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Introduction: Physical activity (PA) is associated with higher quality of life and probably better prognosis among colorectal cancer (CRC) patients. This study focuses on determinants of PA among CRC patients from diagnosis until 5 yr postdiagnosis., Methods: Sociodemographic and disease-related factors of participants of two large CRC cohort studies were combined. Moderate-to-vigorous PA during sport and leisure time (MVPA-SL) was measured at diagnosis (T0) and 6, 12, 24, and 60 months (T6 to T60) postdiagnosis, using the SQUASH questionnaire. Mixed-effects models were performed to identify sociodemographic and disease-related determinants of MVPA-SL, separately for stage I-III colon (CC), stage I-III rectal cancer (RC), and stage IV CRC (T0 and T6 only). Associations were defined as consistently present when significant at ≥4 timepoints for the stage I-III subsets. MVPA-SL levels were compared with an age- and sex-matched sample of the general Dutch population., Results: In total, 2905 CC, 1459 RC and 436 stage IV CRC patients were included. Patients with higher fatigue scores, and women compared with men had consistently lower MVPA-SL levels over time, regardless of tumor type and stage. At T6, having a stoma was significantly associated with lower MVPA-SL among stage I-III RC patients. Systemic therapy and radiotherapy were not significantly associated with MVPA-SL changes at T6. Compared with the general population, MVPA-SL levels of CRC patients were lower at all timepoints, most notably at T6., Conclusions: Female sex and higher fatigue scores were consistent determinants of lower MVPA-SL levels among all CRC patients, and MVPA-SL levels were lowest at 6 months postdiagnosis. Our results can inform the design of intervention studies aimed at improving PA, and guide healthcare professionals in optimizing individualized support., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Background: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported., Materials and Methods: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models., Results: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status., Conclusions: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials., Competing Interests: Disclosure PJvD has advisory relationships with Paige, Pantarei and Samantree, paid to the institution, and research grants paid to the institute from Pfizer. NS received institutional research funding from Pfizer. ZV has a consulting role for Roche. CHMvD received institutional research funding from AstraZeneca/Daiichi Sankyo. SMW has a consulting role for Roche, and received institutional research funding from Roche, Pfizer, Bayer, MSD, AstraZeneca/Merck and Amgen. SMW has a consulting role for IDDI, Sensorion, Biophytis, Servier, Yuhan, Amaris Consulting and Roche. JW received institutional research funding from Cancer Research UK and KWF Dutch Cancer Society. AR has a consulting role for MSD Oncology, Amgen, Roche, AstraZeneca/Daiichi Sankyo and Bristol Myers Squibb/Pfizer. SCL reports grants from ZonMw and A Sister’s Hope during the conduct of the study; has been an advisory board member for AstraZeneca, Cergentis, IBM, Novartis, Pfizer, Sanofi and Roche; and received institutional research grants from Agendia, AstraZeneca, Eurocept-pharmaceuticals and Merck and Pfizer. In addition, SCL received institutional research grants and institutional non-financial support from Agendia, Genentech, Novartis, Roche, Tesaro and Immunomedics and other institutional support from AstraZeneca, Pfizer, Cergentis, Daiichi Sankyo, IBM and Bayer outside the submitted work. MK is an advisory board member and/or received speakers’ fee for/from Alderaan, Bristol Myers Squibb (BMS), Domain Therapeutics, Gilead, Roche, Medscape, MSD and AZ/Daiichi and received institutional research support from AstraZeneca/Daiichi, BMS and Roche outside the submitted work. RS reports non-financial support from Merck and BMS, research support from Merck, Puma Biotechnology and Roche, and personal fees from Roche, BMS and Exact Sciences for advisory boards. IRK received research grants from Novartis and Gilead. RHTK is an advisory board member for Amgen, AstraZeneca, Bayer, BMS, MSD, Novartis, Pfizer, Pierre Fabre Sante, Sanofi and Servier. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Guidelines recommend endocrine treatment for estrogen receptor-positive (ER+) breast cancers for up to 10 years. Earlier data suggest that the 70-gene signature (MammaPrint) has potential to select patients that have an excellent survival without chemotherapy and limited or no tamoxifen treatment. The aim was to validate the 70-gene signature ultralow-risk classification for endocrine therapy decision making., Methods: In the IKA trial, postmenopausal patients with non-metastatic breast cancer had been randomized between no or limited adjuvant tamoxifen treatment without receiving chemotherapy. For this secondary analysis, FFPE tumor material was obtained of ER+HER2- patients with 0-3 positive lymph nodes and tested for the 70-gene signature. Distant recurrence-free interval (DRFI) long-term follow-up data were collected. Kaplan-Meier curves were used to estimate DRFI, stratified by lymph node status, for the three predefined 70-gene signature risk groups., Results: A reliable 70-gene signature could be obtained for 135 patients. Of the node-negative and node-positive patients, respectively, 20% and 13% had an ultralow-risk classification. No DRFI events were observed for node-negative patients with an ultralow-risk score in the first 10 years. The 10-year DRFI was 90% and 66% in the low-risk (but not ultralow) and high-risk classified node-negative patients, respectively., Conclusion: These survival analyses indicate that the postmenopausal node-negative ER+HER2- patients with an ultralow-risk 70-gene signature score have an excellent 10-year DRFI after surgery with a median of 1 year of endocrine treatment. This is in line with published results of the STO-3-randomized clinical trial and supports the concept that it is possible to reduce the duration of endocrine treatment in selected patients., (© 2022. The Author(s).)

