 Volume 47 n° 2 |
Atualização Científica
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epidemiologia, prevenção, diagnóstico,
estadiamento, tratamento e prognóstico do câncer.
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Molecular predictors of survival after adjuvant chemotherapy for colon cancer
Background: Adjuvant chemotherapy improves survival among patients with stage III colon cancer, but no reliable molecular predictors of outcome have been identified.
Methods: We evaluated loss of chromosomal material (also called loss of heterozygosity or allelic loss) from chromosomes 18q, 17p, and 8p; cellular levels of p53 and p21WAF1/CIP1 proteins; and microsatellite instability as molecular markers. We analyzed tumor tissue from 460 patients with stage III and high-risk stage II colon cancer who had been treated with various combinations of adjuvant fluorouracil, leucovorin, and levamisole to determine the ability of these markers to predict survival.
Results: Loss of heterozygosity at 18q was present in 155 of 319 cancers (49 percent). High levels of microsatellite instability were found in 62 of 298 tumors (21 percent), and 38 of these 62 tumors (61 percent) had a mutation of the gene for the type II receptor for transforming growth factor (ß1 (TGF-ß1). Among patients with microsatellite-stable stage III cancer, fiveyear overall survival after fluorouracil-based chemotherapy was 74 percent in those whose cancer retained 18q alleles and 50 percent in those with loss of 18q alleles (relative risk of death with loss at 18q, 2.75; 95 percent confidence interval, 1.34 to 5.65; P=0.006). The five-year survival rate among patients whose cancer had high levels of microsatellite instability was 74 percent in the presence of a mutated gene for the type II receptor for TGF-ß1 and 46 percent if the tumor did not have this mutation (relative risk of death, 2.90; 95 percent confidence interval, 1.14 to 7.35; P=0.03).
Conclusion: Retention of 18q alleles in microsatellite-stable cancers and mutation of the gene for the type II receptor for TGF-ß1 in cancers with high levels of microsatellite instability point to a favorable outcome after adjuvant chemotherapy with fluorouracil-based regimens for stage III colon cancer.
Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck
Background: Oncogenic human papillomaviruses (HPVs), especially HPV type 16 (HPV-16), cause anogenital epithelial cancers and are suspected of causing epithelial cancers of the head and neck.
Methods: To examine the relation between head and neck cancers and HPVs, we performed a nested casecontrol study within a joint Nordic cohort in which serum samples were collected from almost 900,000 subjects. Samples collected at enrollment from 292 persons in whom squamous-cell carcinoma of the head and neck developed, on average, 9.4 years after enrollment and from 1568 matched controls were analyzed for antibodies against HPV-16, HPV-18, HPV-33, and HPV-73 and for cotinine levels as a marker of smoking habits. Polymerase-chain-reaction (PCR) analyses for HPV DNA were performed in tumor tissue from 160 of the study patients with cancer.
Results: After adjustment for cotinine levels, the odds ratio for squamous-cell carcinoma of the head and neck in subjects who were seropositive for HPV-16 was 2.2 (95 percent confidence interval, 1.4 to 3.4). No increased risk was observed for other HPV types. Fifty percent of oropharyngeal and 14 percent of tongue cancers contained HPV-16 DNA, according to PCR analysis.
Conclusion: HPV-16 infection may be a risk factor for squamous-cell carcinoma of the head and neck.
Understanding the experience of pain in terminally ill patients
Background: Terminally ill patients commonly experience substantial pain. Unresolved pain has been cited as evidence that end-of-life care is of poor quality. However, the data on which that conclusion is based are limited. We aimed to provide additional data on the experience of pain in such patients.
Methods: We interviewed 988 terminally ill patients from six randomly selected US sites. We asked them who had treated their pain in the previous 4 weeks (primary-care physician, pain specialist, or both), and whether they more pain medication than they were receiving, or why they did not want more.
Findings: 496 (50%) terminally ill patients reported moderate or severe pain. 514 (52%) individuals had seen a primary-care physician for treatment of pain in the previous 4 weeks and 198 (20%) saw a pain specialist. Of those who been treated by their primary-care physician, 287 (29%) wanted more therapy, 613 (62%) wanted their pain therapy to remain the same, and 89 (9%) wanted to reduce or stop their pain therapy. Several reasons for not wanting additional therapy were offered-fear of addiction, dislike of mental or physical side-effects, and not wanting to take more pills or injections. We saw no association between disease and amount of pain between disease and the desire for more treatment. Black patients were more likely to seek additional pain therapy, see a pain specialist, and refuse additional medication because of fear of addiction than other populations.
Interpretation: Although half of terminally ill patients experienced moderate to severe pain, only 30% of them wanted additional pain treatment from their primary-care physician. The number of patients experiencing pain remains too high. However, the number is not as large as perceived. Additionally, most are willing to tolerate pain. Furthermore, the experience of pain is constant across major terminal diseases.
