Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers.

BACKGROUND: The BRCA1/2 proteins are involved in regulation of cellular proliferation by DNA damage repair via homologous recombination. Therefore, BRCA1/2 mutation carriers with pancreatic cancer may have distinct biologic outcomes. METHODS: Patients with BRCA1/2-associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994 and December 2012 were identified from databases at three participating institutions. Clinical data were collected. Disease-free survival and overall survival (OS) were analysed. RESULTS: Overall, 71 patients with PDAC and BRCA1 (n=21), BRCA2 (n=49) or both (n=1) mutations were identified. Mean age at diagnosis was 60.3 years (range 33-83), 81.7% (n=58) had any family history of malignancy; 30% (n=21) underwent primary resection. Out of 71 participants, 12 received experimental therapy; one patient had missing data, these 13 cases were excluded from OS analysis. Median OS for 58 patients was 14 months (95% CI 10-23 months). Median OS for patients with stage 1/2 disease has not been reached with 52% still alive at 60 months. Median OS for stage 3/4 was 12 months (95% CI 6-15). Superior OS was observed for patients with stage 3/4 treated with platinum vs those treated with non-platinum chemotherapies (22 vs 9 months; P=0.039). CONCLUSION: Superior OS was observed for advanced-disease BRCA-associated PDAC with platinum exposure.

Lonidamine as a modulator of alkylating agent activity in vitro and in vivo.

We are searching for relatively nontoxic compounds that can positively modulate the efficacy of antitumor alkylating agents. Lonidamine inhibits cellular energy metabolism and could potentially increase damage by alkylating agents if cellular defenses are energy requiring. Exposure of cells to lonidamine (500 microM) for 2 h under hypoxic conditions followed by 1-h exposures to lonidamine plus alkylating agents under normally oxygenated conditions in vitro significantly increased the cell kill achieved by cis-diamminedichloroplatinum(II) (CDDP) approximately 5-fold and by D-tetraplatin approximately 10-fold at 90% inhibitory concentration in MCF-7/CDDP (CDDP-resistant) cells. Carboplatin cytotoxicity, however, was little changed. In the MCF-7 parent cell line, treatment with lonidamine increased CDDP cytotoxicity by approximately 10-fold, D-tetraplatin by approximately 10-fold, and carboplatin by approximately 8-fold at the 90% inhibitory concentration. For L-phenylalanine mustard (melphalan), N,N',N"-triethylenethiophosphoramide (thiotepa), and N,N'-bis(2-chloroethyl)-N-nitrosourea, little resistance was evident in the MCF-7/CDDP lines compared with the parent line. Treatment with lonidamine increased the cytotoxicity of each drug by 1.5- to 3-fold in both cell lines. When exposure to lonidamine was extended to 24 h before and 12 h after drug exposure in MCF-7 normally oxygenated cultures, CDDP (250 microM) cytotoxicity was increased by approximately 100-fold, but melphalan cytotoxicity was increased only 2- to 3-fold over the concentration range tested. In the FSaIIC murine fibrosarcoma tumor system, five i.p. injections of 50 mg/kg of lonidamine over 36 h increased the tumor cell kill by CDDP and carboplatin approximately 2- to 3-fold over the dose range tested when the platinum complexes were given i.p. immediately after the third lonidamine injection. When cyclophosphamide and thiotepa were given in the same schedule, 10-fold increases in tumor cell killing were evident on tumor excision assay over the dosage ranges. The increase in bone marrow toxicity caused by lonidamine in addition to the alkylating agents was less than for tumor cells. Finally, in the EMT6 murine mammary carcinoma, use of lonidamine at 500 mg/kg twice daily along with CDDP, carboplatin, thiotepa, and cyclophosphamide significantly increased tumor growth delays by approximately 1.6- to 3.0-fold. The results suggest that lonidamine can positively modulate antitumor alkylating agent cytotoxicity and may be a clinically useful adjunctive therapy with these drugs.

Single-photon emission computed tomography quantitation of gallium citrate uptake for the differentiation of lymphoma from benign hilar uptake.

