Dexamethasone, high-dose cytarabine, and oxaliplatin (DHAOx) as salvage treatment for patients with initially refractory or relapsed non-Hodgkin''s lymphoma.

Background:Dexamethasone, cytarabine (ara-C), and cisplatin(DHAP) can be used effectively to treat patients withnon-Hodgkins lymphoma (NHL). We hypothesized that substitution ofcisplatin by oxaliplatin (L-OHP) could result in less toxicity andgreater efficacy. L-OHP is active in patients with lymphoma. It producesmild myelosuppression and is devoid of renal toxicity. We report on aphase II study of dexamethasone, high-dose ara-C, and L-OHP (DHAOx) usedto treat patients with NHL who were previously treated withchemotherapy. Patients and methods:Fifteen patientswere given DHAOx. They had failed to achieve a CR with initialchemotherapy or had recurrent disease. DHAOx consisted of dexamethasone,40 mg/day (days 1 to 4); L-OHP, 130 mg/m² (day 1); and ara-C,2000 mg/m² every 12 h (day 2). Treatment was repeated every21 days. Results:Patients received a median of fourcourses of DHAOx. Myelosuppression and transient sensory peripheralneuropathy were the most prominent toxic effects. Serum creatininelevels did not increase in patients with normal renal function, nor inpatients who had renal impairment before DHAOx. The median follow-uptime from the start of DHAOx treatment was 17 months. Eight patients(53%) achieved a CR, and three patients (20%) had a PR.Responses were achieved by patients with lymphomas of varioushistologies that included mainly the follicular subtype, and by patientswith and without resistance to prior chemotherapy. None of the eightresponders have relapsed from CR at 4+, 6+, 14+, 15+, 19+, 20+, 24+, and24+ months. They had various types of therapy after DHAOx. Disappearanceof molecular markers was observed in all four patients who achieved a CRand whose tumor cells carried molecular abnormalities. Conclusion:DHAOx possesses characteristics of toxicitywhich compare favorably to those reported with DHAP, and it is useful asa salvage treatment for patients with NHL. Larger studies are requiredto establish the therapeutic potential of the regimen.     

Pitfalls in imaging Hodgkin''s disease with computed tomography and positron emission tomography using fluorine-18-fluorodeoxyglucose.

We report on a patient with Hodgkins disease who presented with hypodense splenic lesions and corresponding increased glucose metabolism in FDG-PET imaging, four months after completion of initial treatment, suggestive of early relapse. Serological testing for toxoplasma gondii, however, showed evidence of a recently reactivated or newly acquired infection. Three weeks after immediate antibiotic treatment with Daraprime and Sulfadiazin, the splenic lesions had completely resolved. Additionally, serological titers for toxoplasma gondii were normalized and whole body FDG-PET imaging showed no metabolic activity. Although the positive predictive value of PET imaging to indicate lymphoma is reported to be higher than CT, hypermetabolic lesions are not specific for malignant tissue. Whereas benign tumors typically show low glucose metabolism, activated granulocytes and macrophages may display significantly increased glucose consumption. In conclusion, our case report shows that although therapeutic decisions are often based on the results of imaging modalities, the taking of a detailed history and the acquisition of histological confirmation of the suspected lymphoma relapse are also advisable where possible. Cellular immunodeficiency can result in severe infections even in patients with intermediate stage Hodgkins lymphoma in remission after combined modality treatment. Therefore, despite the high sensitivity of FDG-PET imaging for the detection of recurrent lymphoma, the differential diagnosis of infectious lesions should be kept in mind, in particular in immunocompromised patients.     

The timing of treatment in breast cancer: gaps and delays in treatment can be harmful

Timing of treatment in breast cancer may refer to intervals within a single management or between different managements. Rates of shrinkage of breast cancers in response to treatment are related to histological grade and may be used as surrogates for growth rates. Histological grade should predict appropriate timing of treatment. Four cases of locally advanced breast cancer that illustrate a number of different types of interval are presented. Two tumours of differing histological grade (II and III) had been managed by historical split-course radiotherapy and two similar grade III tumours were managed by primary medical treatment, followed at different intervals by radiotherapy. In the grade III tumours different radiotherapy fractionation régimes and effects of varying intervals between mangements are compared. The theoretical advantage of shrinkage (leading to reoxygenation) during the gap in split-course radiotherapy is realized only in relatively slowly growing and shrinking tumours. Grade III tumours grow rapidly. They have the potential to shrink rapidly in response to appropriate treatment, namely intensive chemotherapy or radiotherapy but not hormones. Inadequate treatment leads to growth in intervals between individual doses, whether of drugs or radiation, and to failure of local control. The advantage of surgery or primary medical treatment will be lost if the interval between managements is too long in relation to the volume doubling time. Histological grade is a good guide of this parameter; the grade III tumours are particularly vulnerable to gaps in treatment.     