Molecular and kinetic features of transitional cell carcinomas of the bladder: biological and clinical implications
Molecular and kinetic analyses have contributed to our understanding of the biology of transitional cell carcinomas (TCC) of the bladder. The concordant pattern of X-chromosome inactivation of multiple TCCs appearing at different times and at different sites and concordant genetic abnormalities in a subset of muscleinvasive TCC strongly support a monoclonal origin and a homogeneous tumor cell selection throughout the neoplasm. However, topographic intratumor heterogeneity results from the accumulation of genetic lesions in tumor suppressor genes, predominantly neurofibromatosis (NF)I-defective in the superficial compartment and tumor protein p53 (TP53)-defective in the deep one, with lower proliferation and down-regulation of apoptosis in the latter. TCCs follow the general concept of multistep carcinogenesis and proceed through two distinct genetic pathways responsible for generating different TCC morphologies. These are the inactivation of cyclin-dependent kinase inhibitors (p15, p16, and p21WAF/CIP1) in lowgrade TCC and early TP53-mediated abnormalities in high-grade TCC. TCC progression correlates with genetic instability and accumulation of collaborative genetic lesions mainly involving TP53, retinoblastoma (RB)-1, and growth factors. Distinctive genetic (low incidence of RB-1 and NF-1 abnormalities) and kinetic (slower cell turnover) profiles also correlate with a “single-file” infiltration pattern and poor survival in muscle-invasive TCCs. The underlying molecular changes of carcinoma in situ involve multiple and more extensive deletions (normally TP53-defective) than coexistent invasive TCC, suggesting an independent genetic evolution, while lowgrade dysplasia is mainly polyclonal and shows a low rate of gene deletions.
Key words: Bladder - Transitional cell carcinoma Oncogene - Tumor Suppressor Gene - Cell kinetics Tumor progression -Tumor heterogeneity
Immunotherapy by non-myeloablative allogeneic stem cell transplantation in multiple myeloma: results of a pilot study as salvage therapy after autologous transplantation
Non-myeloablative allogeneic stem cell transplantation has been reported to induce sustained complete remission even in advanced diseases (acute leukemia, lymphomas). The tolerance of this procedure allows treatment of poor candidates to conventional allogeneic transplantation with persisting or relapsing myeloma patients. Twelve patients previously treated with at least VAD regimen and autologous transplantation were . included. All patients had a serum b2 microglobuline >3 mg/l at diagnosis. The conditioning regimen consisted of fludarabine 25 mg/m/day x 5, antithymoglobulin 2.5 mg/kg/day x 5, busulphan 2 mg/kg/day x 2; the transplant was peripheral stem cells (except one) from an HLA-matched sibling and was followed by cyclosporin for 45 to 90 days. This treatment results in a well-tolerated procedure (no mucositis, duration of aplasia <7 days). A dramatic graft anti-myeloma effect is documented even in progressive disease (11/12 PR + CR, 4/12 CR). However, five patients underwent CMV disease, one died of CMV encephalitis (UPN 3) and delayed severe GVHD occurred in four patients. Our data suggest that a better survival could be achieved when patients are transplanted with a controlled disease. In high risk patients, we now propose a non-myeloablative transplantation in addition to the conventional and intensive chemotherapy as first-line of treatment.
Key words: myeloma; allogeneic transplantation; non-myeloablative; conditioning.
Long-term clinical and molecular remission after allogeneic stem cell transplantation (SCT) in patients with poor prognosis non-Hodgkin’s lymphoma
From 1987 to 1999 35 patients with poor prognosis non-Hodgkin’s lymphoma (NHL) underwent allogeneic stem cell transplantation (SCT) at the University Hospitals of Vienna and Graz. Initial biopsy specimens were reclassified according to the Revised European-American Classification of Lymphoid Neoplasms (REAL). All patients surviving 28 days engrafted. Twenty-eight of them (93%) attained clinical remission. At the last follow-up 14 patients were alive and disease-free at a median of 5.0 (range, 2.3-12.9) years after allogeneic SCT. The actuarial overall survival is 35%. Five patients relapsed 1.8 to 27.6 months after transplant, the probability of relapse is 23%. Of the 21 deaths following SCT, seven were due to relapse/refractory disease and 14 due to transplant-related causes. The probability of treatment-related mortality is 48%. After SCT, minimal residual disease (MRD) was monitored by polymerase chain reaction (PCR) in seven patients with a BCL2/IgH translocation and in 13 with a clonal immunoglobulin heavy chain (IgH) rearrangement. All 20 patients attained clinical remission rapidly and converted to PCR negativity. In the follow-up nine of these patients are in long-term clinical and molecular remission, six PCR-negative patients died of transplant-related causes and five patients relapsed. In summary, allogeneic stem cell transplantation has a curative potential for patients with refractory and recurrent non-Hodgkin’s lymphoma. In our series long-term disease-free survival was associated with molecular disease eradication after SCT. Treatmentrelated mortality rate was high, thus earlier referral of selected patients to allogeneic SCT should be considered.
Key words: alloSCT; non-Hodgkin’s lymphoma; polymerase chain reaction; BCL2/IgH; immunoglobulin rearrangement.
Integration of Amplified BCR/ABL Fusion Genes Into the Short Arm of Chromosome 17 as a Novel Mechanism of Disease Progression in Chronic Myeloid Leukemia
We describe the cases of two patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML), in whom the extramedullary blastic phase developed during disease progression. The similar clinical presentations of these patients was accompanied by gain of identical secondary chromosome abnormalities, that is, monosomies 9, 14, and 22, and by a clustered amplification of the BCR/ABL fusion gene. The additional copies of the BCR/ABL fusion gene were integrated into the short arm of structurally abnormal chromosomes 17 in both patients. The conformity of these genetic features in two patients with a rare disease manifestation leads us to the assumption that either the clustered amplification of the BCR/ABL fusion gene or the integration of this cluster into the short arm of chromosome 17 or both are associated with extramedullar disease progression in CML. Furthermore, the insertion of amplified BCR/ABL fusion genes into structurally abnormal chromosomes provides a novel mechanism of disease progression in BCR/ABL-positive CML.
