Cancer gene and immunotherapy: recent developments

Gene and immunotherapeutic approaches to treat human malignant tumors are reviewed. Special attention is given to the different strategies of cancer gene therapy and to recent aspects of cytokine-supported tumor immunotherapy or tumor-specific vaccination. The limitations of these therapy approaches are critically discussed especially with respect to immune escape mechanism

A phase I Study with oral SU5416 in patients with advanced solid tumors: A drug inducing its clearance

Summary: Vascular endothelial growth factor (VEGF) is a potent stimulant of angiogenesis. SU5416, is a small molecule tyrosine kinase inhibitor, and a potent inhibitor of VEGF- mediated Flk-1 receptor signaling. Intravenous agent SU5416 has shown evidence of biological activity against a variety of tumor types. The current intravenous dosing regimen is not optimal for long-term administration, which is needed for optimal efficacy. The aim of this study was to evaluate the safety profile and pharmacokinetics of a Nanocrystal Colloidal DispersionTM (NCD) SU5416 formulation in humans. Patients with advanced and/or metastatic solid organ tumors were included in the trial; various SU5416 regimens were tested for tolerability, safety and were evaluated concerning pharmacokinetics. The results of this study indicate that induction of clearance after oral dosing of NCD SU5416 in humans occurs and is greater than following IV administration. It has been confirmed that SU5416 is a high clearance compound, also as an oral NCD formulation. The NCD formulation was well tolerated, but no effective drug serum levels could be achieved. These data help to understand the ADME (Absorption, Distribution, Metabolism, Excretion) properties of indoline chemical class compounds. The lessons learned should be applied in the development of next generation indoline anti-angiogenic and anti-tumor compound

Hodgkin's Lymphoma and Paraneoplastic Phenomena in the Central Nervous System: A Case Report and Review of the Literature

A 25-year-old male patient presented to our Ear, Nose and Throat clinic with a history of nausea, vomiting, headache, vertigo and weight loss of 5 kg over the preceding 3 months. An enlarged cervical lymph node was detected at clinical examination. Lymph node biopsy showed nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL, nodular paragranuloma). Because of the neurological symptoms a cerebral MRI scan was performed and revealed an intense perivascular, bilateral, contrast-medium enhancing lesion of the temporal lobes suggestive of cerebral vasculitis. Cerebrospinal fluid analysis showed an increased number of mononuclear cells, but there was no indication for neurotropic viral or bacterial infections. EEG revealed a left temporal epileptic focus, and anti-epileptic therapy was initiated. NLPHL was treated with 2 cycles of ABVD chemotherapy and 20 Gy involved-field radiotherapy. Steroid therapy (prednisone 100 mg q.d.) for the presumed paraneoplastic neurological manifestation was started 1 week before chemotherapy and led to the rapid disappearance of complaints. Because of renewed onset of nausea and vertigo after 3 weeks of treatment with ABVD chemotherapy and 4 weeks of treatment with steroids, a follow-up brain MRI and EEG were performed and demonstrated complete disappearance of the ‘vasculitic’ changes without additional pathologic findings. Five months after therapy, the patient is without neurological symptoms and a PET-CT showed a complete remission. This case is a unique example of paraneoplastic central nervous system (CNS) involvement in a patient with newly diagnosed NLPHL. We present a review of the literature on paraneoplastic CNS symptoms in Hodgkin's lymphoma

Impact of overweight and obesity on postmenopausal breast cancer: analysis of 20-year data from Switzerland

