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.     

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.     

Clearing of cells bearing the bcl-2 [t(14;18)] translocation from blood and marrow of patients treated with rituximab alone or in combination with CHOP chemotherapy

Purpose:Patients who were PCR-positive for B-cellleukemia-lymphoma 2 (bcl-2) gene rearrangement [t(14;18)] wereevaluated for responses to rituximab alone or combined with CHOP. Patients and methods:Patients had relapsed or refractorylow-grade or follicular non-Hodgkins lymphoma (IWF: A–D). Thesingle-agent trial used 375 mg/m² weekly · 4; combinationtherapy included six cycles of CHOP and six 375 mg/m² infusions ofrituximab. Bcl-2analyses of bone marrow (BM) and peripheral blood(PB) samples at base-line and following therapy were performed using a PCRassay. Results:In the single-agent trial, of 70 patients whoseperipheral blood (PB) was bcl-2positive at baseline, 36 becamebcl-2-negative, 13 remained positive, and 21 varied between positive andnegative. The overall response rates (ORRs) were 72%, 31%, and57%, respectively. Twelve of twenty-two patients with repeat bonemarrow (BM) samples were bcl-2-negative three months post-treatment.Of 18 patients in the combination trial, 8 were bcl-2positive in PBand/or BM. All of seven patients positive in PB at baseline and six of sevenpatients positive in BM were negative at the end of therapy; all patientsresponded to treatment (100% ORR). Conclusions:Rituximab, alone or combined with CHOP, eradicatedbcl-2positive cells from PB and BM in over half of the patientstreated and was associated with a high overall clinical response rate. Theimpact on disease-free and overall survival awaits long-term follow up.     

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.     

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.     

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.     

Single-agent high-dose melphalan salvage therapy for Hodgkin's disease: Cost, safety, and long-term efficacy

Background: Few data are available on the cost, safety, and long-termefficacy of single agent high-dose melphalan (HDM) followed by autologousbone marrow (ABMT) or blood stem cell (ABSCT) transplantation in the salvagetherapy of Hodgkins disease (HD).Patients and methods: From February 1981 to September 1996, 23 patientswith relapsed (n = 15) or refractory (n = 8) HD received salvage therapywith HDM 140–200 mg/m² followed by non-cryopreservedABMT (n = 18) or cryopreserved ABSCT (n = 5). The cost of HDM/ABSCT in 1996,from initial consultation until transfer back to referring physician, wasdetermined and compared to the estimated costs of two multi-agent regimenscommonly used for HD.Results: HDM was well tolerated with no early transplant-relatedmortality. The five-year overall and progression-free survival rates were52% and 50%, respectively. The average total cost in Canadianfunds of HDM/ABSCT in 1996 was $34,400/patient. This cost wasestimated to be $4,700–6,800 cheaper per patient than themulti-agent high-dose regimens.Conclusion: These data suggest that HDM is safe, feasible, active, andreasonably inexpensive salvage therapy for patients with relapsed/refractoryHD.     

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.     

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.     

Interferon effect on glycosaminoglycans in mouse gliomain vitro

Summary The effect of mouse interferon / (MuIFN /) on the production of glycosaminoglycans (GAGs) by mouse glioma G-26in vitro was evaluated. Two GAG species secreted extracellularly by the mouse glioma G-26 were isolated using cellulose acetate electrophoresis. They were identified as hyaluronic acid (HA) and chondroitin sulfate (CS) following enzymatic digestion with enzymes: hyaluronidase and chondroitinase ABC. Further characterization of CS by enzymatic digestion with specific chondroitinases for chondroitin 4-sulfate (CSA) and chondroitin 6-sulfate (CSC), revealed that the isolated CS was neither CSA nor CSC. Therefore, it may be either chondroitin sulfate B (CSB) (dermatan sulfate) or one of the chontroitin sulfate isomers (D-H).The three day incubation of glioma G-26 cells with 8×10-8×104 U/ml of MuIFN / resulted in a dose dependent inhibition of cell proliferation measured by³H-thymidine incorporation and the MTT assay. The significant decrease of the CS (p < 0.008) but not the HA level, (measured densitometrically), was observed following 72 hours (hrs) incubation of G-26 cells with 8 × 10³ U/ml of MuIFN / (IFN treated cells: 0.03 ± 0.007 integrated optical density (IOD); control cells: 0.07 ± 0.01 IOD). The decreased CS production may be the underlying cause of IFN mediated inhibition of glioma cell proliferation.     

