Helicobacter pylori Status May Differentiate Two Distinct Pathways of Gastric Adenocarcinoma Carcinogenesis.

BACKGROUND: We evaluated the phenotype of sporadic gastric cancer based on HP status and binding of a tumor risk marker monoclonal, Adnab-9. METHODS: We compared a familial GC kindred with an extremely aggressive phenotype to HP-positive (HP+) and -negative (HP-) sporadic gastric adenocarcinoma (GC) patients in the same community to determine if similar phenotypes exist. This might facilitate gene discovery to understand the pathogenesis of aggressive GC phenotypes, particularly with publications implicating immune-related gene-based signatures, and the development of techniques to gauge the stance of the innate immune system (InImS), such as the FERAD ratio (blood ferritin:fecal Adnab-9 binding OD-background binding). Resection specimens for the sporadic and familial group were stained for HP and examined for intestinal metaplasia (IM) and immunostaining for Adnab-9. Familial kindred specimens were also tested for the E-cadherin mutation and APC (adenomatous polyposis coli). Survival was evaluated. RESULTS: Of 40 GC patients, 25% were HP+ with a greater proportion of intestinal metaplasia (IM) and gastric atrophy than the HP- group. The proband of the familial GC kindred, a 32-year-old mother with fatal GC, was survived by 13-year-old identical twins. Twin #1 was HP- with IM and Twin #2 was HP+. Both twins subsequently died of GC within two years. The twins did not have APC or E-cadherin mutations. The mean overall survival in the HP+ sporadic GC group was 2.47 ± 2.58 years and was 0.57 ± 0.60 years in the HP- group (p = 0.01). Survival in the kindred was 0.22 ± 0.24 years. Adnab-9 labeling was positive in fixed tissues of 50% of non-familial GC patients and in gastric tissue extract from Twin #2. The FERAD ratio was determined separately in six prospectively followed patient groups (n = 458) and was significantly lower in the gastric cancer patients (n = 10) and patients with stomach conditions predisposing them to GC (n = 214), compared to controls (n = 234 patients at increased risk for colorectal cancer but without cancer), suggesting a failure of the InImS. CONCLUSION: The HP+ sporadic GC group appears to proceed through a sequence of HP infection, IM and atrophy before cancer supervenes, and the HP- phenotype appear to omit this sequence. The familial cases may represent a subset with both features, but the natural history strongly resembles that of the HP- group. Two different paths of carcinogenesis may exist locally for sporadic GC. The InImS may also be implicated in prognosis. Identifying these patients will allow for treatment stratification and early diagnosis to improve GC survival.

Pregnancy outcomes in female childhood and adolescent cancer survivors: a linked cancer-birth registry analysis.

OBJECTIVE: To compare birth outcomes among female survivors of childhood and adolescent cancer who subsequently bear children, relative to those of women without a history of cancer. DESIGN: Retrospective cohort study. SETTING: Four US regions. PARTICIPANTS: Cancer registries identified girls younger than 20 years who were diagnosed as having cancer from 1973 through 2000. Linked birth records identified the first live births after diagnosis (n = 1898). Comparison subjects were selected from birth records (n = 14 278). Survivors of genital tract carcinomas underwent separate analysis. MAIN EXPOSURE: Cancer diagnosis at younger than 20 years. MAIN OUTCOME MEASURES: Infant low birth weight, preterm delivery, sex ratio, malformations, mortality, and delivery method, and maternal diabetes, anemia, and preeclampsia. RESULTS: Infants born to childhood cancer survivors were more likely to be preterm (relative risk [RR], 1.54; 95% confidence interval [CI], 1.30-1.83) and to weigh less than 2500 g (1.31; 1.10-1.57). For the offspring of genital tract carcinoma survivors, RRs were 1.33 (95% CI, 1.13-1.56) and 1.29 (1.10-1.53), respectively. There were no increased risks of malformations, infant death, or altered sex ratio, suggesting no increased germ cell mutagenicity. In exploratory analysis, bone cancer survivors had an increased risk of diabetes (RR, 4.92; 95% CI, 1.60-15.13), and anemia was more common among brain tumor survivors (3.05; 1.16-7.98) and childhood cancer survivors whose initial treatment was chemotherapy only (2.45; 1.16-5.17). CONCLUSIONS: Infants born to female survivors of childhood and adolescent cancer were not at increased risk of malformations or death. Increased occurrence of preterm delivery and low birth weight suggest that close monitoring is warranted. Increased diabetes and anemia among subgroups have not been reported, suggesting areas for study.

