effect of drug sequence on toxicity and pharmacology and to evaluate the activity of this combination in women with anthracycline-resistant disease. PATIENTS AND METHODS: Thirty-seven women with metastatic breast cancer were treated. Starting doses were paclitaxel 135 mg/m2 and cyclophosphamide 750 mg/m2, with filgrastim 5 microG/kg/d subcutaneously beginning 24 hours after chemotherapy. Four patients were treated at each dose level. The sequence of drug administration was alternated between sequential patients, and with subsequent courses of therapy in each patient, to enable evaluation of effects of drug sequence on toxicity and pharmacology. Patients were treated every 21 days and disease status was reevaluated every two courses. RESULTS: Paclitaxel 200 mg/m2 and cyclophosphamide 1,250 mg/m2 is the MTD for this combination on this schedule. The hematopoietic toxicity of therapy was sequence-dependent. Paired analysis of toxicity data indicated more severe toxicity in courses in which paclitaxel was administered first. Sequence-dependent pharmacologic effects did not account for this phenomenon. Responses were noted in 29% of patients with anthracycline-resistant disease. CONCLUSION: Paclitaxel 200 mg/m2 and cyclophosphamide 1,250 mg/m2 with filgrastim administered every 21 days are the doses recommended for further study.

Concurrent chemotherapy and radiation therapy followed by transhiatal esophagectomy for local-regional cancer of the esophagus.

Forty-three patients with local-regional squamous-cell carcinoma of the esophagus or adenocarcinoma of the esophagus, cardia, or gastroesophageal junction were treated with concurrent cisplatin, vinblastine, fluorouracil (5-FU), and radiation therapy (RT) over 21 days. A transhiatal esophagectomy (THE) was planned on day 42. Seventy-nine percent had T2 primaries by clinical staging and 56% had enlarged regional nodes (N) on computed tomographic (CT) scan. Forty-one patients completed the preoperative treatment and went to surgery (95% operability rate), and 36 (84%) were completely resected. Ten of the 41 operative candidates had no evidence of tumor in the resected esophagus and nodal tissue (tumor0 node0; T0N0), 24% complete response (CR). Myelosuppression was the major toxicity with grade 3 or 4 leukopenia in 93% of patients and two preoperative treatment-related deaths. At a median follow-up of 26 months, the median survival time (MST) of all 43 patients registered on study has not been reached. The MST of the 36 completely resected patients and the 10 complete responders has not been reached; 70% and 100%, respectively, are alive at 24 months. The MST by histology is 21 months for the 22 squamous patients and has not been reached for the 21 adenocarcinoma patients registered on study. In a prognostic factor analysis, clinical N status, histology, and the percent of cisplatin and vinblastine tolerated were significant predictors for survival. These survival results suggest a significant improvement over the 14-month MST observed in our previous trial using preoperative chemotherapy only in a similar patient population, and a 12-month MST in a historic control group undergoing THE. A randomized trial is now in progress to convincingly determine if survival is prolonged by this therapy.

Bone marrow transplantation of chronic myelogenous leukemia in chronic phase: evaluation of risks and benefits.

PURPOSE: Allogeneic bone marrow transplantation (BMT) is an option for some patients with chronic myelogenous leukemia (CML). We retrospectively evaluated the effect of various risk factors observed at diagnosis and at transplantation on survival, event-free survival (EFS), and relapse after BMT. PATIENTS AND METHODS: Seventy-nine patients with CML in chronic phase (CP) were treated with cyclophosphamide and total body irradiation followed by BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CsA) in most instances or CsA plus the use of lymphocyte-depleted bone marrow (BM). RESULTS: Survival at 4.5 years was 52%. Stratified by age and GVHD prophylaxis, the actuarial survival was 65% (95% confidence interval [CI], 47% to 78%) in patients aged less than 30 years receiving unmanipulated BM, 33% (95% CI, 12% to 56%) in patients greater than or equal to 30 years old receiving unmanipulated BM, and 38% (95% CI, 14% to 63%) in patients greater than or equal to 30 years old receiving lymphocyte-depleted BM. In univariate analysis, patient age (greater than or equal to 30 years) and the use of lymphocyte-depleted BM negatively influenced EFS. When stratified by age and GVHD prophylaxis, however, ABO incompatibility, cytomegalovirus (CMV) seropositivity, and chronic GVHD significantly reduced the probability of EFS. Factors that have been associated with early death in nontransplanted patients (ie, sex, spleen size, blast and platelet counts at presentation) were not predictive of long-term survival outcome after BMT. CONCLUSIONS: The data suggest that (1) BMT should be offered early after diagnosis to all patients with CML in CP who have compatible sibling donors regardless of prognostic factors at presentation, (2) GVHD remains the principal cause of mortality after BMT in patients receiving CsA, and (3) T-cell depletion by the physical separation method of counterflow elutriation (CE) is associated with a significant risk of relapse.