PURPOSE: To assess the role of quantitative gallium citrate (Ga 67) single-photon emission computed tomography (SPECT) in differentiating lymphoma from benign hilar uptake, concentrations of Ga 67 in 29 sites of documented lymphoma and in 75 benign lesions were compared. PATIENTS AND METHODS: One hundred seven thoracic Ga 67 SPECT studies obtained in 101 consecutive lymphoma patients were reviewed. Fifty-nine studies detected Ga 67 uptake in the hilar and or mediastinal regions. Forty-eight studies showed no such abnormality. The concentration of Ga 67 in the thoracic lesions was measured using a quantitative SPECT technique and its nature was determined by correlation with computed tomographic (CT) scans and follow-up evaluation of the sites. RESULTS: In 20 of 59 abnormal studies (34%), there was lymphoma in the hilar and or mediastinal regions. In the remaining 39 abnormal studies (66%), Ga 67 uptake was benign. There were 29 sites of lymphoma and 75 benign lesions. The concentration of Ga 67 in lymphoma was significantly higher than in benign hilar uptake (13.2 +/- 5.4 %ID/mL x 10(-3) v 5.6 +/- 1.5 % injected dose (ID)/mL x 10(-3); P < .001). A concentration value of 8.3 %ID/mL x 10(-3) was found to best separate lymphoma and benign uptake, with a sensitivity of 90%, a specificity of 93%, a positive predictive value of 84%, and a negative predictive value of 96%. CONCLUSION: Lymphoma and benign hilar uptake differ significantly in their concentration of Ga 67. The present study shows that quantitative Ga-67 SPECT reliably differentiates lymphoma and benign uptake.

Utility of gallium-67 scintigraphy in low-grade non-Hodgkin's lymphoma.

PURPOSE: Low-grade non-Hodgkin's lymphoma (LGNHL) has traditionally been considered non-gallium-avid. The sensitivity of gallium 67 (67Ga) scintigraphy when using modern equipment and techniques in patients with LGNHL was investigated. MATERIALS AND METHODS: Fifty-seven consecutive patients with LGNHL underwent 67Ga scintigraphy at initial presentation (n = 40), when tumor progression occurred during treatment (n = 3), and at suspected disease recurrence after continuous clinical remission (CCR) (n = 14). Planar and tomographic images were obtained with either a very large field-of-view or a dual-head digital camera. Of 45 patients with Ga-avid LGNHL, 30 underwent 93 follow-up scans (one to six studies per patient). Scan findings were correlated with clinical and computed tomographic (CT) findings and with patient outcomes. RESULTS: 67Ga scintigraphy was positive in 45 of 57 patients (sensitivity, 79%) and in 113 of 164 disease sites (sensitivity, 69%). The sensitivity was higher in the more common types of LGNHL: follicular, predominantly small cleaved cell (FSC), and follicular, mixed small cleaved and large cell (FM) (84% and 91% in patients and 72% and 71% in disease sites, respectively). Sensitivity was lower in patients with mucosa-associated lymphoid tissue lymphoma (MALT) and small lymphocytic lymphoma (SL). Among 28 patients with disease recurrence after CCR (14 with and 14 without baseline studies), 67Ga scan was positive in 25, for a sensitivity of 89% for detection of disease recurrence. CONCLUSION: When modern technology is used, 67Ga scintigraphy has good sensitivity in patients with LGNHL. It therefore can be used to monitor response to therapy and to provide early detection of disease recurrence in these patients.

Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial.