Phase I study of BBR 2778, a new aza-anthracenedione, in advanced or refractory non-Hodgkin''s lymphoma.

Background:BBR 2778 is a novel aza-anthracenedione showing no cardiotoxicity and superior activity compared to doxorubicin and mitoxantrone in animal models. Objectives of this phase I study included the determination of the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), clinical pharmacokinetics (PK), and antitumor activity. Patients with relapsed or refractory, advanced non-Hodgkins lymphoma were included. Patients and methods:Patients were treated with a q1w × 3 schedule on the basis of a modified Fibonacci dose escalation method. Seven groups with a total of twenty-six patients were treated at dosages of 5, 10, 16.5, 25, 34, 56 or 84 mg/m²/w, respectively. Results:DLT was observed on the seventh dose level with neutropenia WHO grade 4 in three of six patients. Pharmacokinetic analysis showed a large volume of distribution (13.5–17.5 l/kg), a high plasma clearance (0.65–1.74 l/h/kg) and a long elimination half-life (14.7–31.9 h). Tumor response included three complete remissions and two partial remissions. Conclusions:Neutropenia is the DLT of the new aza-anthracenedione BBR 2778. The recommend dose is 84 mg/m² in a q1w × 3 schedule. PK data are consistent with a linear kinetic of BBR 2778 comparable to mitoxantrone. This new drug shows promising activity in intensively pretreated patients with relapsed or refractory NHL. Based on this results, phase II studies with this new compound are underway.     

Primary intestinal diffuse large B-cell non-Hodgkin''s lymphoma: clinical features, management, and prognosis of 66 patients.

Background:In Saudi Arabia, primary gastrointestinalnon-Hodgkins lymphoma (NHL) is common. Recently we have reported oneof the largest series of primary gastric (PG) diffuse large B-cell lymphoma(DLCL). This has prompted the analysis of another series of patients withprimary intestinal DLCL to depict the clinical features and the outcome ofthat disease and to compare those with that for PG involvement. Patients and methods:The data of 66 adult patients with primaryintestinal NHL having DLCL histology were retrospectively reviewed. Results:Patients had a median age of 45 years. Of 64 treatedpatients, 16% and 84% received single and multiple modalitytreatment, respectively. Seventy-six percent, ten percent, and fourteenpercent attained complete remission (CR), partial remission (PR), and noresponse/progressive disease, respectively. Multivariate analysis failed toidentify any variable that predict the likelihood of attaining CR. Over amedian follow-up of 81 months for all 66 patients, 32 (48%) were aliveand disease-free, 5 (8%) were alive with evidence of disease, and theremaining 29 (44%) were dead. The median overall survival (OS) was 101months and it was 58% (· 6%) and 48% (·7%) at 5- and 10-year, respectively. Of the 54 patients who achievedCR or PR, the median event-free survival (EFS) was not reached, but thepredicted 5- and 10-year EFS was 61% (· 7%) and52% (· 7%), respectively. Only low serum albumin(<30 g/l) was associated with adverse OS and EFS in a univariate analysis,however, multivariate analysis was not possible. Our analysis showed thatcompared with single-modality management, multi-modality strategy attainedsignificantly higher CR, and advantageous EFS, but without a significantsuperior effect on OS. In comparison with patients with PG DLCL, those withprimary intestinal disease demonstrated more adverse prognostic features, buthad an equivalent survival. Conclusions:This series characterized the clinico-pathologicfeatures and outcome of patients with primary intestinal DLCL. While surgicalresection in primary intestinal NHL seems beneficial, only prospectiverandomized studies can ascertain its precise role. Compared with patients withPG NHL, patients with primary intestinal disease had more prevalence ofadverse prognostic features.     

18FDG-PET following treatment as valid predictor for disease-free survival in Hodgkin''s lymphoma.