Regular physical activity (PA) is associated with improved overall survival (OS) in stage I-III colorectal cancer (CRC) patients. This association is less defined in patients with metastatic CRC (mCRC). We therefore conducted a study in mCRC patients participating in the Prospective Dutch Colorectal Cancer cohort. PA was assessed with the validated SQUASH questionnaire, filled-in within a maximum of 60 days after diagnosis of mCRC. PA was quantified by calculating Metabolic Equivalent Task (MET) hours per week. American College of Sports and Medicine (ACSM) PA guideline adherence, tertiles of moderate to vigorous PA (MVPA), and sport and leisure time MVPA (MVPA-SL) were assessed as well. Vital status was obtained from the municipal population registry. Cox proportional-hazards models were used to study the association between PA determinants and all-cause mortality adjusted for prognostic patient and treatment-related factors. In total, 293 mCRC patients (mean age 62.9 ± 10.6 years, 67% male) were included in the analysis. Compared to low levels, moderate and high levels of MET-hours were significantly associated with longer OS (fully adjusted hazard ratios: 0.491, (95% CI 0.299-0.807, p value = 0.005) and 0.485 (95% CI 0.303-0.778, p value = 0.003), respectively), as were high levels of MVPA (0.476 (95% CI 0.278-0.816, p value = 0.007)) and MVPA-SL (0.389 (95% CI 0.224-0.677, p value < 0.001)), and adherence to ACSM PA guidelines compared to non-adherence (0.629 (95% CI 0.412-0.961, p value = 0.032)). The present study provides evidence that higher PA levels at diagnosis of mCRC are associated with longer OS.

Background: Metastatic colorectal cancer patients with deficient mismatch repair (dMMR mCRC) benefit from immunotherapy. Interpretation of the single-arm immunotherapy trials is complicated by insignificant survival data during systemic non-immunotherapy. We present survival data on a large, comprehensive cohort of dMMR mCRC patients, treated with or without systemic non-immunotherapy., Methods: Two hundred and eighty-one dMMR mCRC patients (n = 54 from three prospective Phase 3 CAIRO trials; n = 227 from the Netherlands Cancer Registry). Overall survival was analysed from diagnosis of mCRC (OS), from initiation of first-line (OS1) and second-line (OS2) systemic treatment. Cox regression analysis examined prognostic factors. As comparison for OS 2746 MMR proficient mCRC patients were identified., Results: Of 281 dMMR patients, 62% received first-line and 26% second-line treatment. Median OS was 16.0 months (13.8-19.6) with antitumour therapy and 2.5 months (1.8-3.5) in untreated patients. OS1 was 12.8 months (10.7-15.2) and OS2 6.2 months (5.4-8.9) in treated dMMR patients. Treated dMMR patients had a 7.6-month shorter median OS than pMMR patients., Conclusion: Available data from immunotherapy trials lack a control arm with standard systemic treatment. Given the poor outcome compared to the immunotherapy results, our data strongly suggest a survival benefit of immunotherapy in dMMR mCRC patients.