Long-term results of blood and marrow transplantation for Hodgkin's lymphoma.

PURPOSE: To evaluate the long-term outcome after allogeneic (allo) and autologous (auto) blood or marrow transplantation (BMT) in patients with relapsed or refractory Hodgkin's lymphoma (HL). PATIENTS AND METHODS: We analyzed the outcome of 157 consecutive patients with relapsed or refractory HL, who underwent BMT between March 1985 and April 1998. Patients

CD44 expression in the stromal matrix of colorectal cancer: association with prognosis.

CD44, a cell hyaluronate receptor, is implicated in the metastatic behavior of some cancer cells. This study analyzed CD44 expression in topographic tissue sites of colorectal cancers to determine its association with patient survival and clinicopathological characteristics. Immunohistochemical localization of the core CD44 and the v6 splice variant domains was examined by use of paraffin-fixed sections from 133 stage II or III colorectal cancers that previously had been evaluated for other diagnostic markers. Expression in malignant epithelium, stromal matrix, and stromal cells was compared to patient survival by univariate, multivariate, and bootstrap (reproducibility) analysis. Core CD44 staining was present in the malignant epithelium of 85% of tumors, the stromal matrix of 90%, and the stromal cells of 98%. The v6 splice variant domain was present in the epithelium of 77% of tumors but was less frequent in the stromal matrix (12%; P < 0.001) and stromal cells (17%; P < 0.001). Absence of core CD44 immunoreactivity in the stromal matrix was associated with increased death rate (hazard ratio, 2.4; 95% confidence interval, 1.2-4.8; P = 0.02), making this one of the most significant adverse prognostic variables, along with an age of 60 years or older, poor differentiation of the cancer, extramural venous invasion, chromosome 18q allelic loss, and nonwhite race. This study shows that core CD44 and v6 splice variant antigens are differentially expressed in the epithelium and stroma of colorectal cancers. A model that includes core CD44 immunoreactivity in stromal matrix along with other prognostic factors may improve identification of high-risk and low-risk patients.

Impact of chromosome 14q loss on survival in primary head and neck squamous cell carcinoma.

We screened 73 primary head and neck squamous cell carcinoma (HNSCC) specimens for loss of heterozygosity (LOH) on chromosome 14q. Analysis of 20 polymorphic microsatellite markers identified 29 (40%) HNSCCs exhibiting LOH of 14q in at least one locus. Six tumors had probable monosomy of 14q, displaying allelic loss for all informative markers tested, and 23 demonstrated partial losses on 14q. Fine mapping with 1-10 additional markers revealed two poorly defined regions of loss (4-7 cM) at 14q13-21 and 14q31-32.1 in seven tumors. In 53 patients with previously untreated tumors treated with curative intent, LOH of 14q in these tumors correlated with poor survival. Compared to patients with tumors that retain heterozygosity of 14q, those with 14q LOH had a 3-fold increased risk of death in multivariate analysis (hazards ratio, 3.2; 95% confidence interval = 1.2-8.4). These data have confirmed a high frequency of chromosome 14q loss in HNSCC and suggest that LOH of any region on chromosome 14q is an indicator of poor outcome.

Sequence-dependent hematological toxicity associated with the 3-hour paclitaxel/cyclophosphamide doublet.

