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Solid tumour models for the assessment of different treatment modalities: VII: single vs fractionated doses of 5-fluorouracil on two solid tumours and their hosts.

The effects of one large single dose of 5-fluorouracil (FU) have been compared to the same amount given in divided doses daily over a 3- or 5-day period. Comparison of the effects of single vs fractionated dosage was made on 2 types of experimental solid tumour with different growth, cell kinetic, histological and metastasizing properties. The tumour response was essentially the same for both the single and fractionated dose schedules.There were marked increases in animal mortality from drug toxicity following fractionated doses of FU compared to one large single dose. Mortality in animals with Tumour 3924A increased from 10% following one large single dose to 60% for animals given daily fractionated doses for 3 days, and 80% for animals given daily fractionated doses for 5 days. Total marrow reserve was measured by the total DNA content of tibial marrow. The nadir of 6 days for loss of total tibial marrow DNA following one large dose of FU was increased to 9 days for both fractionated schedules of FU. The 3-day delay in recovery of the marrow prevented recovery within the time frame necessary for animal survival. The inference from these experimental cancer-treatment studies is that daily fractions of chemotherapeutic agents such as FU result in increased morbidity and mortality, without benefit in the control of the solid tumour. The results question the advisability of the clinical practice of initially giving small daily "loading doses" of proliferation-dependent agents such as FU.These results emphasize the need for more precise information on the temporal relationship between the response and recovery of the host and the response and recovery of the solid tumour. They also emphasize the need for a better clinical understanding of the time sequence of solid-tumour recovery in relation to the time sequence of marrow recovery.

Animals

The effect of hyperthermia 42.5 degrees C on the incorporation of 3H-thymidine into the DNA of solid tumours in childhood.

Supranormal temperatures inhibit selectively the growth of malignant cells more than that of normal cells. The autoradiographic determination of the 3H-thymidine-labelling-index (LI) in vitro is a suitable method for the examination of thermosensitivity of individual human tumours. 44 solid tumours of children (Wilms' tumours, neuroblastomas, osteogenic sarcomas, non-Hodgkin-Lymphomas and other tumours) were studied by the temperatures 37.5 and 42.5 degrees C/120 min, with this method. 90% of the histologically undifferentiated tumours showed a highly significant inhibition of the 3H-thymidine incorporation between 28.6 and 79.9% with an average of 51.1%. In 4 histologically mature tumours (carcinoma of the adrenal cortex, malignant hepatoblastoma, fibrosarcoma, hamartoblastoma) no significant decrease of the LI was present. The inhibition of incorporation with hyperthermia cannot be correlated with the primary magnitude of the LI with normothermia. In 1 neuroblastoma a 75% rise of the LI was found possibly due to exogenic caused thermotolerance. The individuality of the reaction towards heat may contribute to the biological characterization of tumours.

Adolescent

First impressions of I.V. C. parvum in patients with solid tumours.

6 patients with solid tumours (4 malignant melanomas, one fibrosarcoma, one osteogenic sarcoma) received i.v. C. parvum alone or in combination therapy (radiotherapy, Levamisole and/or vitamin A). The single doses of C. parvum ranged from 5.0-7.5 mg/m2; No. of doses ranged from 1-8; interval between doses ranged from 2-140 days. 2 patients with malignant melanoma had no measurable disease, one of them (stage I) still has no evidence of disease. The patient with fibrosarcoma appeared to have a minor decrease in size of some of the lung metastases for a short time (ca 4 weeks), but soon progressed as well as the other 4 patients. Except for the one patients still having no evidence of disease the other 5 are dead of disease. Survival time did not appear to correlate either with systemic reaction to C. parvum or with No. of doses of C. parvum. The one minor response was observed in a patient receiving a total of 8 doses; but response was seen already after 3 doses, and progression occurred after 6 doses. So this change of lung metastases might have been unrelated to this therapy. Summarizing, there was no evident anti-tumour effect observed after i.v. C. parvum in these patients with solid tumours.

Humans

Solid tumours in RASopathies: insights from a large monocentric cohort and systematic review of the literature.