This case report presents an adult patient with decreased levels of consciousness and bizarre behavior. A silent delirium was first suspected however, symptoms did not improve and further examination revealed elevated ammonia levels. A hepatic cause and portosystemic shunting were excluded and eventually a diagnosis of ornithine transcarbamylase deficiency was made. After treatment with high carbohydrate intake, a low protein diet and supplementation with arginine and sodium benzoate, the patient recovered.

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients., Material and Methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future., Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing., Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

Background: Bleomycin is used in the treatment of different cancers, but possible side effects of interstitial pneumonitis and fibrosis are associated with increased concentrations of oxygen. Therefore, clinicians are reluctant to declare young people fit for scuba diving after bleomycin treatment, because scuba divers might be exposed to high partial pressures of oxygen., Methods: Based on a survey, 16 patients treated with bleomycin for either testicular/germ cell cancer or Hodgkin's disease were evaluated according to an algorithm to assess their fitness to dive. The algorithm is based on a review of the literature related to oncology, anesthesiology, and diving medicine., Results: According to our protocol, 12 of the 16 patients were fit for scuba diving. However, the two groups of cancer patients showed considerable difference with regard to fitness for diving, i.e., 10 of 11 patients with testicular/germ cell cancer compared with 2 of 5 patients with Hodgkin's disease., Conclusions: The algorithm can be used by physicians and diving organizations to assess fitness for scuba diving after bleomycin treatment. However, patients with Hodgkin's disease treated with a combination of bleomycin and radiation may be at higher risk of radiation-induced pulmonary problems and are therefore more likely to be unfit for scuba diving.

Objective: In the Netherlands, high risk gestational trophoblastic disease (GTD) patients are treated in different referral hospitals with a national working party on trophoblastic tumours having a co-ordinating function. Our purpose was to evaluate whether this policy is a satisfactory alternative to complete centralisation., Design: A retrospective study of all etoposide, methotrexate, actomycin D, cyclophosphamide and vincristine (EMA/CO)-treated women in the Netherlands between 1986 and 1997. Data regarding risk factors, treatment results and toxicity were collected., Setting: Ten hospitals; 2 general, 6 academical and 2 oncology centres., Population: Fifty EMA/CO-treated women registered by the central registration unit of the Dutch Working Party on Trophoblastic Disease., Methods: Patients files and quarterly reports of the Dutch Working Party., Main Outcome Measures: Cure rate and consistency of treatment in different hospitals., Results: EMA/CO treatment was administered in 10 different hospitals. All patients were discussed during the meetings of the Dutch Working Party and overall, 86% of patients were cured. Consistency in treatment was good., Conclusions: Cure rates were comparable with results of single institution series. We conclude that treatment of high risk GTD patients in different referral hospitals with concentration of expertise in a working party is a good alternative to centralisation of treatment in GTD specialised hospitals.

Objective: Whole-body hyperthermia (WBH) in combination with chemotherapy is a relatively new promising treatment modality for patients with cancer. The objective of this report is to present the development of an acute systemic inflammatory response syndrome (SIRS) with multiple organ dysfunction syndrome (MODS) following WBH in combination with chemotherapy. Although WBH can also induce cytokine production, MODS has not been described before in association with WBH., Design: Case report. The patient was treated with WBH (core temperature 41.8 degrees C using a radiant heat device (Aquatherm) ) in combination with polychemotherapy (ifosfamide, carboplatin and etoposide (ICE) ) in the context of a clinical trial for metastatic sarcomas., Setting: Department of medical oncology and intensive care unit of a university hospital., Patient: A 58-year-old Caucasian woman treated for disseminated leiomyosarcoma of the uterus, who developed SIRS with brain dysfunction, hypotension, respiratory failure and renal dysfunction following WBH/ICE., Interventions: She was successfully treated in the intensive care unit by mechanical ventilation, inotropics and antibiotics., Measurements and Results: There was a remarkable recovery within 2 days: she regained full conciousness, could be extubated, inotropic support was stopped and creatinine levels returned to pre-treatment levels. All cultures remained sterile. After almost complete recovery, 5 days later a second episode of fever during neutropenia occurred and, despite antibiotic treatment, she died of Bacteroides distasonis sepsis., Conclusion: WBH should be added as a new cause to the already known list of physical-chemical insults which can result in MODS.