Paclitaxel is active in metastatic breast cancer. Combination studies have demonstrated complex interactions between paclitaxel and other cytotoxic agents, including sequence-dependent cytotoxic, toxicological, and pharmacological effects. The principal objectives of this study were to determine the maximum tolerated doses of paclitaxel (3-h infusion) and cyclophosphamide (1-h infusion) administered every 3 weeks with granulocyte colony-stimulating factor (Filgrastim) and to determine if the sequence-dependent toxicological effects that have previously been observed with this combination when paclitaxel was administered over 24 h were evident when paclitaxel was administered over 3 h. Fifteen women with metastatic breast cancer were treated. Starting doses were 200 mg/m2 paclitaxel and 1600 mg/m2 cyclophosphamide, with granulocyte colony-stimulating factor (5 micrograms/kg/day) given s.c. beginning 24 h after chemotherapy. Doses of both drugs were escalated in cohorts of at least four patients. The sequence of drug administration was alternated with each consecutive patient and with each subsequent course of therapy in each individual patient, enabling the evaluation of sequence-dependent toxicological and pharmacological effects. Severe myelosuppression was the principal dose-limiting toxicity for this regimen, precluding dose escalation above 200 mg/m2 paclitaxel and 1600 mg/m2 cyclophosphamide, the maximum tolerated dose for this combination on this schedule. As has been previously demonstrated with this combination, when paclitaxel is administered over 24 h, the hematopoietic toxicity was sequence dependent. Paired analysis of toxicity data using each patient as her own control indicated more severe hematological toxicity in courses in which paclitaxel was administered first. There was no evidence of sequence-dependent effects on the pharmacokinetics of these drugs that might account for this phenomenon. The impact of drug sequencing on toxicity should be considered in the further development of combination therapy containing alkylating agents and paclitaxel, when the latter is administered over 3 h.

Change in PSA velocity is a predictor of overall survival in men with biochemically-recurrent prostate cancer treated with nonhormonal agents: combined analysis of four phase-2 trials.

BACKGROUND: Multiple phase-2 trials in men with biochemically-recurrent prostate cancer (BRPC) have assessed the impact of nonhormonal agents on PSA kinetics. We have previously demonstrated that changes in PSA kinetics correlate with metastasis-free survival; however, it is unknown whether these changes also correlate with overall survival (OS). METHODS: We performed a combined retrospective analysis of 146 men with BRPC treated on phase-2 trials using one of four investigational drugs: lenalidomide (n=60), marimastat (n=39), ATN-224 (n=22) and imatinib (n=25). We examined factors influencing OS, including within-subject changes in PSA kinetics (PSA slope, PSA doubling time and PSA velocity), before and 6 months after treatment initiation. RESULTS: After a median follow-up of 83.1 months, 49 of 146 men had died. In univariate Cox regression analysis, two factors were associated with OS: baseline PSA velocity and change in PSA velocity on therapy. In a landmark multivariable model, stratified by study (which controlled for age, Gleason score, type of local therapy and use of androgen-deprivation therapy prior to metastases), baseline PSA velocity and increase in PSA velocity on therapy remained independent predictors of OS. Median OS for men with an increase in PSA velocity on treatment was 115.4 months and was not reached for men with a decrease in PSA velocity (hazard ratio=0.47, 95% confidence interval 0.25-0.88; P=0.02). CONCLUSIONS: This hypothesis-generating study suggests that within-subject changes in PSA velocity after initiation of nonhormonal therapy may correlate with OS in men with BRPC. If validated in prospective trials, change in PSA velocity may represent a reasonable intermediate end point for screening new agents in these patients.

Differential effects of nitrogen mustard in vivo on the cancer and host cells in MCa-11 tumours.