Molecular cytogenetic characterization of early and late renal cell carcinomas in von Hippel-Lindau disease
Deletions of 3p25, gains of chromosomes 7 and 10, and isochromosome 17q are known cytogenetic aberrations in sporadic renal cell carcinoma (RCC). In addition, a majority of RCCs have loss of heterozygosity (LOH) of the Von Hippel-Lindau (VHL) gene located at chromosome band 3p25. Patients who inherit a germline mutation of the VHL gene can develop multifocal RCCs and other solid tumors, including malignancies of the pancreas, adrenal medulla, and brain. VHL tumors follow the two-hit model of tumorigenesis, as LOH of VHL, a classic tumor suppressor gene, is the critical event in the development of the neoplastic phenotype. In an attempt to define the cytogenetic aberrations from early tumors to late RCC further, we applied spectral karyotyping (SKY) to 23 renal tumors harvested from 6 unrelated VHL patients undergoing surgery. Cysts and low-grade solid lesions were near-diploid and contained 1-2 reciprocal translocations, dicentric chromosomes, and/or isochromosomes. A variety of sole numerical aberrations included gains of chromosomes 1, 2, 4, 7, 10, 13, 21, and the X chromosome, although no tumors had sole numerical losses. Three patients shared a breakpoint at 2p21-22, and three others shared a dicentric chromosome 9 or an isochromosome 9q. In contrast to the near-diploidy of the low-grade lesions, a high-grade lesion and its nodal metastasis were markedly aneuploid, revealed loss of VHL by fluorescence in situ hybridization (FISH), and contained recurrent unbalanced translocations and losses of chromosome arms 2q, 3p, 4q, 9p, 14q, and 19p as demonstrated by comparative genomic hybridization (CGH). By combining SKY, CGH, and FISH of multiple tumors from the same VHL kidney, we have begun to identify chromosomal aberrations in the earliest stages of VHL-related renal cell tumors. Our current findings illustrate the cytogenetic heterogeneity of different VHL lesions from the same kidney, which supports the multiclonal origins of hereditary RCCs.
Prognostic importance of the axillary lymph node ratio in autologous transplantation for high-risk stage II/III breast cancer
The role of autologous peripheral blood progenitor cell (PBPC) transplantation for high-risk stage II/III breast cancer remains controversial. New prognostic indicators defining subsets of patients who may benefit from autologous PBPC transplantation would be clinically useful. The axillary lymph node ratio, defined by the total number of axillary nodes involved with cancer divided by the number of axillary nodes surgically sampled, has been reported to be of potential prognostic importance in transplantation for high-risk, stage II/Ill breast cancer. We therefore retrospectively reviewed 111 women with high-risk, stage II/III breast cancer with at least four positive axillary lymph nodes undergoing autologous PBPC transplantation from 1991 to June 1999. None of the patients had received prior radiotherapy and all had completed one, and only one, course of at least three cycles of adjuvant chemotherapy. The median number of axillary nodes sampled was 20 (range 6-40) and the median number of positive axillary nodes was 12 (range 4-35). The median node ratio, dividing the number of positive nodes by the number of sampled nodes, was 0.68. Event-free survival was strongly influenced by node ratio. Patients having a node ratio of <0.7 had a 5-year event-free survival of 68%, vs those with a node ratio of >0.7 with a 5-year event-free survival of 46% (P = 0.03). Forty percent of patients with a high node ratio have relapsed vs 20% with a low node ratio (P = 0.02). Multivariate analysis revealed that positive estrogen receptor status and a node ratio of <0.7 were independent factors related to better event-free survival (P = 0.0001 and P = 0.004, respectively). We conclude that patients having a node ratio of <0.7 have a significantly better prognosis following autologous PBPC transplantation than do patients with a ratio >0.7.
Key words: autologous progenitor cell transplantation; breast cancer; axillary lymph node ratio; prognostic factors.
Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma
This study compares the probability of disease progression, progression-free survival, and overall survival between patients undergoing an allogeneic or autologous transplant for multiple myeloma using an identical preparative regimen. Patients received a preparative regimen of TBI, busulfan, and cyclophosphamide followed by an allogeneic or autologous transplant. In the allogeneic group (n = 21), six patients received bone marrow and 15 received G-CSF mobilized PBSC; all autologous patients (n = 35) received PBSC mobilized with cyclophosphamide and G-CSF. Allogeneic donors were HLA-identical (n = 20) or one-antigen mismatched (n = 1) siblings. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (n = 10), tacrolimus/methotrexate (n = 6), cyclosporine/methotrexate (n = 4), or cyclosporine (n = 1). The groups were evenly matched for gender, pretransplant therapy, disease status at time of transplant, myeloma subtype, and time from diagnosis to transplant. The median age was significantly lower in the allogeneic group (48 vs 55 years, P < 0.01). In the allogeneic group the probabilities of developing acute GVHD grade II-IV and chronic GVHD were 55 % and 82 %, respectively. The Kaplan-Meier probability of disease progression was significantly lower in the allogeneic group (11% vs 64%, P < 0.001) compared to the autologous group. Although progression-free (60% vs 30%, P=0.19) and overall survival at 2 years (60% vs 42%, P=0.39) favored the allogeneic group, this did not reach statistical significance. Within the allogeneic transplant group, patients age 50 years or under had a 3-year overall survival significantly higher when compared to older patients (79% vs 29%, P = 0.03). Using identical preparative regimens, allogeneic transplantation reduced disease progression compared to autologous transplantation for myeloma. This suggests that allogeneic transplantation induces a graft-versus-myeloma (GVM) effect.