Reproductive outcomes in male childhood cancer survivors: a linked cancer-birth registry analysis.

OBJECTIVE: To compare the risk of reproductive and infant outcomes between male childhood cancer survivors and a population-based comparison group. DESIGN: Retrospective cohort study. SETTING: Four US regions. PARTICIPANTS: Cancer registries identified males younger than 20 years diagnosed with cancer from 1973 to 2000. Linked birth certificates identified first subsequent live offspring (N = 470). Comparison subjects were identified from remaining birth certificates, frequency-matched on year and age at fatherhood, and race/ethnicity (N = 4150). MAIN EXPOSURE: Cancer diagnosis before age 20 years. OUTCOME MEASURES: Pregnancy and infant outcomes identified from birth certificates. RESULTS: Compared with infants born to unaffected males, offspring of cancer survivors had a borderline risk of having a birth weight less than 2500 g (relative risk, 1.43 [95% confidence interval, 0.99-2.05]) that was associated most strongly with younger age at cancer diagnosis and exposure to any chemotherapy (1.96 [1.22-3.17]) or radiotherapy (1.95 [1.14-3.35]). However, they were not at risk of being born prematurely, being small for gestational age, having malformations, or having an altered male to female ratio. Overall, female partners of male survivors were not more likely to have maternal complications recorded on birth records vs the comparison group. However, preeclampsia was associated with some cancers, especially central nervous system tumors (relative risk, 3.36 [95% confidence interval, 1.63-6.90]). CONCLUSIONS: Most pregnancies resulting in live births among partners of male childhood cancer survivors were not at significantly greater risk of complications vs comparison subjects. However, there remains the possibility that prior cancer therapy may affect male germ cells with some effects on progeny and on female partners.

Epidemiologic findings of cancer detected in a pediatric emergency department.

This study describes epidemiologic findings of pediatric cancer diagnosed in the emergency department (ED) setting. Medical records are retrospectively reviewed on all patients in the hospital's cancer database between 2000 and 2004 who were diagnosed as having cancer or whose oncologic diagnosis was missed during their ED presentation. Of 427 patients identified in the cancer database, 18% (77 of 427) are analyzed. Oncologic diagnosis was missed in 5% (4 of 77) of the eligible patients initially presenting to the ED. The incidence of cancer in the ED is 22.8 cases per 100,000 ED visits. The most prevalent cancer is related to the hematologic system (37.7%), followed by the central nervous system (31.2%) and the abdomen (22.1%). Hematologic, central nervous system, and abdominal cancers constitute approximately 90% of all childhood cancers. Cancer is diagnosed frequently in our ED patient population. Based on the prevalence of certain tumors, the diagnostic approach to children with hematologic, neurologic, or abdominal complaints should include evaluation for any underlying cancer.

Histologic alterations from neoadjuvant chemotherapy in high-grade extremity soft tissue sarcoma: clinicopathological correlation.

Histologic response to chemotherapy is generally regarded as an independent prognostic variable in bone sarcomas, both osteosarcoma and Ewing's sarcoma. In soft tissue sarcomas, however, descriptions of histologic alterations from chemotherapy and correlative outcome studies are much more limited. Herein we report clinicopathological findings from a homogeneously treated group of 31 patients with tumor stage T2 grade 3 extremity soft tissue sarcomas treated with the same neoadjuvant chemotherapy followed by surgical excision, treated by the same medical oncologist and orthopedic surgeon. Histologic response to therapy was evaluated by multiple parameters using a semiquantitative grading system. Based upon the percentage of post-treatment viable tumor, tumors were arbitrarily categorized similarly to Huvos score as showing excellent (< or =5% viability), moderate (6%-49% viability), or poor (> or =50% viability) responses. Nineteen percent had excellent, 10% had moderate, and 71% had poor responses. These histologic response groups did not correlate with overall or event-free survival. For example, of the 22 patients showing a "poor" response, 13 were cured. Similarly, other histologic parameters, including percentages of necrosis, fibrosis/hyalinization, and cellular degeneration, did not correlate with outcome. Chemotherapy induces profound tissue alterations in soft tissue sarcomas. However, histologic alteration by itself may not be a reliable prognostic variable. Correlation of all data from clinical, imaging, and pathological observations by a multidisciplinary tumor board should have greater prognostic value than histology alone. Finally, although the histologic grading system used in this study could not be validated, the criteria we employed are simple and reproducible and take into account the major histologic patterns seen after therapy, and would be amenable for use in future studies.