We analysed the effects of nitrogen mustard (HN2) on the growth, cell cycle distributions, and ratios of tumour cells to host cells for MCa-11 tumours grown in vivo. Treatment of tumour-bearing BALB/c mice with 3 mg/kg of HN2 produced a significant slowing of MCa-11 tumour growth. Seventy-two hours after treatment in vivo with either 3 or 4 mg/kg of HN2, the host cells in the treated tumours showed a significantly decreased G0/G1 peak and an increased G2/M peak (P < 0.01), whereas the cancer cells in the treated tumours showed significant increases in the G0/G1 peak coupled with relatively decreased proportions of S and G2/M tumour cells (P < 0.001). The ratio of the total number of cancer cells to the total number of host cells in the tumours was significantly increased 72 h after HN2 administration (P < 0.01). Thirty-two days after treatment with HN2, the cell cycle distributions of the host and tumour cells in the treatment and control tumours had returned to being identical, but the ratio of the total number of cancer cells to the total number of host cells remained increased in the treated tumours (P < 0.01). These results show that the administration in vivo of HN2 can lead to entirely different cell cycle effects for the host and cancer cells in the same tumour, and that the partial growth arrest of MCa-11 tumours from HN2 treatment may be due in part to the preferential destruction of host cells rather than solely to a direct cytotoxic effect on the cancer cells.

Carcinoma of the major salivary glands treated by surgery or surgery plus postoperative radiotherapy.

From 1975 to 1987, 87 patients with carcinomas of the major salivary glands (70 parotid and 17 submandibular) were treated at our institution by either surgery or surgery followed by postoperative radiotherapy (RT). Surgical procedures included superficial (24%) or total (56%) parotidectomies and submandibular gland resection (20%). Postoperative RT usually began 2 to 4 weeks following surgery. Using 4 MV photons or, infrequently, 60Co, the majority of patients received 6000 cGy in 6 weeks to the parotid region (ranged from 4500 to 7000 cGy). Determinant actuarial survival was 74% at 5 years and 71% at 10 years. For patients with previously untreated disease, 5 of 19 (26%) treated by surgery alone experienced local recurrence, whereas only 2 of 50 (4%) recurred locally following surgery plus postoperative RT (p = 0.01). For patients presenting with recurrent disease, 4/4 (100%) failed locally following surgery as opposed to 3/14 (21%) following surgery plus postoperative RT (p = 0.01). The determinant 5-year actuarial survival for patients receiving postoperative RT was 75% versus 59% for surgery alone. Results were analyzed by multivariate methods using determinant survival or recurrence as endpoints. Five important prognostic factors were identified. (a) Facial nerve paresis was predictive of poor outcome (p less than 0.001) with 3-year relapse free survival of 13%. (b) Undifferentiated histology was associated with decreased survival (p = 0.002). (c) Male sex was associated with poor outcome (p = 0.008). (d) Skin invasion resulted in decreased survival (p = 0.012). (e) Radiotherapy was associated with improved survival (p = 0.014). In addition, postoperative RT was effective in preventing local recurrence (p less than 0.001). The data demonstrate the efficacy of postoperative RT in improving survival and local control for patients with carcinomas of the major salivary glands.

Early evaluation of abdominal/hepatic irradiation and 5-fluorouracil/leucovorin infusion after pancreaticoduodenectomy.

PURPOSE: To describe the toxicities of a combined modality adjuvant regimen for patients with resectable periampullary adenocarcinoma. METHODS AND MATERIALS: Fourteen patients with surgically resected periampullary adenocarcinoma were treated with adjuvant therapy consisting of prophylactic hepatic irradiation and pancreatic bed irradiation and concurrent infusional 5-fluorouracil and leucovorin (5-FU/LV). Starting within 60 days of surgery, patients received radiation treatments of 1.8 Gy per fraction to the liver and pancreatic bed (13 fractions), followed by 1.8 Gy per fraction to the pancreatic region (15 fractions). All radiation treatments were given with infusional 5-FU (200 mg/m2/day) and leucovorin (5 mg/m2/day) for 5 out of every 7 days during the 38-day treatment sequence. After a 1-month break, patients were scheduled to receive four cycles of infusional 5-FU/LV (2 weeks on/2 weeks off). RESULTS: All 14 patients completed the initial combination treatment. Toxicities were tolerable; three patients had Grade 3/4 toxicities that were primarily gastrointestinal in nature. Six patients required hospitalization during therapy for treatment-related toxicities. Two patients required radiation treatment breaks of less than 1 week, and two others had radiation held for 2-4 weeks. Three patients required chemotherapy dose reductions secondary to toxicities. Toxicities in the subsequent chemotherapy-alone cycles were few and primarily manifested by Grade 2 rises in liver injury tests. Higher toxicity grades were associated with tumor progression. Twelve patients have developed recurrent disease with an equal number of recurrences occurring in the pancreatic bed as in the liver over the 12-month median follow-up. Median survival for this cohort is 417 days, not significantly different from previously reported adjuvant trials in this patient population. CONCLUSION: These data indicate that adjuvant therapy with concomitant large-field radiation and infusional chemotherapy is feasible and associated with mangeable toxicities in patients undergoing pancreaticoduodenectomy for periampullary adenocarcinoma. Improvement in survival over other adjuvant regimens has not thus far been observed. Modification of this strategy may be required.

Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: survival results and observations regarding patterns of failure, radiotherapy dose and CA19-9 levels.

PURPOSE: Primary endpoints were 1. To determine if, in the context of postoperative adjuvant therapy of pancreatic and nonpancreatic periampullary adenocarcinoma, continuous infusion (C.I.) 5-fluorouracil (5-FU) and leucovorin (Lv), combined with continuous-course external-beam radiotherapy (EBRT) to liver (23.4-27.0 Gy), regional lymph nodes (50.4-54.0 Gy) and tumor bed (50.4-57.6 Gy), followed by 4 months of C.I. 5-FU/Lv without EBRT could be given with acceptable toxicity. 2. To determine an estimate of disease-free and overall survival (DFS, OS) with this treatment in this context. Secondary endpoints were 1. To observe the effects of therapy at two different dose levels of irradiation, and 2. To observe for correlations among DFS, OS and CA 19-9 levels during therapy. METHODS: Patients received C.I. 5-FU 200 mg/m2 and Lv 5 mg/m2 Monday through Friday during EBRT, and 4 cycles of the same chemotherapy without EBRT were planned for each 2 weeks of 4, beginning 1 month following the completion of EBRT. Therapy was to begin within 10 weeks of surgery and patients were monitored for disease recurrence, toxicity, and CA 19-9 levels before the start of EBRT/5-FU/Lv, before each cycle of C.I. 5-FU/Lv, and periodically after the completion of therapy. There were two EBRT dosage groups: Low EBRT, 23.4 Gy to the whole liver, 50.4 Gy to regional nodes and 50.4 Gy to the tumor bed; High EBRT, 27.0 Gy to the whole liver, 54.0 Gy to regional nodes, and 57.6 Gy to the tumor bed. RESULTS: 29 patients were enrolled and treated (23 with pancreatic cancer, and 6 with nonpancreatic periampullary cancer). Of these, 18 had tumor sizes > or = 3 cm and 23 had at least one histologically involved lymph node; 6 had histologically positive resection margins. Mean time to start of EBRT/5-FU/Lv was 53 +/- 2 days following surgery. The first 18 patients were in the Low EBRT Group and the last 11 in the High EBRT Group. Toxicity was moderate and manageable, including a possible case of late radiation hepatitis. Median DFS was 8.3 months (pancreatic cancer patients 8.5 months) and OS was 14.1 months (pancreatic cancer patients 15.9 months). Among patients with pancreatic cancer, results were similar for the Low and High EBRT Groups (DFS: 8.3 vs. 8.6 months; OS: 14.4 vs. 16.9 months, respectively). With a mean follow up of 2.6 +/- 0.3 years for the surviving patients and a minimal follow-up of 2.5 years, 27 of 29 pts have relapsed and 25 pts have died. A rise in CA 19-9 levels preceded clinical relapse by 9.1 +/- 1.5 months. Time to first relapse by site showed inverse correlation with dose of radiotherapy to that site: peritoneal (5 +/- 1 month), hepatic (7 +/- 0.9 months), regional nodes/tumor bed (9.6 +/- 1.8 months). Mean postresection CA 19-9 level was 63.3 +/- 16.2 U/ml. Postresection CA 19-9 values did not correlate with survival, margin status, or with the identification of metastatic carcinoma in resected lymph nodes. However, among patients with histologically involved nodes in the resected specimen, postresection CA 19-9 values did correlate with the number of positive nodes identified (p = 0.05). CONCLUSIONS: Although toxicity was acceptable, survival results were not improved over those seen with standard adjuvant treatment. Most patients relapsed before the planned chemotherapy cycles were completed, or within 100 days thereof, suggesting disease resistance to C.I. 5-FU/Lv as used in this study. Although this regimen is not recommended for further study, the doses of EBRT utilized may be suitable for evaluation with other chemotherapy combinations. Postoperative CA 19-9 levels did not correlate with survival, but did correlate with the number of histologically involved lymph nodes found in the resected specimen among node-positive patients. Moreover, rising CA 19-9 levels anticipated ultimate clinical failure by 9 months.