Key words: multiple myeloma; autologous; allogeneic stem cell transplantation; sibling donor.
Megadose transplantation of purified peripheral blood CD34+ progenitor cells from HLA-mismatched parental donors in children
We performed HLA-mismatched stem cell transplantation with megadoses of purified positively selected mobilized peripheral blood CD34+ progenitor cells (PBPC) from related adult donors in 39 children lacking an otherwise suitable donor. The patients received a mean number of 20.7 ± 9.8 x 106/kg purified CD34+ and a mean number of 15.5 ± 20.4 x 103/kg CD34+ T lymphocytes. The first seven patients received short term (<4 weeks) GVHD prophylaxis with cyclosporin A, whereas in all the following 32 patients no GVHD prophylaxis was used. In 38 evaluable patients, five patients experienced primary acute GVHD grade I and one patient grade II. In 32 patients, no signs of primary GVHD were seen and GVHD only occurred after T cell add backs. T cell reconstitution was more rapid if the number of transplanted CD34+ cells exceeded 20 x 106/kg. Of the 39 patients, 15 are alive and well, 13 died due to relapse and 10 transplant-related deaths occurred. We conclude that the HLA barrier can be overcome by transplantation of megadoses of highly purified mismatched CD34+ stem cells. GVHD can be prevented without pharmacological immunosuppression by the efficient T cell depletion associated with the CD34+ positive selection procedure. This approach offers a promising therapeutic option for every child without an otherwise suitable donor.
Key words: mismatch transplantation; CD34-positive selection; donor lymphocyte infusion.
Prospective Study of Serum Selenium Levels and Incident Esophageal and Gastric Cancers
Background: From March 1986 through May 1991, we conducted a randomized nutritional intervention trial, the General Population Trial, in Linxian, China, a region with epidemic rates of squamous esophageal and adenomatous gastric cardia cancers. We found that participants who received selenium, (b-carotene, and vitamin E had significantly lower cancer mortality rates than those who did not. In the current study, we examined the relationship between selenium levels measured in pretrial (1985) sera from participants and the subsequent risk of developing squamous esophageal, gastric cardia, and gastric non-cardia cancers during the trial.
Methods: This study was designed and analyzed in accord with a stratified case-cohort sampling scheme, with the six strata defined by sex and three age categories. We measured serum selenium levels in 590 case subjects with esophageal cancer, 402 with gastric cardia cancers, and 87 with gastric non-cardia cancers as well as in 1062 control subjects. Relative risks (RRs), absolute risks, and population attributable risk for cancers were estimated on the basis of the Cox proportional hazards models. All statistical tests are two-sided.
Results: We found highly significant inverse associations of serum selenium levels with the incidence of esophageal (P for trend <10-4) and gastric cardia (P for trend <10-6) cancers. The RR and 95% confidence interval (CI) for comparison of highest to lowest quartile of serum selenium was 0.56 (95% CI = 0.44-0.71) for esophageal cancer and 0.47 (95% CI = 0.33-0.65) for gastric cardia cancer. The population proportion of these cancers that is attributable to low selenium levels was 26.4% (95% CI = 14.4538.36). We found no evidence for a gradient of serum selenium associated with incidence of gastric non-cardia cancer (P for trend = .96), with an RR of 1.07 (95% CI = 0.55-2.08) for the highest to lowest quartile of serum selenium.
Conclusions: Our study supports findings from previous prospective studies and randomized trials that variations in selenium levels affect the incidence of certain cancers. In the United States, where intervention trials of selenium are in the planning stages, consideration should be given to including populations at high risk for squamous esophageal and gastric cardia cancers.
How successful are oncologists in identifying patient distress, perceived social support, and need for psychosocial counselling?
20-40% of cancer patients show emotional distress. Psychosocial support should be offered to severely distressed patients. However, little is known about the selection of patients to whom such support should be offered. This study investigated oncologists’ ability to identify such patients. In a consecutive series of 298 cancer patients undergoing radiotherapy, distress, perceived social support and desire for supportive counselling were assessed using screening instruments. Simultaneously, 8 oncologists estimated patient distress and need for psychosocial support. A complete set of data was obtained in 80.2% of cases. Concordance of the oncologists’ estimation of patient distress and perceived social support with the results of the screening instruments was weak (k = 0.10 and k = 0.05). Oncologists recognized the presence of severe distress only in 11 of the 30 severely distressed patients. Correct perception of distress was lower in patients with head and neck cancer and lung cancer and in lower class patients. Oncologists’ recommendations for supportive counselling did not correlate with patient distress or the amount of perceived support but rather with progressive disease and less denial behaviour. Our results underline the need for educating oncologists in order to improve their ability to identify patient distress.