BACKGROUND: Dysregulation of the RAS-mitogen-activated protein kinase signalling pathway underlies RASopathies, a family of neurodevelopmental disorders associated with variable cancer predisposition. However, the prevalence and spectrum of solid tumours and the contribution of specific variants to tumour susceptibility remain poorly defined. METHODS: We assessed solid tumour prevalence and spectrum in the largest single-centre cohort of individuals with RASopathies (n=138), excluding neurofibromatosis type 1 and integrated these findings with a systematic literature review to evaluate tumour distribution and genotype-phenotype correlations. RESULTS: In our cohort, at least one solid tumour was identified in 10.8% of individuals with Noonan syndrome (NS), 47.8% with Costello syndrome (CS) and 7.3% with cardiofaciocutaneous syndrome (CFCS). Malignant tumours occurred in 5.4%, 30.4% and 2.4%, respectively. CS showed the highest tumour burden, frequently with multiple primary tumours, predominantly of the bladder. In NS, low-grade central nervous system (CNS) tumours were most common, particularly among individuals carrying PTPN11 variants. Tumour onset occurred with a median age of 19, 14 and 13 years in NS, CS and CFCS, respectively. Literature data analysis identified candidate variants in HRAS, PTPN11 and SOS1 genes associated with increased risk for solid tumours, which differed from mutational hotspots reported in childhood leukaemia or sporadic cancers. CONCLUSION: Solid tumour risk in RASopathies is syndrome-dependent and genotype-dependent, with CS showing a high burden of bladder tumours and NS mainly associated with CNS tumours. These findings may support tailored surveillance strategies.

Human Genetics

Association of host immunoglobulins with solid tumours in vivo.

Using a direct radioimmune antiglobulin technique and a competitive double-antibody radioimmune assay, we have demonstrated the presence of appreciable amounts of host immunoglobulins on the surface and in extracts of cell suspensions from freshly excised solid tumours. IgA appeared to have the greatest concentrations from freshly excised solid tumours. IgA appeared to have the greatest concentration, followed in turn by IgM congruent to IgG2a greater than IgG1 congruent to IgG2b greater than IgG3. The amount of immunoglobulin appeared to be influenced by the tumour under investigation and its mode of maintenance. It could also be increased by the administration of C. parvum but was not significantly influenced by the T-cell status of the host.

Animals

Response kinetics of host and experimental solid tumour after adriamycin.

The effects of adriamycin (Adr) on the solid-tumour model, hepatoma 3924A, and on critical organs of the host, were determined at intervals after single injections of 60 mg/m2 of the agent. A reduced rate of tumour growth was evident 4 days after treatment, continued to Day 11, and then returned to rates comparable to control values. On Day 11 tumour volumes of treated animals were 38% of control. During the period of reduced growth, 3H-TdR incorporation into tumour DNA and percentage labelled tumour cells were less than control values. DNA concentration in tumour was not affected by drug treatment, which differs from observations made in other studies employing 5-fluorouracil (FU). No evidence of significantly increased necrosis or fibrosis of the tumour was found after Adr. The Adr treatment caused loss of 60% of the tibial marrow by Day 4, as measured by total DNA content. Marrow DNA recovered to control levels between Days 7 and 11. Incorporation of 3H-TdR into heart DNA was reduced more than 40% during the first week after Adr treatment; enhanced incorporation was observed on Day 11, and control levels were attained by Day 17. No significant pathological evidence of cardiac toxicity was found 2-21 days after Adr but degeneration of myocardial cells and oedema was prominent at 14 weeks.

Animals

[DTIC in the therapy of solid tumours (author's transl)].

From 1975 to 1977 42 patients with advanced solid tumours were treated with imidazole-carboxamide (DTIC). It was applied in 18 cases as monotherapy: in the remaining patients it was administered in combination with other cytostatic agents. Tumour remission was recorded in 4/22 patients with melanoma, 2/2 with Kaposi sarcoma and 2/7 with soft tissue sarcoma. No change in tumour behaviour was recorded in 6/22 melanomas, 2/7 soft tissue sarcomas, 1/7 head and neck tumours and 1/1 thymoma. Side effects of DTIC monotherapy were comparably low. The optimum dosage and frequency of DTIC therapy have not yet been established. Combinations with other cytostatic agents are still being tested.

Antineoplastic Agents

The application of clinical trials to solid tumour management: an introduction.