Purpose:The value of ¹⁸FDG-PET to predict the outcomeafter therapy in Hodgkins lymphoma was compared to morphologic stagingand ESR. Patients and methods:A total of 50 concurrent¹⁸FDG-PET and CT studies were performed in 37 patients withHodgkins lymphoma. ESR was evaluated 32 times after treatment wascompleted. Results:Out of 39 residual masses found by CT 8 relapses couldbe proven. Out of 11 CT exams with CR 3 relapses occurred. CT turned out toshow a sensitivity, specificity, PPV, NPV, and accuracy of 72%,21%, 21%, 73%, and 32%, with respect to predictdisease-free survival (DFS). ¹⁸FDG-PET was positive in 22examinations with 10 recurrences in this group. Out of 28 negative¹⁸FDG-PET 1 relapse developed 3 years later. ¹⁸FDG-PETturned out to show promising sensitivity, specificity, PPV, NPV, and accuracyof 91%, 69%, 46%, 96%, 74%, with respectto predict DFS. ESR was elevated in 12 studies of which 5 relapses could beproven, while out of 20 normal ESR-studies 3 relapses occurred. Thus, ESRturned out to show sensitivity, specificity, PPV, NPV, and accuracy of63%, 71%, 42%, 85%, and 75%, with respectto predict DFS. In summary, only ¹⁸FDG-PET was able to predict DFSstatistically significant. Conclusion: ¹⁸FDG-PET can be very useful in patientswith residual masses after treatment.     

Transformation of Hodgkin''s disease to high-grade B-cell lymphoma: remission after Rituximab monotherapy.

Purpose:We demonstrate the usefulness of immunotherapy with theCD20 antibody Rituximab in a case of transformation of Hodgkins disease(HD) to high-grade non-Hodgkins lymphoma (NHL). Case report:A 45-year-old women suffering from lymphocytepredominant HD of paragranuloma type (stage IVb) since 1995 showed mediastinalrelapse despite of 6 cycles of chemotherapy following the COPP/ABVD-protocolin 1998. Again complete remission could be achieved after escalated BEA-COPPII therapy in May 1998. Six months later chest radiograph and CT depictedpulmonary nodules. The non-typical resection of the lung revealed pulmonaryinvolvement of a high-grade T-cell rich large B-cell lymphoma with 100%of the tumoral cells CD20 positive. Since the symptoms occurred shortly afterthe BEA-COPP-escalated protocol chemotherapy resistance had to be assumed.Because of this problems and supported by the refusal of a high-dosechemotherapy with stem-cell transplantation by the patient we decided toperform a mono-immunotherapy with the monoclonal CD20 antibody Rituximab.Today, 14 months later, the patient is still in complete remission includingthe absence of B symptoms. Conclusions:Immunotherapy against CD20 positive cells in casesof sequential HD and NHL seems to be an effective therapy in chemotherapyresistant cases because of the suspected clonally relation of bothdiseases.     

Hereditary persistence of {alpha}-fetoprotein: Case report and review of the literature

Persistently elevated -fetoprotein (AFP) levels of 24 to 30µg/ml (normal <10 µg/ml) were found in a 38-year-old healthyman. Subsequently, AFP was found to be elevated in another five out of 13family members within three generations. The pedigree is consistent with anautosomal dominant inheritance pattern. No discernible disease and nofunctional abnormality appears to be associated with this clinically benigndisorder which has been recorded in the literature on four occasions todate. The reported AFP levels in these other cases ranged from 18 to 198µg/ml.Physiologically, AFP is mainly produced in the liver and the yolk sac ofhuman fetuses more than four weeks old, with peak values of up to 4 mg/ml at12 to 16 weeks of gestation. After birth, AFP levels usually fall, withineight to 12 months, to a very low concentration of <10 µg/ml andpersist at low levels throughout life. However, AFP levels can rise abovenormal in both children and adults in distinct conditions and diseases whichwill be discussed.Hereditary persistence of -fetoprotein (HPAFP) should be consideredin both children and adults with unexplained and persistent elevation of AFPe.g., those screened for hepatocellular carcinoma or diagnosed for germ celltumor. It should also be recognized in AFP screening for neural tube defectsor Down's syndrome during pregnancy. Hereditary persistence of AFP can beeasily confirmed by analyzing AFP levels in family members.     