PURPOSE: To compare the efficacy and tolerability of the combination of doxorubicin and paclitaxel (AT) with a standard doxorubicin and cyclophosphamide (AC) regimen as first-line chemotherapy for metastatic breast cancer. PATIENTS AND METHODS: Eligible patients were anthracycline-naive and had bidimensionally measurable metastatic breast cancer. Two hundred seventy-five patients were randomly assigned to be treated with AT (doxorubicin 60 mg/m(2) as an intravenous bolus plus paclitaxel 175 mg/m(2) as a 3-hour infusion) or AC (doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2)) every 3 weeks for a maximum of six cycles. A paclitaxel (200 mg/m(2)) and cyclophosphamide (750 mg/m(2)) dose escalation was planned at cycle 2 if no grade >or= 3 neutropenia occurred in cycle 1. The primary efficacy end point was progression-free survival (PFS). Secondary end points were response rate (RR), safety, overall survival (OS), and quality of life. RESULTS: A median number of six cycles were delivered in the two treatment arms. The relative dose-intensity and delivered cumulative dose of doxorubicin were lower in the AT arm. Dose escalation was only possible in 17% and 20% of the AT and AC patients, respectively. Median PFS was 6 months in the two treatments arms. RR was 58% versus 54%, and median OS was 20.6 versus 20.5 months in the AT and AC arms, respectively. The AT regimen was characterized by a higher incidence of febrile neutropenia, 32% versus 9% in the AC arm. CONCLUSION: No differences in the efficacy study end points were observed between the two treatment arms. Treatment-related toxicity compromised doxorubicin-delivered dose-intensity in the paclitaxel-based regimen

Primary lymphoma of the liver: clinical features and outcome of 9 patients.

PURPOSE: Primary liver lymphoma (PLL) is a rare lymphoproliferative disorder of unknown etiology. The prognosis in affected patients is poor, consisting of brief remissions, rapidly developing resistance to chemotherapy, early recurrence, and short survival. Most studies related to PLL are based on case reports. The aim of this retrospective study was to review our experience with PLL. PATIENTS AND METHODS: From 1985 to 2000, 9 patients who fulfilled the diagnostic criteria for PLL were treated at our hospital. All patients underwent a thorough work-up and were staged accordingly. RESULTS: The disease occured in middle and higher-aged patients (median age 63 years). Primary presenting complaints were abdominal pain, mainly in the right upper quadrant, and hepatomegaly. Liver function tests and lactate dehydrogenase (LDH) levels were elevated. Liver imaging (computed tomography-CT) and isotopic methods (gallium scan) demonstrated liver involvement either as solitary or multiple space-occupying lesions. Pathologic examination demonstrated diffuse, large cell (DLCL), B-type lymphoma in 7/9 (78%) patients. Doxorubicin-based chemotherapy was the mainstay of treatment. Good partial or complete remission rates were achieved in 7 patients, albeit for a brief period of time. CONCLUSION: Most patients with PLL succumb to their illness, despite its being relatively chemotherapy-sensitive. The introduction of intensive chemotherapy, plus/minus radiotherapy, and/or surgery has been considered in some studies.

Interaction of D,L- and D-tetraplatin with hyperthermia in vitro and in vivo.

The cytotoxicities of D,L-tetraplatin and D-tetraplatin were evaluated at 37 degrees C, 42 degrees C and 43 degrees C at normal pH, at pH 6.45 and under normally oxygenated and hypoxic conditions in EMT-6 cells in vitro. The D-isomer was also tested in FSaIIC cells in vitro. Under these various conditions the pure D-isomer was very similar in cytotoxicity with the racemic mixture. Like cisplatin, both D,L- and D-tetraplatin were selectively cytotoxic toward normally oxygenated cells under acidic pH (6.45) conditions at 37 degrees C. In both cell lines the cytotoxicity of D,L- and D-tetraplatin was markedly increased at hyperthermic temperatures. Under the same conditions platinum levels in EMT-6 cells exposed to D,L- or D-tetraplatin were higher than in cells exposed to cisplatin, and unlike cisplatin there was an increase in intracellular platinum levels when the cells were exposed to D,L- or D-tetraplatin at 42 degrees C compared with 37 degrees C. The tumour growth delay of the FSaIIC fibrosarcoma was the same for D,L- and D-tetraplatin. A dose of 10 mg/kg intraperitoneally of tetraplatin produced a tumour growth delay of about 4.3 days which was increased to about 6 days with the addition of local hyperthermia (43 degrees C, 30 min) to the drug treatment. The tumour cell survival assay also showed no difference between D,L- and D-tetraplatin and a log-linear increase in tumour cell killing with increasing drug dose which was increased 1.5-3-fold with local hyperthermia. D,L- and D-tetraplatin were relatively much more cytotoxic toward bone marrow colony forming units of granulocyte-macrophage progenitors (CFU-GM) than was cisplatin and this cytotoxicity was increased about 5-10-fold under hyperthermic conditions. There was an increase in DNA crosslink formation in tumours when hyperthermia accompanied tetraplatin treatment. Overall, D,L- and D-tetraplatin produced very similar responses under hyperthermic conditions in both tumour and normal tissues, and may be a useful agent in combination with local hyperthermia.