Key words: cancer; psychological co-morbidity; oncologist estimation of patient distress; social support; psychotherapeutic support; social class.
Chromosomal changes during development and progression of prostate adenocarcinomas
Chromosomal copy number changes were investigated in 16 prostate carcinomas, 12 prostatic intraepithelial neoplasias (PIN; 4 low-grade and 8 high-grade) adjacent to the invasive tumour areas, and 5 regional lymph node metastases. For this purpose, comparative genomic hybridization (CGH) was performed and a copy number karyotype for each histomorphological entity was created. CGH on microdissected cells from non-neoplastic glands was carried out on 3 different cases to demonstrate the reliability of the overall procedure. None of the non-neoplastic tissue samples revealed chromosome copy number changes. In PIN areas, chromosomal imbalances were detected on chromosomes 7, 8q, Xq (gains), and on 4q, 5q, 8p, 13q and 18q (losses). In the primary tumours, recurrent (at least 25% of cases) gains on chromosomes 12q and 15q, and losses on 2q, 4q, 5q, Xq, 13q and 18q became apparent. Losses on 8p and 6q as well as gains on 8q and of chromosome 7 were also detected at lower frequencies than previously reported. The pooled CGH data from the primary carcinomas revealed a novel region of chromosomal loss on 4q which is also frequently affected in other tumour entities like oesophageal adenocarcinomas and is supposed to harbour a new tumour suppressor gene. Gains on chromosome 9q and of chromosome 16 and loss on chromosome 13q were observed as common aberrations in metastases and primary tumours. These CGH results indicate an accumulation of chromosomal imbalances during the PIN-carcinoma-metastasis sequence and an early origin of tumour-specific aberrations in PIN areas.
Key words: prostate carcinoma; prostatic intraepithelial neoplasia; tumour progression; comparative genomic hybridization.
Occupations and social habits and head and neck cancer
Within the past decade, occupational exposures have gained importance as risk factors for head and neck cancer. Today, it is assumed that 4 to 10% of cancer cases are work related. Combined exposures to occupational and nonoccupational risk factors, as well as the interaction of different occupational agents, may have a synergistic effect on cancer risk. It is likely that the cancer risk resulting from occupational factors is modulated by host factors such as DNA repair capacity and enzymatically controlled activation and inactivation of carcinogens. Marijuana smoking and cigar smoking, like cigarette smoking, increase the risk of head and neck cancer. Cigarette smoking-associated risk decreases slowly after cessation of the habit. In women, even moderate alcohol consumption causes a substantial, dose-dependent increase in cancer risk. Frequent consumption of vegetables such as tomatoes seems to have a protective effect.
Sentinel node biopsy in head and neck cancer
Sentinel node biopsy is a new development in the investigation of solid tumors. Few studies have reported the use of this technique in head and neck squamous cell carcinoma. Early results are encouraging and suggest that the technique should be evaluated in the context of multicenter trials, which are now starting. This paper reviews the literature on sentinel node biopsy and its role in head and neck squamous cell carcinoma to date.
Surgical principles and techniques for functional rehabilitation after oral cavity and oropharyngeal oncologic surgery
Effective functional rehabilitation following surgery for oral and oropharyngeal cancer is a priority if the well being of patients is to be maintained. Decisive components include appearance, speech, swallowing, chewing, nutrition, and shoulder disability. The most suitable methods of preserving and promoting function are dependent on site, the extent of resection, and the type of reconstruction. Appropriate treatment selection and the utilization of microvascular free tissue transfer mean that gross functional compromise is now largely avoided. In addition, there are several adjunctive surgical techniques, such as pharyngeal flaps and osseointegrated implants, that help enhance outcome. This paper reviews the basis of functional compromise following tumor ablation and explores the various techniques available in the armamentarium of the surgeon to assist in the restoration of function.
Gene-Environment Interactions in Renal Cell Carcinoma
The majority of renal cell carcinomas (RCCs) are sporadic, and increasing incidence rates suggest that such environmental risk factors as smoking play a role in the etiology of the disease. Cases with RCC were selected from the population-based cancer registry of Orange County, California, between 1994 and 1997; controls were recruited by telephone using random digit dialing. A total of 115 case and 259 control subjects were genotyped for I-acetyltransferase 2 (NAT2), which codes for a polymorphic enzyme involved in tobacco-carcinogen metabolism. Subjects with slow acetylator genotypes were found to be at twofold increased risk (odds ratio (OR) = 1.8; 95 percent confidence interval (CI): 1.1, 2.9) of RCC. Although cancer risk doubled among smokers (OR = 2.2; 95 percent C1:1.3, 3.7), stratified analysis revealed gene-environment interaction among slow acetylators that smoked (OR = 3.2; 95 percent CI: 1.7, 6.1) compared with rapid acetylators that smoked (OR =1.4; 95 percent CI: 0.7, 2.9). A dose response was found for pack-years among slow acetylators (p < 0.01) but not among rapid acetylators (p = 0.06). Although smoking is a well-established risk factor of RCC, our data suggest that the risk is pronounced among slow rather than rapid acetylators.
