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.

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.

Differences of chemoresistance assay between invasive micropapillary/low-grade serous ovarian carcinoma and high-grade serous ovarian carcinoma.

The objective of this study was to evaluate the pattern of chemoresistance in invasive micropapillary/low-grade serous ovarian carcinoma (invasive MPSC/LGSC) and high-grade serous ovarian carcinoma (HGSC) according to extreme drug resistance (EDR) assay testing. Surgical specimens of 44 recurrent ovarian cancer patients harvested at the time of cytoreductive surgery between August 1999 and February 2004 were identified retrospectively from the tumor registry database. Thirteen patients (29.5%) had recurrent invasive MPSC/LGSC and 31 (70.5%) patients had recurrent HGSC. Eight drugs were evaluated; EDR assay results were compared between LGSC and HGSC groups using Fisher exact tests and exact logistic regression models. Compared to HGSC, invasive MPSC/LGSC were more likely to manifest EDR to the drugs paclitaxel (69% vs 14%, P < 0.001), carboplatin (50% vs 17%, P= 0.05), cyclophosphamide (40% vs 23%, P= 0.41), gemcitabine (36% vs 19%, P= 0.40), and cisplatin (33% vs 28%, P= 0.72) and less likely to be resistant to etoposide (0% vs 44%, P= 0.007), doxorubicin (8% vs 45%, P= 0.03), and topotecan (8% vs 21%, P= 0.65). Exact logistic regression estimates revealed that invasive MPSC/LGSC patients had significantly increased probabilities of paclitaxel resistance odds ratio (OR) = 12.5 (95% CI: 2.3-100.0), P= 0.001 and carboplatin resistance OR = 4.8 (95% CI: 0.9-25.0), P= 0.07, while the HGSC cases were more likely to be resistant to etoposide OR = 12.1 (95% CI: 1.7-infinity), P=0.009 and doxorubicin OR = 8.6 (95% CI: 1.0-413.7), P= 0.05. In this retrospective analysis, patients with recurrent invasive MPSC/LGSC were more likely to manifest EDR to standard chemotherapy agents (platinum and paclitaxel). These observations may help to guide chemotherapeutic decision making in these patients if confirmed in a large-scale study.

FIGO stage IIIC endometrial carcinoma: resection of macroscopic nodal disease and other determinants of survival.

The objective of this study was to evaluate the potential survival benefit of debulking macroscopic adenopathy and other clinical prognostic factors among patients with node-positive endometrial carcinoma. Demographic, operative, pathologic, and follow-up data were abstracted retrospectively for 41 eligible patients with FIGO stage IIIC endometrial cancer. Survival curves were generated using the Kaplan-Meier method and statistical comparisons were performed using the log rank test, logistic regression analysis, and the Cox proportional hazards regression model. All patients had positive pelvic lymph nodes and 20 patients (48.8%) had positive para-aortic lymph nodes. Postoperatively, all patients received whole pelvic radiation therapy, 17 received extended-field radiation therapy, and 15 patients received chemotherapy. The median disease-specific survival (DSS) time for all patients was 30.6 months (median follow-up 34. 0 months). Patients with completely resected macroscopic lymphadenopathy had a significantly longer median DSS time (37.5 months), compared to patients left with gross residual nodal disease (8.8 months, P = 0.006). On multivariate analysis, independent predictors of DSS were gross residual nodal disease (HR 7.96, 95% CI 2.54-24.97, P < 0. 001), age > or = 65 years (HR 6.22, 95% CI 2.05-18.87, P = 0.001), and the administration of adjuvant chemotherapy (HR 0.22, 95% CI 0.07-0.76, P = 0.016). We conclude that in patients with stage IIIC endometrial carcinoma, complete resection of macroscopic nodal disease and the administration of adjuvant chemotherapy, in addition to directed radiation therapy, are associated with improved survival.

Endoscopic findings predict the histologic diagnosis in gastrointestinal graft-versus-host disease.