This paper discusses the relevance of clinical trials to the management of solid tumours. It introduces the types of clinical trials, the requirements for patient assessment, and an overall strategy for importance of statistical and ethical considerations is discussed. There is an invitation for practising surgeons to participate in trials relevant to their speciality. The necessay framework and requirements for a clinical protocol are discussed separately in the following paper.

Breast Neoplasms

Comparison of intravenous and oral high-dose methotrexate in treatment of solid tumours.

An outpatient regimen of oral high-dose methotrexate was studied in 14 patients with solid tumours over 12 months. Detailed pharmacokinetic analysis in five patients showed high oral bioavailability (mean +/- SE of mean 87.6 +/- 1.5%), indicating that with this regimen oral methotrexate was well absorbed and the first-pass effect low. Oral administration resulted in peak plasma methotrexate concentrations of 8.4 +/- 0.5 mumol/l (382 +/- 23 microgram/100 ml) and was almost as effective as intravenous administration, which achieved peak concentrations of 9.9 +/- 0.4 mumol/l (450 +/- 18 microgram/100 ml). In all 14 patients the clinical response to oral treatment was comparable to that reported to intravenous administration of high-dose methotrexate used in combination with other cytotoxic drugs. The disease-free interval in cases of adult sarcoma was 7.4 +/- 1.3 months and the relapse rate 29%. Out of four patients with small-cell carcinoma, two showed an objective response to oral treatment. We suggest that oral high-dose methotrexate given in divided doses is a rational alternative to expensive intravenous high-dose methotrexate regimens, but further clinical evaluation is necessary.

Administration, Oral

Antibody-drug conjugates in selected solid tumours: a position statement update based on findings from the third workshop held by the ETOP IBCSG Partners Foundation.

The European Thoracic Oncology Platform (ETOP) International Breast Cancer Study Group (IBCSG) Partners Foundation initiated a series of workshops for experts to review current evidence and offer recommendations to guide future antibody-drug conjugate (ADC) research. Here, we summarise key findings from the third workshop, which included experts in various solid tumours, basic/translational research scientists and pharmaceutical industry representatives. Recent positive phase III trial data have further incorporated ADCs into the standard of care [e.g. lung: sacituzumab tirumotecan; breast: trastuzumab deruxtecan (T-DXd), sacituzumab govitecan, datopotamab deruxtecan; muscle-invasive bladder cancer: enfortumab vedotin; ovarian cancer: mirvetuximab soravastine; cervical cancer: tisotumab vedotin]. Thus, research priorities must be tailored according to tumour type, potentially focussing initially on settings where ADCs could replace chemotherapy. Many phase III ADC trials have been initiated based on positive phase I data and although these trials are larger than those conducted historically, prespecified criteria (e.g. patient numbers and magnitude of efficacy) should be met to justify proceeding directly to phase III. Importantly, although several ADCs have been successfully developed without mandatory biomarker selection, biomarker-driven ADC development enables rational patient selection, as illustrated by multiple ADCs (e.g. T-DXd, mirvetuximab soravtansine and telisotuzumab vedotin). The identification, development and validation of predictive biomarkers are therefore essential, particularly given several critical nuances, including the algorithms used to assess biomarker status and the type of specimen analysed, all of which may be influenced by temporal and spatial heterogeneity. Additional ADC research priorities include the optimisation of ADC constructs to enhance efficacy/tolerability and the identification of reliable ADC targets, including work to elucidate attributes of already-identified targets. Finally, considering the vast amount of ADC-related data being generated, artificial intelligence could be leveraged to analyse combined datasets and generate composite biomarkers, including tumour histology, optimal target expression thresholds, molecular alterations and activated pathways affecting payload activity and target function, to accelerate research.

Humans

[Abnormal left-ventricular contraction and filling in patients receiving adriamycin for solid tumours (author's transl)].

Various ventricular functions, as obtained by echocardiography (M-mode), were measured on 14 patients with solid tumours receiving adriamycin (mean total dosage 330 +/- 188 mg/m2 body surface area), the results being compared with those on 14 normal subjects of similar ages. There were statistically highly significant differences between the two groups. In those receiving the drug there was (1) a decrease in the percentage shortening fraction and (2) a reduction in the maximal velocity of endocardial circumferential fibre shortening, as expression of reduced contractility. The abnormal filling was characterized by a marked decrease in maximal velocity of endocardial fibre stretch, diminution of diameter increase during the rapid filling phase, and a shortened duration of the rapid filling phase. There was no electrocardiographic or radiological evidence of myocardial damage. The findings suggest that it will be possible by serial echocardiography to recognize a higher tolerance to the drug in some individuals and, at the same time, reveal abnormal contractility and filling due to adriamycin before irreversible heart failure has occurred.