Symptoms of Early Cancer Especially Barrett＇s Carcinoma

The incidence of the adenocarcinoma of the esophagus (AC) has been rising exponentially in the Western World within the last 30 years. The reasons for this increase are not yet understood.Massive and long lasting gastroesophageal reflux causes the Barrett‘s esophagus which is considered to be a precancerosis. Therefore early diagnosis and appropriate treatment of gastroesophageal reflux is essential for the prevention of this tumor. This makes heartburn the leading clinical symptom in the patient‘s history. In patients with heartburn it is possible to early endoscopically diagnose a Barrett‘s esophagus or adenocarcinoma of the esophagus. However only few patients with this increased risk receive an index-endoscopy. In clinical studies a high rate of early carcinomas could be found and could be treated with mucosectomie or ablation. The majority of patients with AC present with symptoms suggestive of progressed disease such as dysphagia or weight loss. The prognosis in patients in late disease stages are with a 5-year survival of only 30% far worse than in patients with early carcinoma (85%). However the early symptoms such as heartburn or regurgitation are unspecific and make an effective diagnostical strategy difficult. To optimize screening it would be beneficial to identify patients with high risk for the development of adenocarcinoma of the esophagus.     

Genetic polymorphisms of platelet adhesive molecules: association with breast cancer risk and clinical presentation

The main platelet adhesive receptors integrin 21, integrin IIb3 and glycoprotein (GP) Ib are also expressed in breast carcinoma cells. They play a key role in tumor cell-induced platelet aggregation and in adhesive interactions necessary for tumoral invasion and metastasis. Several polymorphisms affecting these molecules, two in integrin 2 (C807T and G1648A), one in integrin 3 (T1565C) and one in GP Ib (VNTR), influencing their levels, structure, and possibly their function, have been previously described and associated with cardiovascular diseases. In this study, we investigated the association of these polymorphisms with breast cancer risk or clinical presentation. We studied 101 patients with invasive breast cancer. The main prognostic variables were recorded, and genomic PCR analysis of these polymorphisms was performed. A group of 101 control subjects matched on age and sex was studied and compared with patients. No association was found between VNTR (GP Ib) polymorphism and breast cancer risk or presentation. Genotype and allele frequencies of C807T and G1648A polymorphisms of integrin 2 were not statistically different in breast cancer patients and controls, although we found an association between the 1648G/G genotype and higher disease stages (III and IV) (p = 0.02). Breast cancer risk was higher in carriers of 3 integrin T/T genotype (OR = 2.08, 95% CI = 1.04–4.16, p = 0.04). Furthermore, genotype 1565T/T was also associated with axillary nodal metastasis (p = 0.017) and with tumoral diameter greater than 2 cm (p = 0.02). Although confirmatory studies are needed, our results suggest that polymorphic genetic variation of integrins expressed in platelets and epithelial breast cells could modify the risk and the biological aggressiveness of breast carcinomas.     

Efficacy of ‘8-drugs-in-one-day’ combination in treatment of recurrent GBM patients

Summary Thirty-five adult recurrent GBM patients, divided randomly in two groups of 19 and 16 cases, had been treated with two regimens of chemotherapy: a) eight-drugs-in-one-day; b) procarbazine + CCNU + vincristine (PCV) respectively. Chemotherapy was planned at the tumor relapse and delivered as long as tolerated without irreversible sequelae or until the CT scan showed tumor progression.Multiple agents are used simultaneously in the therapeutic approach using eight-in-one to kill as many heterogeneous cells of malignant glial tumor as possible and minimize the emergence of cellular resistance to chemotherapy. Rate response to chemotherapy and the median adjunctive survival time (6.5 and 6 months, respectively) are not significantly different in the two arms of this study. Our experience with such an aggressive multi-drugs combination eight-in-one-day was disappointing if compared with less toxic, better tolerated and easy delivered (PCV) regimen.     

Reactivation of chronic hepatitis B infection following intensive chemotherapy and successful treatment with lamivudine: A case report and review of the literature

Background:Hepatitis B virus reactivation has been reported incancer patients following administration of chemotherapy or immunosuppressivetherapy and may result in liver damage of varying degrees of severity.Although treatment is supportive in nature, lamivudine, a nucleoside analoguehas been found to suppress HBV replication as evidenced by reports of 13 casesin the medical literature. Patients and methods:We report a patient who achieved asuccessful outcome with lamivudine following reactivation of HBV duringcombination chemotherapy for non-Hodgkins lymphoma, and provide a briefoverview of the literature including the 13 published case reports. Results:Lamivudine therapy resulted in clinical improvement aswell as in normalization of liver function tests and coagulation profile. Conclusions:Lamivudine has been found to suppress HBV replicationmanifested both by histology and serum HBV-DNA levels in chronic carriers ofHBV who developed reactivation of hepatic disease following chemotherapy.Physicians caring for such patients should be able to recognize this clinicalchallenge, and lamivudine should be considered.     