EO9 phase II study in advanced breast, gastric, pancreatic and colorectal carcinoma by the EORTC Early Clinical Studies Group.

In a phase II trial, the activity of EO9, a new bioreductive alkylating agent, was assessed. EO9 was used as second-line chemotherapy in breast cancer patients and as first-line chemotherapy for patients with gastric, pancreatic and colorectal cancer. EO9 was given as a 5 min i.v. infusion at a weekly dose of 12 mg/m2. 92 patients were entered; 22 with breast cancer, 26 with colon cancer, 24 with pancreatic cancer and 20 with gastric cancer. In general, the drug was well tolerated with nausea and vomiting occurring in 26.42 and 13.3% of courses, respectively. Reversible proteinuria was the main toxicity occurring in 45% of courses. Antitumour activity was not observed. At this dose and schedule, EO9 is not an active drug in the type of tumour studied.

Whole abdominal irradiation following chemotherapy in advanced ovarian carcinoma.

One hundred and sixteen patients with advanced ovarian carcinoma, who underwent primary cytoreductive surgery, received 6-11 courses of chemotherapy by cis-platin (50 mg/m2) and adriamycin (50 mg/m2) every 21 days. This was followed by second look laparotomy in 66 patients with no clinical evidence of disease. Consolidation abdominal irradiation was administered to 43 patients. Two techniques of irradiation were employed: between 1980-1983 whole abdominal irradiation was used and patients were to receive 3000 cGy in 4 weeks (Schedule I). Due to myelosuppression only 13 of 26 patients (50%) completed the planned dose of radiation. Between 1983-1985 the target volume was divided into upper and lower parts. First, the lower abdomen received 3000 cGy in 3 weeks, and then the upper abdomen received the same dose (Schedule II). Sixteen of seventeen patients (94%) thus treated, completed the planned dose of radiation. The actuarial survival for all 116 patients was 28% of 5 years. Irradiated patients with negative second look laparotomy had a survival probability of 100% at 24 months. Irradiated patients with microscopic disease at second look operation had an actuarial 5-year survival of 66%. Patients with minimal residual disease at second look laparotomy, receiving consolidation abdominal irradiation, had an actuarial survival of 5% only at 36 months. It is concluded that consolidation radiotherapy is effective in patients with negative or microscopic residual disease at second-look laparotomy. In regard to bone marrow tolerance, split field technique of irradiation is preferred.

Gallium-67 uptake in a mass of benign transformation mimicking recurrence of nodular lymphocytic predominance Hodgkin's disease.

Gallium-67 is now widely used in the management of lymphoma patients. It is not, however, tumor-specific and reasons for uptake in nonmalignant and premalignant lesions associated with lymphoma should be recognized. Gallium-67 uptake in a mass of progressively transformed germinal centers and sarcoid-like reaction, mimicking recurrence in a 31-yr-old man with nodular lymphocytic predominance Hodgkin's disease, is described. Gallium-67 was taken up on two occasions and a recurrence was suspected. On the first occasion, abnormal uptake was present in axillary lymph nodes and on the second in mediastinal and parahilar lymph nodes. Histology of the lesions on both occasions showed progressively transformed germinal centers and sarcoid-like reaction but no evidence of Hodgkin's disease (HD). Bilateral parahilar abnormal uptake of 67Ga disappeared spontaneously without treatment after several months. The mass on CT regressed but did not disappear. This case demonstrates that the appearance of a new mass which takes up 67Ga in lymphocytic-predominance HD during a continuous clinical remission does not necessarily indicate recurrence and the need for treatment. It suggests that a biopsy should be performed to determine the nature of the lesion.

Residual mass and negative gallium scintigraphy in treated lymphoma.