Adult

A status report on the management of solid tumours.

Progressive improvements in the management of certain paediatric and haematological malignancies have provided guidelines for the current approaches to the management of the more common solid tumours of adults. These include precise histopathological grading; comprehensive evaluation of extent of disease; staging classifications accurately correlated with prognosis and progressive evaluation of available therapeutic modalities for all stages of disease in an attempt to define the best combination of local and systemic forms of therapy. Breast cancer is reviewed in detail as an example of the more responsive tumours where screening programs; improvements in pathological and clinical staging and the introduction of systemic chemotherapy together with optimal use of other methods of treatment for the various stages of disease gives hope for a significant improvement in long term survival statistics. Lung cancer has also been reviewed as an example of the more resistant types of cancer where screening programmes and current therapy including the use of combination chemotherapy have given minor encouragement but not had a definite influence on long term survival. Some further gains may still be achieved with currently available techniques but major improvements will probably require the development of better therapeutic tools including radiotherapy with high linear energy transfer particles; new chemotherapeutic agents and specific forms of immunotherapy. It is also quite possible that completely different forms of therapy for these resistant tumours will be necessary to reach the desired goal of long term improvements in survival.

Aged

Clinical applications of serum carcinoembryonic antigen and alpha-fetoprotein levels in children with solid tumours.

A study was carried out on serum carcinoembryonic antigen (CEA) and alpha-feto-protein (AFP) levels, both measured by radioimmunoassay, in 88 children with malignant solid tumours and in 26 children with nonmalignant disorders, who presented during the years 1973-77. Slightly or moderately raised CEA levels were found at presentation in 11 of 66 children with malignant tumours, in 2 others with recurrent tumours, and in 4 children with nonmalignant disorders. Raised CEA levels generally indicated advanced malignant disease, often affecting the liver, or other hepatic disorders, but were not associated with a specific tumour type. Except in the first months of life, significantly raised AFP levels were detected only in 11 patients with yolk sac-derived tumours, or hepatomas, and in one child with tyrosinosis who later developed a malignant hepatoma. Serial measurements of AFP accurately reflected the clinical response to treatment and in 2 patients indicated recurrence before this could be detected clinically.

Adolescent

Responses of an experimental solid tumour to irradiation: A comparison of modes of fractionation.

Several radiotherapeutic schedules compatible with continued structural-functional integrity of the gastrointestinal (GI) mucosa were compared utilizing the P815X2 murine mastocytoma grown as a solid subcutaneous tumour. Both the tumour and underlying normal tissues were irradiated during the treatments. The tumour exhibited a Do that increased from 210 rad to 397 rad as the tumour aged and in all instances demonstrated minimal shoulders in survival curves. In spite of a relative radioresistance of cells within the solid tumour, quite effective control of localized disease could be accomplished with radiotherapy schemes compatible with GI tolerance limits. Schedules evaluated utilizing this model included acute exposures to 1122 rad, daily exposure to 187 rad, 5 days/week exposures to 281 rad, twice weekly exposures (561 rad on Mondays and 374 rad on Thursdays) and a high dose, two fractions per day, schedule. Tumours were followed for changes in growth patterns during these schedules. Efficacy of tumour control was determined and schedules were compared on this basis. Aggressive radiotherapy approaching the tolerance limits of any of the fractionation schemes proved most effective.

Animals

Solid tumour models for the assessment of different treatment modalities: IV. the combined effects of radiation and 5-fluorouracil.