Tumour necrosis factor‐α and interleukin‐1 and ‐6 in fibrocystic breast disease

The risk of developing breast cancer is higher in women presenting gross cystic disease (cysts > 3mm in diameter) of the breast with intracystic K+/Na+ > 3 as compared with K+/Na+ < 3. The present study reports the levels of tumour necrosis factor (TNF), interleukin1 (IL1), and interleukin6 (IL6) in the breast cyst fluid of women with gross cystic disease and analyses the relationship between the intracystic concentration of these cytokines, sex steroid hormones, and the K+/Na+ ratio. The concentration of these cytokines, estradiol, testosterone, dehydroepiandrosterone sulfate (DHEAS), and 17OHprogesterone were determined in the breast cyst fluid of 54 women with gross cystic disease. No significant differences were found in the cystic levels of IL1 between cysts with intracystic K+/Na+ < 3 and > 3. However, in cysts with intracystic K+/Na+ > 3 we found a lower concentration of IL6 and TNF than in those with intracystic K+/Na+ < 3.Stepwise multiple linear regression analysis demonstrated that the concentration of IL6 in breast cyst fluid was predicted statistically by a negative regression coefficient for the concentration of estradiol and DHEAS, and by a positive regression coefficient for the concentration of TNF. The concentration of TNF in breast cyst fluid was predicted statistically by a positive regression coefficient for the concentration of IL6, and by a negative regression coefficient for the concentration of estradiol. No candidate variable was included in the model to predict concentrations of IL1 in breast cyst fluid. Our results indicate that IL6 and TNF could have a local protector role in gross cystic disease, and that they could be used as a marker to identify cyst type.     

Glucocorticoid-induced long-term remission in primary cerebral lymphoma: case report and review of the literature

We report a 25-year old immunocompetent woman with a high grade primary non-Hodgkins lymphoma of the central nervous system (PNHL-CNS) in whom the administration of dexamethasone alone during three months produced a complete clinical and radiological response lasting over four years. If complete remission of PNHL-CNS induced by glucocorticoids are well known, the opportunity to observe glucocorticoid-induced remission for a long period oftime without radio- and chemotherapy is rare. Only nine othercases of PNHL-CNS with complete remission induced by glucocorticoidslasting from 6 to 60 months, were found in the literature and aresummarized here. Duration of glucocorticoids therapeutic effect inPNHL-CNS is probably underestimated. Glucocorticoids cannotbe recommended as sole initial treatment for PNHL-CNS. However, we suggest standard therapies to be delayed in thosepatients responding completely to glucocorticoids where radio-and chemotherapy should be contraindicated (kidney, liver, bonemarrow failure, pregnancy).     

Fludarabine and mitoxantrone: Effective and well-tolerated salvage therapy?in relapsed indolent lymphoproliferative disorders

Background:Prior studies of the combination of fludarabine,mitoxantrone and dexamethasone have yielded high response rates but areassociated with a significant risk of opportunistic infections,predominantly Pneumocystis Carinii pneumonia (PCP) requiring routineprophylaxis. Patients and methods:We evaluated thecombination of fludarabine (25 mg/m²/day × 3) andmitoxantrone (10 mg/m² × 1) withoutcorticosteroids or PCP prophylaxis in 29 patients with relapsed orrefractory indolent lymphoproliferative disorders; median age 56 years,62% refractory to preceding chemotherapy. Results:A median of four cycles was administered without cumulativemyelosuppression. Neutropenia <0.5 × 10⁹/l was seenin 16% of cycles. Infections complicated 10.4% of cycles,with impaired performance status (ECOG 2) and increased age (>56years) significant risk factors (P 0.01). Nocases of PCP were encountered. The response rate was 90%, medianremission duration 11.9 months and the median survival 57 months.Peripheral blood progenitor cell mobilization was attempted in 11patients and yielded 2 × 10⁶ CD34+ cells/kg in only5 cases (45%). Conclusions:High response ratescan be attained with fludarabine and mitoxantrone in combination withoutcorticosteroids, and routine PCP prophylaxis can safely be omitted.Peripheral blood progenitor collections are problematic in these heavilypretreated patients.     

Atypical protein-kinase Cζ, but neither conventional Ca<Superscript>2+</Superscript>-dependent protein-kinase C isoenzymes nor Ca<Superscript>2+</Superscript>-calmodulin,participates in regulation of telomerase activity in Burkitt’s lymphoma cells