Hyperthermia in combination with chemotherapy has a strong biological rationale based on thermal enhancement of cytotoxicity and partial circumvention of resistance. Weekly locoregional hyperthermia in combination with cisplatin is an effective treatment (response rate: 52%) for patients with a recurrence of a previously irradiated carcinoma of the uterine cervix. A comparative trial versus cisplatin alone was recently started. Hyperthermic intraperitoneal chemotherapy is aimed at situations after optimal cytoreductive surgery in patients with carcinomatous peritonitis. The warmth enhances the penetration of the oncolytic agent. Whole-body hyperthermia using the Aquatherm apparatus in combination with chemotherapy is feasible: results in patients with metastatic sarcomas are promising. Trials with whole-body hyperthermia are in progress in patients with platinum refractory ovarian cancer and in patients with a metastatic carcinoma of the uterine cervix.

Although exacerbations of previously quiescent HBV infection, associated with chemotherapy, have been attributed to enhanced immunological responses to hepatocytes harboring reactivated HBV, the recommended treatment, prednisolone, is often unsuccessful. A young HBsAg-positive, anti-HBe-positive carrier, who received chemotherapy for choriocarcinoma, developed icteric hepatitis. The serum HBV DNA level was 34,000 x 10(6) genomic equivalents per milliliter serum. Treatment with prednisolone alone did not prevent progression to overt hepatic failure. By three days after initiating lamivudine therapy, however, there was reversal of stage III hepatic encephalopathy. With further lamivudine treatment, substantial further improvement in hepatocellular function occurred and HBV-DNA levels became undetectable. When an immunocompromised patient develops an exacerbation of hepatitis B associated with high HBV DNA levels, treatment with prednisolone seems inappropriate, as hepatocytotoxic HBV replication may be stimulated further. In this situation inhibition of HBV replication, eg, by administering lamivudine, may be life-saving.

The taxanes represent a new class of clinical chemotherapeutic agents. A series of in vitro studies were independently of each other initiated in two different institutes (Amsterdam and Madison) to test the hypothesis that hyperthermia might enhance the cytotoxicity of taxanes. Clonogenic capacity experiments (Amsterdam) included the exposure of R1- and SW 1573-cells to 1, 4, or 24 h of paclitaxel with heat 43 degrees C x 60 min in the last hour of drug treatment or at 24, 48 as well as 72 h post drug treatment. Survival assay experiments (Madison) included the exposure of L-929-cells to paclitaxel and docetaxel for 24 h with heat 41.8 degrees C x 60 min the first or last hour of drug treatment as well as 24 and 48 h post treatment. No thermal enhancement of cytotoxicity for the taxanes was observed in these human and murine cell lines, with congruent data in both institutes. In addition, high performance liquid chromatography studies at 41.8 degrees C and 43 degrees C demonstrated paclitaxel and docetaxel were heat stable.