BACKGROUND AND STUDY AIMS: Graft-versus-host disease (GvHD) of the gastrointestinal tract is a major cause of morbidity and mortality after allogeneic bone marrow transplantation (BMT). Whether endoscopic findings predict the histologic diagnosis of GvHD in the gastrointestinal tract remains controversial. We performed a study to determine the diagnostic accuracy of macroscopic endoscopy findings in the diagnosis of acute and chronic histologically proven gastrointestinal GvHD (GI-GvHD). PATIENTS AND METHODS: Endoscopic images from the intestinal mucosa of post-BMT patients were blindly graded as positive or negative for GI-GvHD and compared with corresponding histological findings, which were used as the gold standard. RESULTS: 44 BMT patients were referred for 96 endoscopic evaluations. Using 162 endoscopy-biopsy pairs, a positive association between endoscopic grading and histologic grading of GI-GvHD (odds ratio [OR] = 11.97, 95% CI 3.86, 37.16) was observed. Endoscopic diagnosis correctly predicted histologic diagnosis in both acute and chronic GI-GvHD (OR = 9.3 vs. 23.1, P = 0.31). CONCLUSIONS: The diagnostic accuracy of endoscopy was high in both acute and chronic histologically proven GI-GvHD. Accurate diagnosis of GI-GvHD might be obtained with mucosal biopsies from either the upper or lower gastrointestinal tract. Endoscopy may play a significant role in establishing early diagnosis and treatment for GI-GvHD in patients following BMT, but histologic evaluation of the gastrointestinal mucosa is needed to confirm the final diagnosis.

Risk factors for post-stem cell transplant sinusitis.

An understanding of the factors that place the post-transplant patient at increased risk for sinusitis would help identify patients likely to develop disease and possibly allow for interventions that would decrease the incidence or severity of sinus disease. This retrospective study investigates the ability of screening paranasal sinus computed tomographic scans (CTs), clinical history, and potential risk factors for sinusitis, including history of tobacco use, history of allergies or asthma, IgG level, history of sinusitis, remission status and acute graft-versus-host disease (GVHD) to predict post-transplant sinusitis. Medical records and sinus CTs of 100 allogeneic bone marrow recipients were reviewed. There was no increased risk of developing sinusitis post SCT for patients with significant disease on screening CT, symptoms at time of transplant, a history of tobacco use, asthma or allergies, low IgG level, history of sinusitis or for patients at high risk of relapse. Patients with GVHD were 4.3 times more likely than patients without GVHD to develop sinusitis post transplant (95% CI: 1.7-11.0, P = 0.002). Acute GVHD places patients at greater risk of developing sinus infections.

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

Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: a follow-up study based on 138 cases from a diagnostic variability study.

The objective of endoscopic surveillance in Barrett esophagus (BE) is to assess the risk of subsequent development of invasive carcinoma. Criteria for morphologic evaluation of dysplasia, the presumed precursor lesion, have been established, although there are surprisingly few data in the literature correlating biopsy diagnosis of dysplasia with outcome. We collected follow-up information on 138 patients with BE whose initial endoscopic biopsy specimens had been selected for submission in an interobserver variability study performed by 12 pathologists with special interest in gastrointestinal pathology and reviewed blindly twice each by all the participants. Cases were scored as BE with no dysplasia, atypia indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), intramucosal carcinoma, and frankly invasive carcinoma, thus generating 24 scores on each biopsy specimen. Clinical follow-up was obtained and correlated with both the submitting diagnoses and majority diagnoses. Kaplan-Meier statistics were used to compare both the submitting and majority diagnoses with outcome using detection or documentation of invasive carcinoma as the endpoint. Using the submitting diagnoses, no invasive carcinomas were detected in 44 cases diagnosed as BE (median follow-up, 38.5 months). Carcinomas were detected in 4 of 22 (18%) cases submitted as IND (median progression-free survival of 62 months), in 4 of 25 (15%) cases of LGD (median progression-free survival of 60 months), in 20 of 33 cases of HGD (median progression-free survival, 8 months), and all 13 (100%) cases submitted as adenocarcinoma. Grade on initial biopsy correlated significantly with progression to invasive carcinoma (log-rank P =.0001). Majority diagnosis was achieved in 99 of the cases. Using the majority diagnoses, no invasive carcinomas were found in 50 cases of BE (median follow-up, 48 months), and carcinomas were detected in 1 of 7 (14%) IND cases (80% progression-free survival at 2 months), 3 of 15 (20%) LGD (median progression-free survival, 60 months), 9 of 15 (60%) HGD (median progression-free survival, 7 months), and all 12 (100%) carcinoma. Initial grading again correlated significantly with progression to invasive carcinoma (log-rank P =.0001). However, there were 39 cases without a majority diagnosis. Among these, no carcinomas developed in 8 cases with an average score between BE and IND. Carcinomas were detected in 9 of 21 (43%) cases with an average score between IND and LGD, and 7 of 10 (70%) cases with an average score between LGD and HGD. There were ulcers in 8 of 39 cases (20%) of the "no-majority" group and in 13 of 99 (13%) of the majority cases. Of 21 total ulcerated cases, cancer was demonstrated in 15 (71%) of these on follow-up. These data support combining the IND and LGD categories for surveillance purposes. Cases without dysplasia may be followed up conservatively. The data obtained from submitted diagnoses as opposed to those from blind review suggest that knowledge of the clinical findings aids in diagnosis. The data also support the assertion that HGD is strongly associated with invasive carcinoma. Rebiopsy of ulcerated areas should be considered because they may harbor malignancy. Histologic grading of dysplasia using established criteria is a powerful prognosticator in BE. HUM PATHOL 32:379-388.