Purpose To clarify the role of the pathways dependent on protein-kinase C (PK-C) and Ca²⁺/calmodulin (CaM) in the regulation of telomerase activity in Burkitts lymphoma cells.Methods Burkitts lymphoma cells (Raji and Daudi) were treated with the PK-C inhibitor, bisindolylmaleimide (BIM), or the CaM inhibitor, trifluoperazine (TFPZ), in a dose-dependent manner and in a time-dependent manner. The activities of PK-C isoenzymes were analyzed fluorimetrically using POLARIS assay kits. CaM-kinase II activity was analyzed radiographically, using CaMK-II immunoprecipitation kinase assay kits. Telomerase activity was detected by a conventional telomeric repeat amplification protocol and Stretch PCR. The level of catalytic subunit of telomerase (hTERT) in drug-treated and nontreated cells was analyzed by flow cytometry using anti-hTERT antibody labeled with ZenonAlexa Fluor-488 IgG. Apoptosis was estimated in terms of phosphatidylserine exposure on the cell surface and DNA fragmentation.Results It was found that BIM inhibited telomerase activity and this process preceded apoptosis. The subsequent addition of exogenous PK-C (mixture of isoenzymes) to the cell lysates restored telomerase activity if incubation of cells with BIM was up to 24 h. Using PK-C isoenzymes, it was established that atypical PK-C, but not conventional Ca²⁺-dependent PK-C, PK-C or PK-C, is responsible for the reactivation of telomerase in BIM-treated cells. BIM also showed a well-expressed cytotoxicity against intact leukemia cells. In contrast, the CaM inhibitor TFPZ showed the same cytotoxic effect without any influence on telomerase activity during incubation for 24 h with leukemia cells. After incubation for 48 h, TFPZ markedly suppressed telomerase activity. However, the effect followed apoptosis and appeared to be a result of cell death. The addition of exogenous CaMK-II to the cell lysates obtained from TFPZ-treated cells did not reactivate telomerase.Conclusion The present study confirmed the participation of atypical PK-C, but not conventional Ca²⁺-dependent PK-C isoenzymes (, , ) nor the Ca²⁺/CaM-dependent pathway, in the regulation of telomerase activity in Burkitts lymphoma cells.     

Prognostic significance of Ki‐67 and topoisomerase IIα expression in infiltrating ductal carcinoma of the breast

To evaluate the prognostic relevance of Ki67 and topoisomerase II expression in relation to tumor stage, grade, and hormone receptor content, 942 ductal infiltrating carcinomas of the breast were examined by means of the monoclonal antibodies KiS11 (Ki67) and KiS4 (topoisomerase II). pS2, cerbB2, and p53 were additionally considered as prognostic variables. The median followup time was 149 months. Eighthundredandsixtythree tumors reacted with KiS11 and KiS the labeling indices of the two antigens were closely associated (r=0.93). Both correlated positively with the tumor size, cerbB2, and p53 expression, and negatively with patient age, hormone receptor content, and pS2 immunostaining. In the univariate analysis, KiS11 and KiS4 scores, nodal status, tumor size, tumor grade, and progesterone receptor content strongly predicted both overall and metastasisfree survival (p <0.00001). Estrogen receptor status, p53, and cerbB2 were of minor significance. Concerning overall survival, multivariate Cox regression analysis selected a KiS4 score >25% (p < 0.00001) next to the nodal status, and before tumor size, progesterone receptor content, and patient age. Independent predictors of the occurrence of distant metastases were nodal status, KiS4, tumor size, grade 1, and progesterone receptor negativity, in that order. The KiS11 score was of independent prognostic significance only if examined as a continuous variable. We conclude that topoisomerase II expression as assessed by monoclonal antibody KiS4 may add valuable information to current prognostic models for breast cancer. Its predictive value appears to be essentially related to the proliferative activity of tumor cells.     

A phase I-II study of 9-cis retinoic acid and interferon-alpha2b in patients with advanced renal-cell carcinoma: an NCIC Clinical Trials Group study.

Although advanced renal-cell carcinoma (RCC) responds poorly to standardtherapies, phase I–II trials have shown activity for combinations ofinterferon-2b (IFN) with a retinoid. Alitretinoin (9-cis RA) isan endogenous retinoid with high binding affinity for both RAR and RXRreceptor families. This phase I–II study enrolled 38 patients with RCCin a dose-escalation study of tolerability, pharmacokinetics (PK), andefficacy of twice daily oral 9-cis RA with subcutaneous IFN. Incontrast to studies with similar doses of daily 9-cis RA, PK studiesfound a consistent reduction in 9-cis RA concentrations of about50% after multiple b.i.d. doses of 30 or 50 mg/m²,independent of cotreatment with IFN. In the phase I portion, toxicitiesincluded systemic symptoms typical of IFN and biochemical abnormalitiespreviously associated with retinoids. Two patients experienced dose-limitingtoxicity at 50 mg/m² b.i.d. of 9-cis RA, thus therecommended phase II dose was 30 mg/m² b.i.d. One of twenty-sixevaluable patients achieved a durable objective partial remission, andrepeated dosing with this regimen was poorly tolerated. This combination ofretinoid and interferon is not recommended for further study in RCC.