Two patients with treated lymphoma demonstrated a residual mass on CT following treatment. In both cases gallium-67 (67Ga) scintigraphy demonstrated increased uptake in the original tumor mass and no uptake in the mass after treatment. In both cases the entire residual tumor mass was resected and found to contain no cancer tissue. This is further evidence of the role 67Ga scintigraphy may play in monitoring response of lymphoma patients to treatment. In contrast, other imaging modalities such as ultrasound, plain film x-rays, or CT only show the presence of a mass but not its nature.

Early detection of lymphoma recurrence with gallium-67 scintigraphy.

Early detection of tumor relapse in lymphoma patients is often a difficult diagnostic problem. CT, which detects a mass, often cannot differentiate between fibrosis or relapsed tumor. For this reason, we have studied the value of 67Ga scintigraphy in the diagnosis of tumor recurrence. The sensitivity of 67Ga scintigraphy in the detection of lymphoma recurrence was studied at an average interval of 8.7 mo following treatment in 32 patients who developed recurrent lymphoma. Its specificity was studied in 36 patients with no recurrence who were in continuous clinical remission. At the time of appearance of relapse, the sensitivity of whole-body 67Ga imaging was 95% and the specificity 89%. In 12 events of recurrence in 10 patients, 67Ga scintigraphy was abnormal at sites that later proved to be regions of relapse. In these patients, scintigraphy demonstrated recurrence an average of 6.8 mo before the appearance of clinical symptoms, findings on clinical examination or abnormality on CT or chest x-rays. Gallium-67 scintigraphy, which permits screening of the whole body for recurrence in a single study, was of particular value in evaluating lymphoma recurrence, since 27% of the recurrences were located exclusively in sites different from the original sites of disease. Gallium-67 scintigraphy appears to be a sensitive and specific test for restaging patients with lymphoma recurrence.

Gallium-67 scintigraphy in lymphoma with bone involvement.

UNLABELLED: Both Hodgkin's and non-Hodgkin's lymphoma (NHL) may involve bone. Traditionally, 99mTc-MDP bone scintigraphy has been used to detect such involvement. In recent years, 67Ga scintigraphy has shown to be useful in monitoring treatment response in lymphoma. Although 99mTc-MDP has not been found particularly useful for monitoring bone response to cancer treatment, we were interested in whether 67Ga scintigraphy and SPECT could be used to monitor bone involvement with lymphoma. METHODS: Gallium-67 and 99mTc-MDP uptake were investigated in 20 patients with lymphoma involving the bone before treatment. Gallium-67 scans were done in 16 patients for monitoring response to treatment in the bone lesions. RESULTS: Gallium-67 studies diagnosed bone lesions in 19 of the 20 patients. Technetium-99m-MDP detected bone lesions in all patients investigated. In four patients, uptake by Ga-67 was more intense than 99mTc-MDP and in another four patients 99mTc-MDP uptake was more evident. Gallium-67, however, was useful in detecting other regions of involvement in 18 of the 19 patients with soft-tissue lymphoma lesions. Gallium-67 scintigraphy also correctly monitored bone response to treatment in all but one of the 16 patients who had 67Ga scintigraphy after completing therapy. CONCLUSION: Gallium-67 uptake by lymphoma involving the bone can be used to monitor osseous response to treatment.

Enzyme-linked-immunosorbent-assay for the detection of a novel 21-kda protein associated with the clinical course of patients with urogenital tumors.

A novel 21 kDa protein (p21) was detected in sera of patients with urogenital tumors by ELISA, using rabbit polyclonal antibodies generated against the p21 polypeptide. Eight out of 11 patients (72%) exhibited a 2-5 fold increase in pre-treatment p21 serum levels as compared with 20 healthy individuals. A decrease of p21 levels was observed in 6 out of 8 patients in which a regression of the disease was shown post-treatment. An increase or no change in p21 levels was observed in 3 patients with no change or progression of the disease. The ELISA described herein may be useful for clinical monitoring of patients with urogenital tumors, some of which have no available tumor marker.