Key words: acetyltransferases; hypertension; kidney neoplasms; smoking.
Cancer Incidence after Childhood Nasopharyngeal Radium Irradiation: A Follow-up Study in Washington County, Maryland
PA population from a hearing clinic in Washington County, Maryland, in 1943-1960 was followed to assess the risk of developing neoplasms from radium treatment of the nasopharynx for adenoid hypertrophy. Of the 2,925 subjects who attended the clinic, 904 received radium treatment. A nonconcurrent prospective study compared the cancer incidence among the irradiated persons with that among persons with other treatments. Seven brain tumor cases (three malignant and four benign) were identified in the irradiated group versus none in the nonirradiated group (relative risk = 14.8, 95% confidence interval: 0.76, 286.3). A nonsignificant excess risk of thyroid cancer was detected in the irradiated group based on two cases in the exposed group and one case in the nonexposed group (relative risk = 4.2, 95% confidence interval: 0.38, 46.6). Decreased risks of breast cancer, female genital cancers, and prostate cancer were observed among the irradiated individuals, although these deficits were not statistically significant individually. The decreased risk of sex hormone-related cancers in the irradiated group suggests possible radiation damage to the pituitary, with consequent reduction in pituitary hormone output and alterations in sexual and other hormonal development in early life. This hypothesis needs further evaluation.
Key words: nasopharynx; neoplasms; radiation; radium.
High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions
Standard allogeneic stem cell transplant (allo-SCT) regimens have been associated with a high transplant-related mortality (TRM) in multiple myeloma (MM). Nonmyeloablative therapy can establish stable engraftment after allo-SCT and maintain the antitumor effect with less toxicity, which is important in heavily pretreated and elderly patients. We report on 16 poor-risk MM patients receiving alto-SCT from an HLA-matched (n = 14) or mismatched (n = 2) sibling following conditioning with melphalan 100 mg/mª (MEL-100). Ten patients had refractory relapse, 4 responsive relapse, and 2 patients were in near complete remission (nCR) with poor-prognosis disease. Patients had received 1 (n = 9) or 2 (n = 7) prior autotransplants. Donor lymphocyte infusions (DLIs) were given to 14 patients with no clinical evidence of graft versus host disease (GVHD) either to attain full donor chimerism (n = 4) or to eradicate residual disease (n = 10). Fifteen patients showed myeloid engraftment, and 12 patients were full donor chimeras at day +21. No TRM was observed during the first 100 days. Acute GVHD developed in 10 patients; 1 had fatal grade IV GVHD. Seven progressed to chronic GVHD, limited in 3 and extensive in 4 patients. At a median follow-up of 1 year, 5 patients achieved and sustained CR, 3 nCR, and 4 partial remission. Of 4 patients progressing after transplantation, 3 achieved a remission following further chemotherapy and DLL Remarkable graft versus myeloma responses were seen in chemotherapy-refractory patients. Two patients died of progressive disease, and 3 died of GVHD complications without active disease. GVHD remains a major problem with this procedure.
Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia
In B-cell chronic lymphocytic leukemia (B-CLL), defective apoptosis causes the accumulation of mature CD5+ B cells in lymphoid organs, bone marrow (BM), and peripheral blood (PB). These cells are the progeny of a proliferating pool that feeds the accumulating compartment. The authors sought to determine which molecular mechanisms govern the proliferating pool, how they relate to apoptosis, and what the role is of the microenvironment. To begin to resolve these problems, the expression and modulation of the family of inhibitor of apoptosis proteins (IAPs) were investigated, with consideration given to the possibility that physiological stimuli, such as CD40 ligand (CD40L), available to B cells in the microenvironment, might modulate IAP expression. The in vitro data on mononuclear cells from PB or BM of 30 patients demonstrate that B-CLL cells on CD40 stimulation express Survivin and that Survivin is the only IAP whose expression is induced by CD40L. Through immunohistochemistry, in vivo Survivin expression in lymph node (LN) and BM biopsies was evaluated. In reactive LN, Survivin was detected only in highly proliferating germinal center cells. In LN from patients with B-CLL, Survivin was detected only in pseudofollicles. Pseudofollicle Survivin+ cells were actively proliferating and, in contrast to Survivin+ B cells found in normal GC, were Bcl-2+. In B-CLL BM biopsies, CD5+, Survivin+ cells were observed in clusters interspersed with T cells. These findings establish that Survivin controls the B-CLL proliferative pool interfacing apoptosis and that its expression may be modulated by microenvironmental stimuli.