Organ specificity of tumor metastasis: role of preferential adhesion,invasion and growth of malignant cells at specific secondary sites

The locations of distant secondary tumors in many clinical cancers and animal tumors are nonrandom, and their distributions cannot be explained by simple anatomical or mechanical hypotheses based on the simple lodgment or trapping of tumor cell emboli in the first capillary bed encountered. Evidence from certain experimental tumor systems supports Paget's seed and soil hypothesis on the nonrandom distributions of metastases, in which the unique properties of particular tumor cells (seeds) and the different characteristics of each organ microenvironment (soil) collectively determine the organ preference of metastasis. Experimentally, differential tumor cell adhesion to organ-derived microvessel endothelial cells and organ parenchymal cells, differential invasion of basement membranes and organ tissues, and differential responses to organ-derived growth-stimulatory and-inhibitory factors all appear to be important determinants in explaining the organ preference of metastasis. Each tumor system may achieve organ specificity because of its own unique set of multiple metastasis-associated properties and responses to host microenvironments. As neoplasms progress to more highly malignant states multisite metastases are more likely and organ-specific metastases may be masked or circumvented owing to stochastic events, tumor cell diversification, host selection processes, and increased production of tumor autocrine molecules that may modulate adhesion, invasion, growth, and other properties important in metastasis. The importance of each of these properties, however, appears to vary considerably among different metastatic tumor systems. These and other tumor cell and host properties may eventually be used to predict and explain the unique metastastic distributions to certain human malignancies.     

Evaluation of response to postradiation eight in one chemotherapy in childhood brain tumors

Ten children, 3 to 15 years of age with high risk primary brain tumors were treated with postradiation eight in one chemotherapy; vincristine, lomustine, procarbazine, hydroxyurea, cisplatin, cytosine arabinoside, cyclophosphamide and methylprednisolone. The tumors comprised of three medulloblastomas, two primitive neuroectodermal tumors, one ependymoblastoma and four anaplastic ependymomas. Treatment involved surgery (two total resection, six subtotal and two biopsy only) followed by conventional radiotherapy (primary tumor: 50–54 Gy, whole brain: 30–45 Gy, and spinal axis: 25–36 Gy). Objective tumor response with radiotherapy was achieved in 7 of 9 patients (78%) (6/8 patients with residual tumor and one patient with complete resection but positive cerebrospinal fluid cytology). Complete response was attained in 4 of 9 patients (44%). Eight in one chemotherapy was initiated four weeks after radiation and repeated at 4 weekly intervals for 5–8 courses. Postradiation eight in one failed to show any additional effect on tumor responses. Median survival was 34 months (range 9–48 months) with five of ten patients alive: four in complete and one in partial remission. All the five survivors were among the patients who had achieved response to initial treatment. This result suggested that degree of response to initial treatment might determine subsequent outcome and thus the choice of modality for initial therapy might be important.     

Down-regulation of transforming growth factor-β and interleukin-10 secretion from malignant glioma cells by cytokines and anticancer drugs

The effect of treatment with interleukin-1 (IL-1), interferon- (IFN-), vincristine, and etoposide was evaluated on the secretion of transforming growth factor- (TGF-) and IL-10 and the expression of major histocompatibility complex (MHC) class I, intercellular adhesion molecule-1 (ICAM-1), and CD80 molecules by malignant glioma cells. Five malignant glioma cell lines were treated with IL-1, IFN-, and/or anticancer agents (vincristine and etoposide). Combined treatment with IL-1 and IFN- caused greater inhibition of TGF- secretion compared to treatment with IFN-, and almost the same levels of inhibition as treatment with vincristine and etoposide. The greatest inhibition of TGF- secretion was achieved by treatment with all agents. Low levels of IL-10 secretion were determined in two out of five malignant glioma cell lines. This IL-10 secretion was inhibited by treatment with IL-1, IFN-, vincristine, and/or etoposide. Treatment with both cytokines and anticancer agents increased the expression of MHC class I and ICAM-1 in all tumor cell lines. The mean increase of expression of MHC class I was 50% and that of ICAM-1 was 12-fold. No tumor cell lines expressed CD80 molecules on the cell surface, and no treatment caused CD80 expression. These results suggest that TGF- and IL-10 secretion by malignant glioma cells can be suppressed by treatment with a combination of IL-1, IFN-, vincristine, and etoposide, and the treatment up-regulates MHC class I and ICAM-1 expression on tumor cells. These results have implications for immunotherapy and chemotherapy in patients with malignant tumors.