Serum acid phosphatase level and biochemical recurrence following radical prostatectomy for men with clinically localized prostate cancer.

OBJECTIVES: Serum acid phosphatase (ACP) was once used as the marker for advanced prostate cancer. However, with the development of assays for prostate-specific antigen (PSA), a more sensitive and specific tumor marker, the use of ACP has diminished. We investigated the prognostic value of preoperative serum ACP in predicting prognosis for men with localized prostate cancer following radical retropubic prostatectomy (RRP). METHODS: Of 2293 men treated from 1982 to 1998, 1681 men had a preoperative ACP measurement using an enzymatic assay. We analyzed the actuarial freedom from biochemical (PSA) progression following RRP according to ACP levels. We used multivariate logistic regression and proportional hazards models to determine the independent prognostic value of ACP level with respect of pathologic stage and biochemical recurrence. RESULTS: ACP was not an independent predictor of organ confinement or lymph node involvement in the multivariate logistic regression models using preoperative variables. However, in the proportional hazards model, ACP was an independent predictor of tumor recurrence following RRP, and there was a statistically significant improvement in biochemical recurrence-free survival for men with lower levels of ACP (P <0.001). Furthermore, the normalized hazard ratios of ACP and PSA for predicting biochemical recurrence were similar. CONCLUSIONS: Stratification of men according to their preoperative ACP levels was predictive of patient outcome after RRP. Proportional hazards modeling using preoperative variables demonstrated that the serum ACP level is an independent predictor of tumor recurrence following RRP.

Development of a prognostic model for grading chronic graft-versus-host disease.

The disease-specific survival (DSS) of 151 patients with chronic graft-versus-host disease (cGVHD) was studied in an attempt to stratify patients into risk groups and to form a basis for a new grading of cGVHD. The data included the outcome and 23 variables at the diagnosis of cGVHD and at the primary treatment failure (PTF). Eighty-nine patients (58%) failed primary therapy for cGVHD. Nonrelapse mortality was 44% after a median follow-up of 7.8 years. The probability of DSS at 10 years after diagnosis of cGVHD (DSS1) and after PTF (DSS2) was 51% (95% confidence interval [CI] = 39%, 60%) and 38% (95% CI = 28%, 49%), respectively. According to multivariate analysis, extensive skin involvement (ESI) more than 50% of body surface area; hazard ratio (HR) of 7.0 (95% CI = 3.6-13.4), thrombocytopenia (TP) (< 100 000/microL; HR, 3.6; 95% CI = 1.9-6.8), and progressive-type onset (PTO) (HR, 1.7; 95% CI = 0.9-3.0) significantly influenced DSS1. These 3 factors and Karnofsky Performance Score of less than 50% at PTF were significant predictors for DSS2. The DSS1 at 10 years for patients with prognostic factor score (PFS) at diagnosis of 0 (none), 1.9 and below [corrected] (ESI only or TP and/or PTO), above 1.9 and not above 3.5 [corrected] (ESI plus either TP or PTO), and more than 3.5 (all 3 factors) was 82%, 68%, 34%, and 3% (P =.05, <.001, <.001), respectively. The DSS2 at 5 years for patients with PFS at PTF of 0, 2 or less, 2 to 3.5, and more than 3.5 were 91%, 71%, 22%, and 4% (P =.2,.005, and <.001), respectively. It was concluded that these prognostic models might be useful in grouping the patients with similar outcome.