Purpose: To evaluate the feasibility of noninvasive imaging of estrogen receptors (ERs) in primary and metastatic breast cancer with the iodine-123-labeled ER-specific ligand cis-11beta-methoxy-17alpha-iodovinylestradiol-17beta (Z-[123I]MIVE) using conventional nuclear medicine techniques., Patients and Methods: Z-[123I]MIVE planar scintigraphy and single-photon emission computed tomography (SPECT) were performed in 12 patients with proven primary breast cancer and 13 patients with proven or from other imaging modalities evident bone, liver, lung, pleura and/or lymph node metastases. The results were compared with those of ER immunohistochemistry (IHC). Blocking studies with the antiestrogen tamoxifen were performed to test whether Z-[123I]MIVE tumor uptake was ER-mediated., Results: Planar imaging showed uptake in 11 of 12 primary carcinomas. ER IHC performed for nine of these was positive. For the planar scintigraphy-negative patient, SPECT was faintly positive, but ER IHC negative (agreement, 90%). In nine of 13 metastatic patients, planar scintigraphy was positive. The agreement between the results of ER IHC on the original primary tumor and of Z-[123I]MIVE scintigraphy was 82%. Specificity of tumor Z-[123I]MIVE uptake was established by complete blockade of uptake by tamoxifen, except in two patients who showed progressive disease. Z-[123I]MIVE scintigraphy also enabled discriminating metastases from confounding nonmalignant abnormalities of the bone scan., Conclusion: Z-[123I]MIVE scintigraphy shows high sensitivity and specificity for the detection of ER-positive breast cancer. This may have impact on diagnostic possibilities and therapeutic management. Since ER imaging shows the functional status, addressing known intratumoral and intertumoral ER heterogeneity, it may improve the characterization of disease and the selection of patients who may benefit from hormonal therapy.

Background: The biologic rationale for combining cisplatin with locoregional hyperthermia (HT) relates to the potentiating effect of HT on cisplatin cytotoxicity., Methods: Patients with recurrent cervical carcinoma, who had a pelvic recurrence after radiotherapy, were treated with weekly cycles of locoregional HT (using the 70-megahertz, 4 antenna-phased array system for 1 hour and cisplatin, 50 mg/m2 intravenously [i.v.], for a maximum of 12 cycles.), Results: Twenty-three patients were entered in this study. A total of 169 cycles were given. Responses were observed in 12 of 23 patients, a response rate of 52% (95% confidence interval, 31-73%). Salvage surgery became possible in 3 of 12 responding patients, whose tumors were previously considered unresectable. The median duration of response was 9.5+ months, the median overall survival was 8+ months, and the 1-year survival was 42%. No correlation was found between treatment outcome and clinical parameters such as age, weight, performance status, and histology. Thermal parameters such as T20, T50, and T90 were higher in responding patients, but were not significantly different from nonresponding patients. Overall toxicity was moderate. Subcutaneous fatty necrosis due to HT occurred in 10% of the cycles, whereas 2 patients developed skin burns. Squamous cell carcinoma antigen proved to be a valuable tool for the evaluation of response and detection of progression., Conclusions: Weekly locoregional HT and cisplatin, 50 mg/ m2 i.v., for a maximum of 12 cycles was effective treatment in patients with a previously irradiated recurrent carcinoma of the uterine cervix.

The cytotoxicity of cisplatin and cisplatin-DNA adduct formation in vitro and in vivo is clearly enhanced by hyperthermia. We investigated whether cytotoxicity and platinum-DNA adduct formation of two promising new third-generation platinum derivatives, lobaplatin [1,2-diamminomethylcyclobutane platinum(II) lactate] and oxaliplatin [oxalato-1,2-diaminocyclohexane platinum(II)], are also enhanced by hyperthermia. Cisplatin was used for comparison. SW 1573 cells were incubated with cisplatin, lobaplatin or oxaliplatin at different concentrations for 1 h at 37 degrees, 41 degrees and 43 degrees C. The reproductive capacity of cells was determined by cloning experiments. Immunocytochemical detection of platinum-DNA adducts was performed with the rabbit antiserum NKI-A59. At 37 degrees C, cisplatin was the most cytotoxic, followed by oxaliplatin and lobaplatin. Hyperthermia clearly enhanced the cytotoxicity of cisplatin, lobaplatin and oxaliplatin. There was no further increase in cytotoxicity at 43 degrees C compared to 41 degrees C for cisplatin and oxaliplatin. A further increase in cytotoxicity at 43 degrees C was observed for lobaplatin. At 43 degrees C thermal enhancement was higher for lobaplatin than for oxaliplatin, with the reverse pattern at 41 degrees C. For both drugs, thermal enhancement of cytotoxicity was lower than observed for cisplatin. Immunocytochemical detection of platinum-DNA adducts was feasible for all the drugs. Adduct formation was enhanced at 43 degrees C for cisplatin, lobaplatin and oxaliplatin with a relative increase of 410%, 170% and 180%. These results seem to confirm that an increase in platinum-DNA adduct formation is involved in the in vitro thermal enhancement of cytotoxicity. The observed thermal enhancement of cytotoxicity of lobaplatin and oxaliplatin in vitro warrants further in vivo investigations.