Bilateral risk for subsequent breast cancer after lobular carcinoma-in-situ: analysis of surveillance, epidemiology, and end results data.

PURPOSE: Noninvasive lesions involving the lobules of the breast are increasingly diagnosed as incidental microscopic findings at the time of lumpectomy or core-needle biopsy. We investigated the incidence rates of invasive breast cancer (IBC) after a diagnosis of lobular carcinoma-in-situ (LCIS) by using Surveillance, Epidemiology, and End Results (SEER) data. PATIENTS AND METHODS: Patients (N = 4,853) having a diagnosis of primary LCIS in the time period of 1973 to 1998 were identified using the SEER Public Use CD-ROM data. The database was then searched for patients with subsequent primary IBC occurrences (n = 350). The clinical and pathologic characteristics of patients with subsequent primary IBCs were compared with the characteristics of patients with primary IBCs attained during the same time period (N = 255,114). RESULTS: The incidence of IBC increased over time from diagnosis of LCIS, with 7.1% +/- 0.5% incidence of IBC at 10 years. IBCs detected after partial mastectomy occurred in either breast (46% ipsilateral and 54% contralateral); however, after mastectomy, most IBCs were contralateral (94.7%). IBCs occurring after LCIS more often represented invasive lobular histology (23.1%) compared with primary IBCs (6.5%). The standardized incidence ratio (the ratio of observed to expected cases) for developing IBC was 2.4 (95% CI, 2.1 to 2.6) adjusted for age and year of diagnosis. CONCLUSION: LCIS is associated with increased risk of subsequent invasive disease, with equal predisposition in either breast. The minimum risk of developing IBC after LCIS is 7.1% at 10 years.

Evaluation of cytotoxicity by flow cytometric drug sensitivity assay in childhood T-cell acute lymphoblastic leukemia.

Risk-based treatment strategies have improved outcome in childhood B-precursor acute lymphoblastic leukemia, and in vitro drug sensitivity assessment using methyl-thiazol-tetrazolium (MTT) assay has been shown to be an independent prognostic marker. To date, such strategies in childhood T-cell acute lymphoblastic leukemia (T-ALL) have proved elusive, and in vitro drug sensitivity testing has had limited success in T-ALL due to poor T-cell lymphoblast survival in vitro. We have developed the flow cytometric drug sensitivity assay (FCDSA) to evaluate in vitro drug sensitivity. We studied 68 cases of childhood T-ALL for cytarabine (Ara-C) and daunorubicin sensitivity by FCDSA and compared the results with those obtained by MTT assay. Spontaneous apoptosis was correlated with cytotoxicity rates for both drugs by FCDSA, but not with the results obtained by MTT assay. Daunorubicin sensitivity had a positive correlation with Ara-C in individual cases by FCDSA; but not by MTT assay. Studies repeated on stored samples had comparable results for both drugs by FCDSA (P<0.01), but not for Ara-C by MTT assay. Comparison of T-ALL sensitivity with acute myeloid leukemia (AML) cases revealed a unique pattern difference. Median cytotoxicity (expressed in arbitrary units) for Ara-C was 8 (0-47) and 27 (0-81), and daunorubicine cytotoxicity for T-ALL and AML samples was 79 (5-100) and 34 (0-98), respectively. Although age or white blood cell count at diagnosis was not associated with any particular drug response pattern, CD13 expression on T-lymphoblasts was associated with in vitro resistance. FCDSA is a reliable, practical and reproducible method that can be integrated into studies of drug-target cell interactions in T-ALL.

Pediatric brain tumors in non-Hispanics, Hispanics, African Americans and Asians: differences in survival after diagnosis.