The prognostic value of tumor markers in patients with glioblastoma multiforme: analysis of 32 patients and review of the literature.

Although several studies have examined brain tumor markers for prognostic value, few investigations have stratified analysis based on specific histologic grade. The objective of this study was to evaluate a single histologic grade of glioma, the grade IV glioma or glioblastoma (World Health Organization Classification), with a comprehensive panel of tumor markers in an attempt to identify those with prognostic significance. Tumor samples from a cohort of patients with glioblastoma multiforme (n = 32) were examined for tumor markers, DNA analysis, and clinical variables in an attempt to determine a 'profile' for this tumor. We used univariate and multivariate statistical analysis to determine the prognostic value of tumor cell ploidy, percent S-phase, DNA index, p53, and Ki-67 labeling index, as well as the variables of gender, race, age, location of tumor, history of chemotherapy, and primary versus recurrent tumor. Two additional tumor markers, multidrug resistance gene 1 and glutathione-S-transferase subtype pi, were included in the sample testing, but were not analyzed statistically. Univariate analysis indicated that increasing age had a strong association with decreased survival. Female gender, increasing Ki-67, no chemotherapy before sample collection, and primary glioblastoma showed some association with decreased survival in the univariate model. The univariate results indicated that race, side of tumor, ploidy, S-phase, DNA index, and p53 had no prognostic value. Multivariate modeling demonstrated that age, gender, and Ki-67 were the strongest factors associated with survival. The relevant literature is reviewed.

Allogeneic bone marrow transplantation in patients with sensitive low-grade lymphoma or mantle cell lymphoma.

PURPOSE: To report survival outcomes of allogeneic BMT in patients with low-grade lymphoma or mantle cell lymphoma (MCL). PATIENTS AND METHODS: Thirty-five patients with low-grade lymphoma (48%), chronic lymphocytic leukemia (26%), or MCL (26%) underwent myeloablative allogeneic BMT from HLA-identical siblings at the Johns Hopkins Oncology Center. Patients had a median age of 46 years, a median of 2 prior treatments, and 31% were in complete remission at the time of transplantation. The preparative regimen was cyclophosphamide/total body irradiation for most patients. All grafts were T-cell depleted by counter flow centrifugal elutriation with CD34+ augmentation. RESULTS: The incidence of acute GVHD grade >2 was 6% and of grades 1 to 2 was 37%. The incidence of chronic GVHD was 6%. The median follow-up time was 25 months. The rate of event-free survival (EFS) was 50% (95% confidence interval [CI], 33%-66%). Only 1 patient relapsed. The transplantation-related mortality (TRM) was 46% for all patients. The TRM was 86% for patients with resistant disease and 14% for patients with sensitive disease and <2 prior treatments; rates of EFS were 0% (95% CI, 0%-0%) and 79% (95% CI, 47%-93%), respectively. CONCLUSION: These data show that, with T-cell depletion, the TRM and relapse rates are modest for patients with sensitive disease and <2 prior treatment courses. Thus, if there is a role for allogeneic BMT in the management of patients with these tumors, it is early in the course of the disease.

Colonization by Streptococcus penumoniae in human immunodeficiency virus-infected children.