Two interesting representatives of a new generation of platinum-based cytostatic drugs that are currently being tested in clinical trials are lobaplatin [1,2-diaminomethylcyclobutane platinum(II) lactate] and oxaliplatin [1,2-diaminocyclohexane platinum (II) oxalate]. Since little is known about the DNA adduct formation of these compounds, we studied their formation in DNA in vitro in calf thymus DNA and in cells. The major adducts formed in vitro were the Pt-GG and Pt-AG intrastrand crosslinks. The latter adducts could be detected using a recently developed 32P-postlabelling method. Using both this assay and atomic absorption spectroscopy, it was shown that there is a substantially higher rate of the in vitro adduct formation by cisplatin, compared with lobaplatin and oxaliplatin. Platinum concentrations required to obtain 90% cell kill during a 2 h incubation of A2780 cells were 15 microM for cisplatin and oxaliplatin and 22 microM for lobaplatin. Using an antiserum originally raised against cisplatin-treated DNA, we were also able to detect platinum-DNA adducts induced by lobaplatin and oxaliplatin. Maximal nuclear staining for all three compounds was observed after a 4 h post-incubation period. The nuclear staining level induced by cisplatin was about 10-fold higher than after lobaplatin and oxaliplatin treatment. GG and AG adducts, measured by 32P-postlabelling, also showed maximum levels at about 4 h after treatment. Relative GG peak levels were 4:1:3 for cisplatin, lobaplatin and oxaliplatin, respectively. The ratios of GG over AG intrastrand crosslinks in the A2780 cells were not significantly different for the various compounds. In conclusion, the 32P-postlabelling technique has been shown to be appropriate for adduct analysis, not only for the classical Pt compounds cisplatin and carboplatin but also for novel platinum compounds like lobaplatin and oxaliplatin. Results indicated large differences in reactivity of the latter compounds to DNA in vitro, compared with cisplatin. This difference was smaller in cells, suggesting enhancement of adduct formation by certain cellular mechanisms and/or compounds. From these studies, no conclusions can be drawn with respect to the cytotoxicity of the different Pt-GG and Pt-AG intrastrand crosslinks formed by these compounds.

Purpose: We have investigated differences in the efficacy of combined treatment with cis-diamminedichloroplatinum(II) (cDDP) and local hyperthermia (HT) in nonirradiated and preirradiated experimental tumors., Methods and Materials: Survival of R-1 rhabdomyosarcoma cells was assessed after treatment with various cDDP-concentrations at 37 degrees C and 42 degrees C in vitro. Rats bearing R-1 rhabdomyosarcomas of 190 mm3 (SE 15 mm3) were treated with cDDP (6 mg/kg i.p.), HT (1 h at 43 degrees C), or cDDP+HT (45 min interval) without preirradiation or at day 16 after the first dose of fractionated irradiation. Fractionated irradiation consisted of four daily doses of 5 Gy of x-rays each and tumor volumes had regrown to their original volume at the time of treatment. Experimental endpoint was tumor growth delay (TGD)., Results: Hyperthermia-enhanced cDDP cytotoxicity in vitro by a factor of about 5. Treatment with cDDP or HT alone resulted in a similar TGD in non- and preirradiated tumors (7.2 vs. 7.4 days and 1.1 vs. 0.9 days, respectively). In non- as well as in preirradiated tumors, HT given in combination with cDDP significantly enhanced the effect of cDDP, prolonging the TGD (11.1 days (p = 0.0001) and 16.2 days (p < 0.0001), respectively) corresponding to a TGD-enhancement of 1.54 and 2.19, respectively. The TGD after cDDP+HT in preirradiated tumors was significantly longer than in nonirradiated tumors (p = 0.0003)., Conclusions: In this tumor model, HT enhanced the antitumor effect of cDDP. Previous radiation treatment did not reduce the HT-enhanced effect of cDDP. Combined cDDP and HT may be useful in the treatment of nonirradiated tumors as well as previously irradiated tumors.