Prolonged daily administration of oral etoposide in lymphoma following prior therapy with adriamycin, an ifosfamide-containing salvage combination, and intravenous etoposide.

Prolonged daily administration of oral etoposide has been reported to be active in refractory lymphoma. The purpose of this phase II trial was to confirm the activity of this schedule of etoposide in a selected group of heavily pretreated patients with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). A total of 26 patients (20 with NHL and 6 with HD) were entered in the trial; all had previously been treated with an Adriamycin-based chemotherapy, an ifosfamide-containing salvage combination, and i.v. etoposide. Etoposide was given in a fixed oral daily dose of 100 mg over 3 weeks; the weekly dose (500-700 mg) was selected such that the average daily dose was approximately 50 mg/m2. Cycles were repeated on day 29. An objective response was seen in 16 patients (62%; 95% confidence interval, 42%-80%), with a complete response (CR) being observed in 3 cases (12%) and a partial response (PR), in 13 (50%). The median duration of PRs was 3 months. CRs lasted for 15 months in one patient and continue at 12+ and 20+ months in the remaining two patients. The overall actuarial survival for the entire group was 40% at 2 years; the median survival time was 12 months. The main toxicity was myelosuppression; WHO grade 3 or 4 leukopenia and thrombocytopenia developed in 31% and 12% of the patients, respectively. There was no drug-related death. We conclude that oral etoposide is an effective and tolerable palliative treatment for heavily pretreated lymphoma patients.

Salvage therapy for non-Hodgkin's lymphoma with a combination of dexamethasone, etoposide, ifosfamide, and cisplatin.

A total of 30 consecutive patients with refractory or relapsing non-Hodgkin's lymphoma (NHL) were treated with a combination of dexamethasone, etoposide (VP-16), ifosfamide, and cisplatin (DVIP). In all, 9 subjects (30%) showed a partial response and 10 (33%) achieved a complete response (CR) lasting from 2.5 to 24+ months. Aggressive histology, no prior therapy with VP-16, a CR to previous chemotherapy, and a treatment-free interval of greater than 6 months prior to the present study were associated with the high CR rate. DVIP caused pronounced myelosuppression (median granulocyte nadir and median platelet nadir, 380/mm3 and 73.000/mm3, respectively), but no drug-related death occurred. We conclude that DVIP is an effective salvage combination, especially in aggressive NHL, that produces acceptable toxicity.

Intermediate and high-grade gastric non-Hodgkin's lymphoma: a prospective study of non-surgical treatment with primary chemotherapy, with or without radiotherapy.

The role of surgery as initial treatment in gastric lymphoma remains controversial. We have prospectively evaluated a stomach conservation strategy in histologically aggressive gastric lymphoma, using primary adriamycin-containing chemotherapy, followed by involved-field radiotherapy in patients with limited disease. Twenty-six patients (median age 69 years) were entered in this study; 15 had stage I disease, 7 had stage II disease and 4 had stage IV disease. The chemotherapy combinations were CHOP (18 patients) and ProMACE/MOPP (8 patients). Radiotherapy was given to 11 patients. Of the 24 patients evaluated for response, 18 (75%) achieved endoscopically-confirmed complete response and 4 (17%) partial response. During follow-up (median 22 months), none of the complete responders developed recurrent lymphoma. Gastric resection was performed in 1/26 patients who did not respond to primary chemotherapy. There were no cases of perforation, but three patients (12%) developed acute gastro-intestinal bleeding a few days after the onset of chemotherapy, one of whom required a surgical devascularization procedure. There was no treatment-related mortality. These data further support the non-surgical approach in histologically aggressive gastric lymphoma, using primary chemotherapy with or without radiation therapy.

Clinical characteristics of non-Hodgkin's lymphoma as a second primary tumor: a population-based survey.