OBJECTIVE: Children with HIV infection are particularly susceptible to invasive pneumococcal disease, yet the effect of HIV infection and its medical management on colonization and resistance to antibiotics are poorly described. To provide a basis for medical practice, we determined the prevalence of nasopharyngeal colonization and antibiotic resistance of Streptococcus pneumoniae in children with HIV infection. METHODS: Cross-sectional prevalence sample of children attending the pediatric HIV and pulmonary clinics to examine nasopharyngeal colonization with S. pneumoniae and antibiotic resistance to beta-lactams and trimethoprim-sulfamethoxazole (T/S). Subjects were matched by age and date of clinic visit. RESULTS: The colonization rate with S. pneumoniae of HIV-infected and -indeterminate children was equal to that of controls (20% vs. 19%). HIV infection, CDC staging or receipt of oral antibiotic therapy did not affect colonization. Isolates from HIV-infected and -indeterminate children were less likely to be penicillin-resistant than those from controls (18% vs. 50%). There was no difference in pneumococcal resistance to T/S among isolates from subjects and controls, despite 72% T/S use in the HIV clinic. CONCLUSION: Colonization with S. pneumoniae in HIV disease is no different from that of comparable children. The high incidence of pneumococcal disease and prophylaxis with T/S are not related to nasopharyngeal colonization. Antibiotic prophylaxis of HIV-infected children does not necessarily lead to increased resistance of S. pneumoniae.

Esthesioneuroblastoma: the Johns Hopkins experience.

BACKGROUND: Esthesioneuroblastoma (ENB) is an uncommon malignant neoplasm of the upper nasal cavity. Therapeutic management approaches for this neoplasm lack uniformity and there is no universally accepted staging system. METHODS: A retrospective review of 27 patients with histologically confirmed ENB managed at The Johns Hopkins Hospital. RESULTS: Eighty-five percent of patients had surgical resection as part of their disease management. Complete surgical resection was achieved in 62% of patients who had a craniofacial resection. Eighty percent of patients with negative surgical margins remain with no evidence of disease, with a median follow-up of 5.6 years. Adjuvant radiation therapy was beneficial to 62% of patients with positive surgical margins. Clinical responses were observed with cisplatin- and etoposide-containing chemotherapy regimens in patients with advanced disease. A revised staging system based on our experience is proposed. CONCLUSIONS: ENB is best managed by craniofacial resection with complete tumor resection. Adjuvant radiation therapy is warranted in patients that remain with positive histologic margins of resection. Chemotherapy with cisplatin- and etoposide-containing regimens may be useful for palliation of advanced disease.

Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity.

Medullary carcinomas of the pancreas are a recently described, histologically distinct subset of poorly differentiated adenocarcinomas that may have a unique pathogenesis and clinical course. To further evaluate these neoplasms, we studied genetic, pathological, and clinical features of 13 newly identified medullary carcinomas of the pancreas. Nine (69%) of these had wild-type K-ras genes, and one had microsatellite instability (MSI). This MSI medullary carcinoma, along with three previously reported MSI medullary carcinomas, were examined immunohistochemically for Mlh1 and Msh2 expression, and all four expressed Msh2 but did not express Mlh1. In contrast, all of the medullary carcinomas without MSI expressed both Msh2 and Mlh1. Remarkably, the MSI medullary carcinoma of the pancreas in the present series arose in a patient with a synchronous but histologically distinct cecal carcinoma that also had MSI and did not express Mlh1. The synchronous occurrence of two MSI carcinomas suggests an inherited basis for the development of these carcinomas. Indeed, the medullary phenotype, irrespective of MSI, was highly associated with a family history of cancer in first-degree relatives (P < 0.001). Finally, one medullary carcinoma with lymphoepithelioma-like features contained Epstein-Barr virus-encoded RNA-1 by in situ hybridization. Therefore, because of medullary carcinoma's special genetic, immunohistochemical, and clinical features, recognition of the medullary variant of pancreatic adenocarcinoma is important. Only by classifying medullary carcinoma as special subset of adenocarcinoma can we hope to further elucidate its unique pathogenesis.

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.

Neoadjuvant chemoradiation followed by surgery for resectable esophageal cancer.