Purpose: The biological rationale for combining locoregional hyperthermia (HT) with cisplatin (CDDP) is the potentiating effect of HT on CDDP uptake and cytotoxicity. Feasibility, toxicity, and preliminary results of a clinical trial of weekly loco-regional HT in combination with cisplatin are described in this article., Methods and Materials: Patients with previously irradiated unresectable local recurrent cervical carcinoma or locally advanced bladder carcinoma were treated with weekly cycles of locoregional HT (70 MHz four antenna phased array system) for 1 h and CDDP 50 mg/m(2) IV for a maximum of 12 courses., Results: Fourteen patients, 10 patients with recurrent cervical carcinoma and 4 with locally advanced bladder carcinoma, were entered in this study. A total of 100 cycles were given. Overall toxicity was acceptable; Grade 3 (WHO) toxicity (gastrointestinal, hematological, and neurotoxicity) was observed in 5 out of 14 patients. No Grade 4 toxicity was seen. Subcutaneously fatty necrosis due to HT occurred in 11% of the cycles, while two patients developed skin burns. Two out of 10 patients with recurrent cervical carcinoma were not evaluable for response. Four out of eight evaluable cervical carcinoma patients responded (two pathologic complete responses, one pathologic confirmed partial response, one partial response): response rate 50% (95% confidence interval 15.7-84.3%). Salvage surgery became possible in three out of four responding patients, whose tumors were previously considered unresectable. Two out of the four evaluable patients with locally advanced bladder carcinoma responded (two partial responses)., Conclusions: Weekly loco-regional HT and CDDP 50 mg/m(2)/week for a maximum of 12 courses is feasible with an acceptable toxicity, which seems not to be enhanced by the addition of loco-regional HT. The encouraging preliminary results of this treatment schedule warrant further study, especially in patients with previously irradiated recurrent cervical carcinomas.

The combination of local hyperthermia (HT) with thermostable liposomal daunorubicin (DaunoXome, DX) was investigated to assess targeted drug delivery to experimental tumors. Female Wag/Rij rats bearing solid R-1 rhabdomyosarcomas received i.v. injections of 10 or 15 mg/kg of DX or free-Daunorubicin (f-Dau). After a 1-h interval, HT (60 min at 43 degrees C) was applied. Pharmacokinetics were studied in relation to tumor growth time (TGT), i.e., the time for tumors to reach their original volumes. Pharmacokinetic studies revealed that DX accumulation in tumor tissue was similar to f-Dau. A 5.4-fold increase (P = 0.0084) in tumor drug delivery was observed when DX was combined with HT, whereas liposomes remained stable. For f-Dau, HT had an additional effect on TGT at both drug doses tested (9.6 and 6.2 days, respectively, for 10 mg/kg, P = 0.0092; 17.7 and 13.7, respectively, for 15 mg/kg, P = 0.0431). For DX, HT significantly enhanced TGT of DX in the lower dose (17.1 and 6.4 days, respectively, P = 0.0005), whereas tumors did not regrow at day 25 after DX + HT in the higher dose. Unfortunately, after this time interval, the animals died of late toxicity, probably not related to HT. These results indicate that HT promotes extravasation of DX into tumor tissue and enhances its effectiveness. The finding that HT-induced drug release from the liposomes was not responsible for enhanced antitumor activity provides a rationale for further investigation of thermostable liposomes in conjunction with HT.