BACKGROUND: Racial differences in survival for children with brain tumors have not been well studied, particularly in Hispanics and Asians. The objective of this study was to assess racial differences in survival of children with brain tumors, focusing on Hispanics, African Americans and Asians compared to Non-Hispanics. METHODS: Subjects identified through the SEER Program were 2799 children, < or =19 years old at diagnosis, newly diagnosed between 1973 and 1996 with primary, malignant brain tumors. Chi-square tests were used to evaluate prognostic variables by race. Kaplan-Meier models and Cox proportional hazards models were used to assess racial differences in overall survival and in survival by histological type of tumor. RESULTS: The distribution histological type of tumor varied significantly by race. Overall survival was similar for Hispanics, African Americans, Asians compared to Non-Hispanics, although trends of increased risk of death for the minority groups were noted when stratifying by histological type of tumor. CONCLUSIONS: Racial differences in survival could exist by histological type of tumor, but further work is necessary for a more complete understanding of these differences.

Second malignant neoplasms after primary central nervous system malignancies of childhood and adolescence.

The standardized incidence ratios (SIR) and cumulative incidence rates were determined for developing second malignant neoplasms (SMNs) after primary central nervous system (CNS) malignancies occurring during childhood using registry data. A total of 4553 cases of primary CNS malignancies were identified. Forty-six cases developed SMNs, 19 occurring in a previously radiated field. The SIRs of developing second malignant neoplasms were 6.3 and 3.1 for those cases receiving and not receiving radiation therapy, respectively. The 20-year cumulative incidences for developing SMNs were 3.3 and 1.2% for cases receiving and not receiving radiation therapy, respectively. Children surviving CNS malignancies have an increased susceptibility for SMNs.

c-Kit expression in desmoid fibromatosis. Comparative immunohistochemical evaluation of two commercial antibodies.

To determine the frequency of c-Kit staining in desmoids and optimize an assay for clinical use, we stained 19 desmoids from various sites at various dilutions with 2 commonly used rabbit polyclonal, anti-c-Kit antibodies (A4502, DAKO, Carpinteria, CA; C-19, Santa Cruz Biotechnology, Santa Cruz, CA), with and without heat-induced epitope retrieval (HIER) in citrate buffer. Approdpriate external and internal control samples were evaluated for each test condition. At dilutions of 1:50 both antibodies stained substantial numbers of desmoids: with/without HIER, A4502, 89%/63%; C-19, 37%/74%. The staining was cytoplasmic without cell membrane accentuation. However, background stromal staining and nonspecific staining of endothelium and smooth and striated muscle were problematic with both antibodies at 1:50. At higher dilutions, C-19 stained no desmoid; however, diminished staining of external and internal control samples made it unreliable. A4502 similarly stained many fewer desmoids at higher dilutions. However, it retained strong staining of both external and internal control samples and showed much less nonspecific staining. Best results were achieved at 1:250 without HIER; only weak focal staining was present in 1 desmoid. With a simple immunohistochemical method optimized for clinical use, desmoid can be regarded as a c-Kit-negative tumor.

t(5;9)(q11;q34): a novel familial translocation involving Abelson oncogene and association with hypereosinophilia.

A 6-year-old girl with hypereosinophilia was found to have a familial constitutional translocation t(5;9)(q11;q34). Flow cytometry and gene rearrangement studies did not show any clonal T-helper cell proliferation. Presence of cryptic Philadelphia translocation was ruled out by reverse transcription polymerase chain reaction. Abelson oncogene translocation on chromosome 5 was confirmed by fluorescent in situ hybridization. This is the first example of a familial translocation involving the abelson oncogene and association with hypereosinophilia. The authors discuss a novel mechanism of hypereosinophilia involving the hybrid product of the abelson oncogene with an unknown partner gene on chromosome 5 (probably granzyme-A).

Osteosarcoma as a second malignant neoplasm.