Neither radiation alone (375 to 1500 rad) nor5-fluorouracil (FU) alone (50-250 mg/kg) is sufficient to prevent an increase in the volume of the solid tumour model hepatoma 3924A. However, as little as 750 rad with 100 mg/kg FU can reduce the tumour below the volume at the time of treatment for as long as 14 days. A series of combined FU and radiation doses given every 11 days should then result in successively smaller tumour volumes until the tumour is eradicated. Changes in tumour volume were analysed by two different methods: (1) tumours in each treatment mode were grouped together and the average response to treatment determined, and (2) tumour volume changes in individual tumours were analyzed utilizing the chi2 technique, which fits the logarithmic tumour volume change with time to polynomials. This two-directional method of analysis has the advantage of permitting both an overview of the main effects of treatment via the averages, and at the same time a detailed examination of the mechanism by which these effects occur through the analysis of individual response. The results suggest that, in addition to concentrating on the cellular response immediately after therapy, greater emphasis should be placed on the kinetic changes of the tumour 1-3 weeks after single or multiple modality therapy. These findings demonstrate how the sequencing of single and/or combined treatment modalities may be investigated in order to detemine how best to obtain maximum effects of treatment on different types of tumours following recovery of the host from the previous treatment series.

Animals

Mechanism-Driven Diagnostic Development: A Specimen-Aware Framework Illustrated by Colorectal Cancer and Solid Tumours.

Translational oncology has moved rapidly from histopathology and single-analyte biomarkers toward multi-dimensional molecular profiling. Yet many clinically deployed tests still use reductionist biomarker strategies that under-represent cancer complexity. This review examines whether a mechanistic, multi-layered, and specimen-aware approach can improve cancer detection, classification, prognosis, minimal residual disease (MRD) assessment, and therapeutic selection. Evidence across solid tumours shows that genomic alterations alone incompletely explain tumour state, metastatic behaviour, immune evasion, or therapeutic vulnerability. Integrated genome and transcriptome analyses, proteogenomics, single-cell atlases, fragmentomic, methylation based cell-free DNA assays, metabolomics and microbiome assessments reveal clinically relevant biology that single modality tests cannot determine. Minimally invasive collected specimens can extend access to screening, diagnosis and longitudinal monitoring, but the choice of specimen should be matched to disease biology and analytes that represent mechanisms of oncogenesis. However, translation remains constrained by pre-analytical variability, contamination, differences in tumour shedding behaviour, clonal haematopoiesis, translation of generated models, incomplete external validation and uncertain downstream clinical utility for emerging platforms. This review provides a commentary on the future of cancer diagnostics, the considerations and barriers to clinical translation, the relationship between utility and dimensionality of biomarkers assessed and the emerging rationale towards mechanistically grounded integrated models.

biomarkers

Lymphocyte sensitization in childhood solid tumours and lymphoblastic leukaemia, measured by electrophoretic mobility test.

A modified electrophoretic mobility (EM) test was performed in 150 children to examine their lymphocyte sensitization to myelin basic protein (encephalitogenic factor). Measurements in the cytopherometer were facilitated by using devitalized sheep erythrocytes as indicator particles instead of macrophages. A significant decrease in EM was found in 29/30 children with acute lymphoblastic leukaemia and in 67/75 children with solid tumours, thus giving a false negative rate in malignant disease of 9/105=8-6%, as compared to 6 false positives among 45 children with non-malignant disorders; 5 of the later "false/positive" 6 patients had autoimmune disease. Results of the EM test in the children with leukaemia were compared with those in 9 patients with non-Hodgkin's lymphoma and 2 with Hodgkin's disease at different stages, but no striking change was seen between different diseases, or after cessation of long-term immunosuppressive chemotherapy. Percentage of "slowing" ranged from 4 to 30%. These results indicate that patients with lymphoid malignancies still have lymphocytes which had been sensitized by a common antigen of the malignant cell clone at the beginning of the disease. The EM test, furthermore, could serve as an additional diagnostic aid in differentiating benign from malignant masses in the abdomen, extremities or intracranial disease.

Abdominal Neoplasms

Combined treatment of a solid tumour by local hyperthermia and actionomycin D.

(BALB/c X C57BL/6)F1 mice bearing an SV-40 fibrosarcoma in the limb were injected with 0.045, 0.09 and 0.18 microgram/g body wt actinomycin D into the tumour. Similar animals were also treated with local hyperthermia (39.7 degrees, 42.3 degrees and 43.6 degrees C intratumour temperature for 30 min). The marked increase in median survival time following the combination of drug and local hyperthermia indicates that the combined treatment has a synergistic effect in the control of solid tumours. The median survival time of animals receiving the two treatments in immediate succession was higher than in animals with 30 min between treatments. This has important implications for the therapy of human cancer.

Animals