Background: In advanced adenocarcinoma of the pancreas treatment with 5-fluorouracil (5-FU) or ifosfamide results in response rates of approximately 20%. Continuous infusion of these drugs is on many grounds theoretically attractive and may therefore offer advantages over bolus or short-term infusion., Patients and Methods: Sixteen patients with advanced adenocarcinoma of the pancreas with progressive measurable disease and no previous chemotherapy entered the study. After implantation of a subcutaneous infusion chamber patients were treated on days 1-12 with ifosfamide (1.0 g/m2/day) and 5-FU (300 mg/m2/day) as a continuous intravenous infusion using a portable infusion pump. Mesna (1.0 g/m2/day) was added as uroprotective agent from day 1-14. Courses were repeated every 4 weeks., Results: Fifteen of the 16 patients were evaluable for response. One partial response was observed (response rate 7% [95% CI: 0%-32%]). Toxicity occurred in 64% of the courses. Dose limiting toxic effects were grade 3 nausea/vomiting (WHO) in 3 patients, grade 2 mucositis in 1 patient and grade 4 leukopenia in 1 patient., Conclusion: Intermittent continuous infusion with ifosfamide, mesna and 5-FU is feasible on an outpatient basis. Although continuous infusion of ifosfamide may have a more favorable toxicity profile, the combination of 5-FU and ifosfamide in this schedule is no more effective than bolus or short-term infusion.

Difluorodeoxycytidine (dFdCyd, gemcitabine) was tested for cytotoxicity in cultured human lung-cancer cells SW1573 in combination with 1 hr hyperthermia at 43 degrees C. The results show that the timing is extremely important. Simultaneous application led to decreased cytotoxicity, whereas an interval of 20 or 24 hr between exposure to dFdCyd and hyperthermia led to enhanced cell killing. The decrease in cytotoxicity after simultaneous hyperthermia and dFdCyd probably results from inhibition of activation of dFdCyd to the triphosphate metabolite. The enhanced cytotoxicity in sequential application of dFdCyd and hyperthermia is not caused by accumulation of cells in a sensitive cell-cycle phase. Our results show that the G1 phase becomes relatively abundant 20 hr after exposure to 0.1 microM dFdCyd, approximately 48% versus 31% in control cultures. Presumably, inhibition by hyperthermia of repair of DNA damage plays a role. Our results confirm earlier data with regard to reutilization of activated dFdCyd at high cell density. dFdCyd was clearly more toxic to SW1573 cells at 4 x 10(5) cells per dish than at 400 cells per dish. This reutilization of activated drug is evidently not a restricted property of a particular cell line and may add to the value of the drug in cancer treatment.

The development of severe adverse reactions to antituberculous drugs in a patient with miliary tuberculosis led to unorthodox, suboptimal antituberculous therapy. The patient's failure to respond to therapy was discovered when acid-fast bacilli were detected in new skin lesions. Such lesions have been described in the literature as tuberculosis cutis miliaris disseminata; 24 cases (in addition to that described herein) have been reported thus far. The patient eventually recovered completely after detection and drainage of a large retrofascial tuberculous abscess. This case illustrates the importance of careful examination of the skin in clinical medicine, as tuberculosis cutis miliaris disseminata is an easily overlooked sign of miliary tuberculosis.

The administration of antibiotics to renal transplant patients using cyclosporin can be difficult because of the risk of severe nephrotoxicity. An investigation was therefore carried out to determine whether aztreonam, a synthetic monocyclic beta-lactam antibiotic, can safely be combined with cyclosporin. In this retrospective study 68 renal transplant patients who received preoperative antibiotic prophylaxis consisting of aztreonam, ampicillin, and lincomycin were compared with 68 patients who received ceftazidime instead of aztreonam. Both groups were treated with cyclosporin and prednisolone and followed for 3 months. After transplantation 28.7% of the patients suffered from an acute renal failure and 1.5% had a wound infection. There were no significant differences between the two groups in acute renal failure, would infections, other infections, incidence of rejections, duration of admission, or graft survival. We therefore conclude that aztreonam can safely be administered together with cyclosporin. We also conclude that the combination of aztreonam, ampicillin, and lincomycin is a good preoperative antibiotic prophylaxis in renal transplant patients.