PURPOSE: The aim of this study is to compare primary and secondary osteosarcomas using data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program. METHODS: Osteosarcoma cases were identified in the SEER Cancer Incidence Public-Use Database, 1973-96 (1,511 primary and 133 secondary osteosarcomas). Secondary osteosarcomas were further classified as occurring within or outside the previously irradiated field. Comparisons among groups were performed by nominal logistic regression. Survival analyses were performed using Kaplan-Meir and proportional hazards regression. RESULTS: Secondary osteosarcomas were more likely to have a non-extremity primary site and an older age at diagnosis (>40 years) (<0.0001 for both). Secondary osteosarcoma cases continued to be more likely to have a non-extremity site when excluding those occurring within the radiation field. Five-year overall survival was 50% lower for secondary osteosarcomas for both extremity and non-extremity sites. Primary malignancies associated with secondary osteosarcomas included 14 lymphomas/leukemias, six sarcomas, 54 carcinomas, and seven other cancers. Secondary osteosarcomas occurring within a field of radiation were more likely to occur at a younger age, have a malignancy with a primary morphology other than carcinoma, a non-limb site, and a longer duration between their primary malignant neoplasms and the development of osteosarcoma. No difference in the overall survival was noted between secondary osteosarcomas occurring within an irradiated field and those that did not. CONCLUSIONS: Secondary osteosarcomas are associated with carcinomas especially in the elderly. Although a 50% decreased 5-year survival was observed for secondary osteosarcomas in this study, this might not reflect the current outcomes with more aggressive therapy.

Cutaneous melanoma in childhood and adolescence.

Using population-based data from the Surveillance Epidemiology and End Results Program of the National Cancer Institute, melanoma occurring during childhood was evaluated. Compared to adult cases of melanoma, childhood cases had a higher proportion of females (61%) and non-Caucasians (6.5%). The incidence of melanoma increased 85% among 15- to 19-year-olds from 1973 to 1996. Incidence for 15- to 19-year-olds was higher in southern (23.9/million) than northern registries (14.5/million). Non-Caucasians had 3-30% of the cases expected compared to Caucasians. Overall survival of children/adolescents with melanoma was 89% and 79% at 5 and 20 years postdiagnosis, respectively. The majority of deaths were directly attributed to melanoma (72%).

Sarcoma as a second malignancy after treatment for breast cancer.

BACKGROUND: Second malignant neoplasms may be a consequence of radiotherapy for the treatment of breast cancer. Prior studies evaluating sarcomas as second malignant neoplasms in breast cancer patients have been limited by the numbers of patients and relatively low incidence of sarcoma. Using data from the Surveillance, Epidemiology and End Results registries, we evaluated the influence of radiation therapy on the development of subsequent sarcomas in cases with primary breast cancer. METHODS: Cases with primary invasive breast cancer (n = 274,572) were identified in the Surveillance, Epidemiology and End Results Cancer Incidence Public-Use Database (1973-1997). The database was then queried to determine the cases developing subsequent sarcomas (n = 263). Eighty-seven of these cases received radiation therapy, and 176 had no radiation therapy. The cumulative incidence of developing secondary sarcoma and the survival post developing secondary sarcoma were determined by the Kaplan-Meier method. RESULTS: The occurrence of sarcoma was low, regardless of whether cases received or did not receive radiation therapy: 3.2 per 1,000 (SE [standard error] = 0.4) and 2.3 per 1,000 (SE = 0.2) cumulative incidence at 15 years post diagnosis, respectively (p = 0.001). Of the sarcomas occurring within the field of radiation, angiosarcoma accounted for 56.8%, compared to only 5.7% of angiosarcomas occurring in cases not receiving radiotherapy. The cumulative incidence of angiosarcoma at 15 years post diagnosis was 0.9 per 1,000 for cases receiving radiation (SE = 0.2) and 0.1 per 1,000 for cases not receiving radiation (SE < 0.1). Overall survival was poor for cases of sarcoma after breast cancer (27-35% at 5 years), but not significantly different between patients receiving or not receiving radiation therapy for their primary breast cancer. CONCLUSIONS: Radiotherapy in the treatment of breast cancer is associated with an increased risk of subsequent sarcoma, but the magnitude of this risk is small. Angiosarcoma is significantly more prevalent in cases treated with radiotherapy, occurring especially in or adjacent to the radiation field. The small difference in risk of subsequent sarcoma for breast cancer patients receiving radiotherapy does not supersede the benefit of radiotherapy.