Neoadjuvant chemoradiation (NAC) therapy protocols were developed to improve survival in patients with resectable esophageal cancer. Our experience with two consecutive NAC therapy trials is reviewed. Both studies included patients with localized squamous cell cancer and adenocarcinoma. Patients were treated with cisplatinum 26 mg/m2/day (days 1-5 and 26-30), 5-Fluorouracil (5-FU) 300 mg/m2/day (days 1-30), concurrent radiotherapy (4400 cGy) followed by esophagectomy. In the second trial, adjuvant taxol was added. The first protocol had 50 patients. Two patients died, both before surgery, one from sepsis. There was no residual viable tumor (CR) in 19 (40%) patients. The median survival time was 31 months. The 5-year survival rate of 36% compared favorably with concurrent 5-year survival of 18% for surgery alone. Forty-one patients were enrolled in the second trial. All underwent surgery. There were no treatment or operative deaths. Survival data for this group is maturing. Combined results from both protocols are: treatment mortality of 2.2%, complete response rate of 37%, and a median and 3-year disease-specific survival of 42 months and 54%, respectively. We conclude that NAC followed by surgery improves survival over surgery alone and that CR is predictive of improved survival.

Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia.

OBJECTIVES: To determine whether patients with ataxia-telangiectasia exhibit oropharyngeal dysphagia with concomitant aspiration and to examine the relationships among swallowing function, age, and nutritional status. STUDY DESIGN: Seventy patients (mean age, 10.7 years; range, 1.8 to 30 years) had feeding/swallowing and nutritional evaluations. Fifty-one patients, in whom there were concerns about swallowing safety, were examined with a standardized videofluoroscopic swallow study. RESULTS: Fourteen of the 51 patients (27%) with histories suggestive of dysphagia demonstrated aspiration. Of these, silent aspiration (aspiration without a cough) occurred in 10 (71%) patients. Aspirators were significantly older than non-aspirators (mean age, 16.9 vs 10.8 years; P =.002). Advancing age was the strongest factor associated with aspiration during continuous drinking (P =.01). In patients with ataxia-telangiectasia, weight and weight/height were abnormally low at all ages and most compromised in older patients. Patients who aspirated had significantly lower mean weight (P <.002) and weight/height z scores (P <.001) than did patients who did not aspirate. CONCLUSIONS: Oropharyngeal dysphagia is common and appears to be progressive in patients with ataxia-telangiectasia. Older patients also have a higher incidence of poorer nutritional status. The relationship between dysphagia and nutritional status deserves further investigation.

Rectal epithelial apoptosis in familial adenomatous polyposis patients treated with sulindac.

BACKGROUND: Sulindac regresses colorectal adenomas in patients with familial adenomatous polyposis (FAP), although the mechanism of polyp regression is unclear. AIMS: To determine whether differences occur in alteration of rectal epithelial apoptotic index and expression of apoptosis related proteins in FAP patients treated with sulindac compared with placebo. PATIENTS: Twenty one FAP patients; 12 had not undergone colectomy. METHODS: Patients with FAP were treated with sulindac 150 mg orally twice a day for three months (n=10) or placebo (n=11). Colorectal polyp number was determined and biopsies of the normal rectal mucosa were performed before and after three months of treatment. Response to treatment and alteration of the apoptotic ratio (index in base of crypt divided by index in surface epithelium) were evaluated. Bcl-2, bax, p21/WAF-1, and p53 proteins were assessed semiquantitatively by immunohistochemistry. RESULTS: Significant decreases in polyp number and in the apoptotic ratio were seen in patients treated with sulindac compared with controls. The mean percentage change in polyp number from baseline was -46% in the sulindac group and +13% in the placebo group (p=0.005). Mean percentage change in the apoptotic ratio was -8% and +25% in the sulindac and placebo treated patients, respectively (p=0.004). No differences in expression or compartmentalisation of apoptosis related proteins were noted between treatment groups. CONCLUSIONS: Sulindac regression of colorectal adenomas is accompanied by alteration of the rectal epithelial apoptotic ratio with relative increase in apoptosis in surface cells compared with the deeper crypt. The utility of the apoptotic ratio as an intermediate biomarker for colorectal tumorigenesis deserves further study.

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.