Methylation profiling in acute myeloid leukemia
Aberrant methylation of multiple CpG islands has been described in acute myeloid leukemia (AML), but it is not known whether these are independent events or whether they reflect specific methylation defects in a subset of cases. To study this issue, the methylation status of 14 promoter associated CpG islands was analyzed in 36 cases of AML previously characterized for estrogen-receptor methylation (ERM). Cases with methylation density of 10% or greater were considered positive. Seventeen cases (47%) were ERM+ while 19 cases were ERM-. Hypermethylation of any of the following, p15, p16, CACNA1G, MINT1, MINT2, MDR1, THBS1, and PTC1 (2 promoters), was relatively infrequent (6% to 31 % of patients). For each of these CpG islands, the methylation density was positively correlated with ERM density (rank order correlation coefficients, 0.32-0.59; 2-tailed P s .058 for each gene). Hypermethylation of MYOD1, PITX2, GPR37, and SDC4 was frequently found in AML (47% to 64% of patients). For each of these genes as well, methylation density was positively correlated with ERM density (correlation coefficients 0.43 to 0.69, P <= .0087 for each gene). MLH1 was unmethylated in all cases. Hypermethylation of p15, MDR1, and SDC4 correlated with reduced levels of expression. There was an inverse correlation between age and the number of genes methylated (P = .0030). It was concluded that CpG-island methylation in AML results from methylation defects in subsets of cases. These results have potential implications for the classification and prognosis of AML and for the identification of patients who may benefit from treatment with methylation inhibitors.
47/45 – Blood. 2001; 97:2830-2838
Regulation of the nuclear proteasome activity in myelomonocytic human leukemia cells after adriamycin treatment
Treatment of different human leukemia cell variants with the anthracycline adriamycin was associated with a rapid activation of the proteasome. Thus, proliferating U937, TUR, and retrodifferentiated U937 cells exhibited a 4.3-fold, 5.8-fold, and 4.3-fold proteasome activation within 15 minutes after adriamycin treatment, respectively. In contrast, little if any proteasome activation was detectable in a growth-arrested differentiated U937 population following adriamycin treatment. Further analysis of this mechanism revealed a significant reduction of adriamycin-induced proteasome activity after inhibition of poly(ADP-ribose) polymerase (PARP) by 3-aminobenzamide (3-ABA) in the proliferating leukemic cell types. These findings suggested that PARP is involved in the regulation of drug-induced proteasome activation. Indeed, anti-PARP immunoprecipitation experiments of adriamycin-treated cells revealed increasing levels of coprecipitated, enzymatically active proteasome particularly in the proliferating cell variants in contrast to the differentiated U937 cells, with a maximum after 15 minutes, and sensitivity to PARP inhibition by 3-ABA. The specific role of the PARP was investigated in U937 and TUR cell clones stably transfected with a constitutively active antisense PARP (asPARP) vector. Thus, asPARP-TUR cells developed a 25fold increased sensitivity to adriamycin treatment. Furthermore, we investigated leukemic blasts isolated from acute myelogenous leukemia patients and obtained a similarly enhanced proteasome activity after adriamycin treatment, which was dependent on the PARP and thus could be coprecipitated with anti-PARP antibodies. Transient transfection of leukemic blasts with the asPARP vector significantly reduced the adriamycin-induced proteasome activation. These data suggest that the PARP-associated nuclear proteasome activation represents a potential target within chemotherapeutic defense mechanisms developed by leukemia cells.
Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma
Hodgkin lymphoma (HL) is characterized by the abnormal expression of multiple cytokines, accounting for its unique clinicopathologic features. We have previously shown that interleukin-13 (IL-13) is secreted by HL cell lines and may serve as an autocrine growth factor. To determine the frequency of IL-13 expression in lymphoma patients, tissue sections from 36 patients with classical HL, 5 patients with nodular lymphocyte predominance HL (NLPHL), and 23 patients with non-Hodgkin lymphoma (NHL) were subjected to in situ hybridization. In 31 of 36 cases (86%) of classical HL patients of all histologic subtypes, between 25% to almost 100% of Hodgkin and Reed Sternberg (HRS) cells were positive for IL-13 expression. In contrast, in no case of NLPHL and in only 4 of 23 NHL cases (1 of 5 T-cell-rich B-cell lymphomas, 2 of 5 anaplastic large cell lymphomas, and 1 of 5 peripheral T-cell lymphomas) did the neoplastic cells express IL-13. The expression of the IL-13 receptor chain a1 (IL-13Ra1) was also analyzed by in situ hybridization. In 24 of 27 (89%) cases of classical HL, between 25% to 75% of HRS cells, as well as a high frequency of lymphocytes and histiocytes, were positive for IL-13Ral expression. These results were confirmed by the construction of complementary DNA libraries from single HRS cells, followed by polymerase chain reaction analysis, in which IL-13Ral transcripts were found to be present in all 6 cases of HL. These data indicate that expression of IL-13 and IL-13Ral is a common feature of HRS cells in HL, consistent with the hypothesis that IL-13 may play a role in autocrine growth in classical HL.
Impact of Number of Nodes Retrieved on Outcome in Patients With Rectal Cancer
Purpose: We postulated that the pathologic evaluation of the lymph nodes of surgical specimens from patients with rectal cancer can have a substantial impact on time to relapse and survival.
Patients and Methods: We analyzed data from 1,664 patients with T3, T4, or node-positive rectal cancer treated in a national intergroup trial of adjuvant therapy with chemotherapy and radiation therapy. Associations between the number of lymph nodes found by the pathologist in the surgical specimen and the time to relapse and survival outcomes were investigated.
Results: Patients were divided into groups by nodal status and the corresponding quartiles of numbers of nodes examined. The number of nodes examined was significantly associated with time to relapse and survival among patients who were node-negative. For the first through fourth quartiles, the 5-year relapse rates were 0.37, 0.34, 0.26, and 0.19 (P = .003), and the 5-year survival rates were 0.68, 0.73, 0.72, and 0.82 (P = .02). No significant differences were found by quartiles among patients determined to be node-positive. We propose that observed differences are primarily related to the incorrect determination of nodal status in node-negative patients. Approximately 14 nodes need to be studied to define nodal status accurately.