Digital imaging of black and white photomicrographs: impact of file size.

The publication of black and white photomicrographs has a long tradition in pathology. High-resolution film and quality objectives have been the backbone of generating quality photomicrographs suitable for publication. However, the digital imaging revolution has changed the way we view and capture images. As the quality of image capture devices increases and as their price decreases, more and more investigators are using digital imaging, and the use of color digital imaging for teleconferencing, telediagnosis, and reproduction is now well established. The purpose of this study was to determine the file sizes needed to obtain publication-quality black and white images using digital imaging technology. In this study, four experts in renal pathology reviewed 70 black and white images of various file sizes obtained from specimens representing a variety of renal histopathology. Without knowledge of the file size, the four renal pathologists graded the degree of pixelation, and the overall diagnostic and publication quality of the images. In all cases, digital imaging was capable of obtaining publication quality images equal to those achieved using film. The file size needed to achieve publication quality black and white images depended on magnification, with lower magnification images requiring larger file sizes.

Pathologic examination accurately predicts prognosis in mucinous cystic neoplasms of the pancreas.

The behavior of pancreatic mucinous cystic neoplasms has long been debated. Some authors contend that histologically benign neoplasms can recur and metastasize. We reviewed the gross and microscopic findings and outcomes of 61 mucinous cystic neoplasms diagnosed at The Johns Hopkins Hospital from March 20, 1984 to July 8, 1998. Each neoplasm was placed into one of four categories based on complete histologic examination: invasive mucinous cystadenocarcinoma, mucinous cystic neoplasm with in situ carcinoma, borderline mucinous cystic neoplasm, and mucinous cystadenoma. Neoplasms in the latter three categories were included only if they were entirely resected and completely examined. Patient outcomes were obtained from hospital records and patient and physician follow-up. Twenty (33%) of the patients had invasive mucinous cystadenocarcinomas, and they had 2- and 5-year disease-specific survival rates of 67% and 33% (mean follow-up of survivors, 4.2 years), respectively. Nine (15%) patients had mucinous cystic neoplasms with in situ carcinoma (mean follow-up of survivors, 4.1 years). Five (8.2%) patients had borderline mucinous cystic neoplasms (mean follow-up of survivors, 5.6 years). Twenty-seven (44%) patients had mucinous cystadenomas (mean follow-up of survivors, 5.1 years). No mucinous cystadenoma, borderline mucinous cystic neoplasm, or mucinous cystic neoplasm with in situ carcinoma recurred or metastasized. No patient with the diagnosis of mucinous cystadenoma, borderline mucinous cystic neoplasm, or mucinous cystic neoplasm with in situ carcinoma died of disease. The difference in disease-specific survival rates between patients with invasive mucinous cystadenocarcinomas and those with noninvasive tumors was significant (p < 0.0001, log-rank test). One case, originally showing only benign histology on incisional biopsy, contained foci of invasive carcinoma on complete resection. Completely resected and entirely examined mucinous cystadenomas, borderline mucinous cystic neoplasms, and mucinous cystic neoplasms with in situ carcinoma follow benign courses. Because invasive carcinoma can be focal, failure to study an entire mucinous cystic neoplasm may result in the miscategorization of a malignant neoplasm as benign.