Data from 29,845 patients with lymphomas, 981 of whom had lymphoma as a second primary tumor, registered in the Surveillance Epidemiology and End Results (SEER) program in the U.S.A. between 1973 and 1986 were analyzed. The characteristics of the 274 patients with lymphoma as a second tumor who had received chemotherapy and/or radiotherapy for their primary tumor (SEP PT) were compared with 675 patients with second primary lymphomas who had no prior treatment (SEP NT) and with patients with single lymphomas (SIP). Patients with SEP PT disease had a significantly higher percentage of intermediate and high-grade tumors (80%) compared to those with SEP NT or SIP tumors (73% and 72%, respectively). The survival of all patients with SIP tumors did not differ from those with SEP tumors, but the median survival of those with SEP PT disease was shorter than for SEP NT disease. This was most probably due to the high percentage of intermediate and high-grade lymphomas in the SEP PT group. This was statistically significant in the group treated by combined chemotherapy and radiotherapy but not in those treated by a single modality alone. These findings relating to a worse prognosis in patients with SEP PT lymphoma are in line with our previous observations of a poor survival in patients with other multiple primary tumors.

Efficacy of pentoxifylline as a modulator of alkylating agent activity in vitro and in vivo.

Pentoxifylline, a methylxanthine that is used to treat veno-occlusive disease, can increase perfusion in undervascularized tissues. Addition of high concentrations, like caffeine, causes progression through radiation or drug induced G2 phase blocks, thereby limiting time for repair of DNA breaks and crosslinks. We have examined the potential of pentoxifylline to augment the effects of antitumor alkylating agents in vitro and in vivo. In MCF-7 human breast cancer cells in vitro, pentoxifylline (2 mM) present for 24 h was only slightly cytotoxic (approximately 10% cell kill at 2 mM), but when present prior to and during AA it increased the cytotoxicity of CDDP by 2 logs at 250 microM. With L-PAM in vitro, pentoxifylline was much less effective and only at a concentration of 250 microM L-PAM did 2 mM pentoxifylline increase cytotoxicity (approximately 0.3 logs). In the FSaIIC murine fibrosarcoma system, 100 mg/kg of pentoxifylline i.p. immediately prior to the alkylating agent or 50 mg/kg x 5 of pentoxifylline over 24 h with the alkylating agent given immediately after the third dose increased the tumor cell kill achieved by CDDP, carboplatin, cyclophosphamide, and thiotepa. The increase in tumor cell killing was modest (2.9-fold). Pentoxifylline in the multiple dose regimen (50 mg/kg x 5 over 24 h) was more effective than in the single dose (100 mg/kg) protocol. In the EMT6 mouse mammary adenocarcinoma, pentoxifylline (100 mg/kg daily x 5) improved the tumor growth delay produced by CDDP (3.3 mg/kg alternate days x 3), carboplatin (25 mg/kg daily x 5), cyclophosphamide (100 mg/kg alternate days x 3) and thiotepa 5 mg/kg (daily x 5). Only with cyclophosphamide, however, did the interaction appear to be large, as a 2.4-fold increase was observed.

Haptoglobin-related protein as a serum marker in malignant lymphoma.

A novel serum 21 kDa haptoglobin-related protein (Hpr) was investigated in patients with malignant lymphoma, to evaluate its correlation with clinical and histologic features at presentation and its possible role as a tumor marker for patient outcome. One hundred fifty eight serum samples were taken from 88 patients with non-Hodgkin's lymphoma (n=58) and Hodgkin's disease (n=30) at presentation and in the course of follow-up. Sera from 61 healthy volunteers served as normal controls. Serum Hpr levels in the lymphoma patients (median 430x10 u/ml, range 0-4000x10 ) were significantly higher than in the control group (median 68x10 u/ml, range 0-180x10 )(p=0.0001). Higher median Hpr values were detected in patients with advanced disease (p=0.013), "B" symptoms (p=0.029) and in males (p=0.053). There was also a significant correlation between Hpr and erythrocyte sedimentation rate (p=0.028). Serial determinations showed a significant decrease of the initial Hpr values obtained after treatment in 41 patients, 38 of whom achieved complete remission. In the follow-up period additional Hpr measurements were taken from 17 patients. Three of them eventually relapsed, and showed increased Hpr levels at the time of relapse. Hpr levels remained low in 11 of 14 patients who maintained complete remission, and increased in three. In conclusion, serum Hpr is a new serum tumor marker of potential use in the clinical setting of lymphoma.