Conclusion: These results suggest that the pathologic assessment of lymph nodes in surgical specimens is often inaccurate and that examining greater number of nodes increases the likelihood of proper staging. Some patients who might benefit from adjuvant therapy are misclassified as node-negative due to incomplete sampling of lymph nodes.
Phase II Study of Rituximab in Combination With CHOP Chemotherapy in Patients With Previously Untreated, Aggressive Non-Hodgkin’s Lymphoma
Purpose: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody Rituxan (rituximab, IDEC-C2B8; Genentech Inc, South San Francisco, CA) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in patients with aggressive non-Hodgkin’s lymphoma (NHL).
Patients and Methods: Thirty-three patients with previously untreated advanced aggressive B-cell NHL received six infusions of Rituxan (375 mg/ms per dose) on day 1 of each cycle in combination with six doses of CHOP chemotherapy given on day 3 of each cycle.
Results: The ORR by investigator assessment confirmed by the sponsor was 94% (31 of 33 patients). Twenty patients experienced a complete response (CR) (61 %), 11 patients had a partial response (PR) (33%), and two patients were classified as having progressive disease. In the 18 patients with an International Prognostic Index (IPI) score > 2, the combination of Rituxan plus CHOP achieved an ORR of 89% and CR of 56%. The median duration of response and time to progression had not been reached after a median observation time of 26 months. Twenty-nine of 31 responding patients remained in remission during this follow-up period, including 15 of 16 patients with an IPI score > 2. The most frequent adverse events attributed to Rituxan were fever and chills, primarily during the first infusion. Rituxan did not seem to compromise the ability of patients to tolerate CHOP; all patients completed the entire six courses of the combination. The bcl-2 translocation of blood or bone marrow was positive at baseline in 13 patients; 11 patients had follow-up specimens obtained (eight CR, three PR), and all had a negative bcl-2 status after therapy. Only one patient has reconverted to bcl-2 positivity, and all patients remain in clinical remission.
Conclusion: This is the first report to demonstrate the safety and efficacy of the Rituxan chimeric anti-CD20 antibody in combination with standard-dose CHOP in the treatment of aggressive B-cell lymphoma. The clinical responses are at least comparable to those achieved with CHOP alone with no significant added toxicity. The presence or absence of the bcl-2 translocation did not affect the ability of patients to achieve a CR with this regimen. The ability to achieve sustained remissions in patients with an IPI score > 2 warrants further investigation with a randomized study.
Flutamide Versus Prednisone in Patients With Prostate Cancer Symptomatically Progressing After AndrogenAblative Therapy: A Phase III Study of the European Organization for Research and Treatment of Cancer Genitourinary Group
Purpose: Time to progression (TTP), overall survival, and quality of life (QL) were compared in patients with hormone-resistant prostate cancer (HRPC) treated with prednisone (5 mg orally, four times a day) or flutamide (250 mg orally, three times a day).
Patients and Methods: Symptomatic patients were randomized to receive either prednisone (101 patients) or flutamide (100 patients). Subjective response was assessed based on performance status, the use of analgesics, and the need to apply alternative palliative treatment. Prostate-specific antigen (PSA)-based biochemical response (> 50% reduction of baseline PSA) was recorded. At baseline and at 6-week intervals during follow-up, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30.
Results: There was no difference between the groups in median TTP (prednisone, 3.4 months; flutamide, 2.3 months) or overall survival (prednisone, 10.6 months; flutamide, 11.2 months). In the prednisone group, 56% of the patients experienced a subjective response, compared with 45% in the flutamide group (P = .18). The median response duration was 4.8 months for prednisone and 4.2 months for flutamide. A biochemical response was observed in 21 % and 23% of the prednisone and flutamide groups, respectively. Gastrointestinal toxicity was the reason for trial discontinuation in seven patients receiving flutamide and two patients receiving prednisone. The QL assessment parameters favored the use of prednisone with statistically significant differences in pain, fatigue, role functioning, appetite loss, gastrointestinal distress, and overall QL.
Conclusion: In symptomatic HRPC, treatment with prednisone or flutamide leads to similar rates of TTP and overall survival and no difference in subjective or biochemical response. The QL results favor the use of low-cost prednisone in patients with HRPC.
The Helsinki Declaration: relativism and vulnerability
The Helsinki Declaration is a crucial ethical landmark for clinical research involving human beings. Since the Declaration was issued, a series of revisions and modifications have been introduced into the original text, but they have not altered its humanist approach or its international force for regulating clinical research. A proposal for an extensive revision of the Declaration’s underlying ethical principles has been debated for the past four years. If the proposal is approved, international clinical research involving human beings will be modified, further increasing the vulnerability of certain social groups. This article discusses the historical process involved in passing the Helsinki Declaration and the most recent debate on the new draft. The article analyzes the new text’s social implications for underdeveloped countries, arguing for a political approach to the vulnerability concept.
Key words:Helsinki Declaration; Research with Human Beings; Bioethics
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Revista Brasileira de Cancerologia - Volume 47 n°2 Abr/Mai/Jun 2001