Purpose: Greater body fatness has been identified as a risk factor for postmenopausal breast cancer. For countries with low overweight/obesity rates, data on prevalence and time course of overweight/obesity in women with breast cancer in comparison to women in the general population is limited. The Swiss female population is distinctive for two reasons: (a) low rates of overweight/obesity compared with other western countries, and (b) no obesity epidemic, i.e. stable rates of overweight/obesity for more than 10years. Methods: Overweight and obesity were analyzed in 51 to 80-year-old breast cancer patients initially diagnosed between 1990 and 2009. Patient data was derived from the Basel Breast Cancer Database (BBCD). This data was compared with the data of women of the same age from the four Swiss Health Surveys (SHS) conducted between 1992 and 2007. Differences between measured (BBCD) and self-reported (SHS) data were corrected using equations approved for the Swiss population. Results: Of 958 postmenopausal BBCD patients, 32% were overweight and 20% were obese. Of the 14,476 women of the SHS, 38% were overweight and 17% were obese. In the BBCD, there was no change in the prevalence of overweight/obesity over the last 20years. The four SHS show a convex curvature for obesity, i.e. a transient increase. No significant differences were observed between BBCD and corrected SHS data for overweight and obesity during this period. Conclusions: In this Swiss study group with a comparably low prevalence of overweight and obesity, no association between body fatness and postmenopausal breast cancer was observe

Addressing decisional conflict about fertility preservation - helping young female cancer survivors' family planning decisions

Background: Health professionals are challenged by a growing number of young long term cancer survivors with their specific needs with regard to family planning. This study aimed at assessing decisional conflict (DC) in young female cancer patients regarding fertility preservation, identifying demographic, fertility and fertility preservation related factors, which may affect DC, and assessing the helpfulness of various decision-supports. Methods: A retrospective cross-sectional web-based survey via an online questionnaire available in three languages with specific items concerning cancer, fertility, fertility preservation and the validated decisional conflict scale targeted at current or former female cancer patients aged 18 to 45 years, with cancer types or treatment potentially affecting reproductive function. Results: The 155 participating women showed considerable DC, especially with regard to missing information and support. DC was significantly lower in patients when the risk of infertility was discussed with a health professional, when they had undergone any procedure to preserve fertility and when they had a university education. A longer time interval since cancer diagnosis was associated with higher DC. The most helpful decision-support tools were specialized websites and leaflets. Conclusions: Young female cancer patients’ DC with regard to fertility preservation is very high. Information and support seem to be deficient. More information through standardized information tools might be an effective strategy to lower their DC at the time when treatment decisions need to be taken, and to improve their reproductive health after they have overcome cancer in the future

Knowledge about and attitude towards fertility preservation in young female cancer patients: a cross-sectional online survey

Recent advances in cancer therapy have resulted in an increased number of long-term cancer survivors. However, because of their treatment, women might be confronted with impaired fertility. The options of fertility preservation (FP) techniques are increasing. The goal of this study was to assess knowledge about, and attitudes towards, fertility preservation in young female cancer patients. A cross-sectional online survey was conducted including 155 former female cancer patients from English and German speaking countries. The survey consists of questions about attitude towards, and knowledge about, fertility preservation. Results show that knowledge about fertility preservation was limited among participants. Positive attitudes towards fertility preservation significantly outweighed negative attitudes. Knowledge and attitude did not differ according to language or different healthcare systems. Confidence of knowledge was significantly higher in women who underwent any FP procedure compared to those who did not. Greater emphasis should be placed on counselling opportunities, the provision of adequate information and supporting material. A better understanding of these issues will hopefully enhance patients’ decision-making about FP options and assist the development of strategies to improve quality of care

A multicenter phase II trial of anti-EGFR-immunoliposomes loaded with doxorubicin in patients with advanced triple negative breast cancer

Advanced triple negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience progression 12 months after the initiation of conventional first-line chemotherapy. Approximately two thirds of TNBC express epidermal growth factor receptor 1 (EGFR). We have developed an anti-EGFR targeted nanocontainer drug by inserting anti-EGFR antibody fragments into the membrane of pegylated liposomes (anti-EGFR-ILs-dox). The payload consists of doxorubicin, a standard drug for TNBC. In a first-in-human phase I trial in 26 patients with various advanced solid malignancies, anti-EGFR-ILs-dox has shown little toxicity and encouraging efficacy. In this single-arm phase II trial, we assessed the efficacy of anti-EGFR-ILs-dox as first-line therapy in patients with advanced, EGFR + TNBC. The primary endpoint was progression-free survival at 12 months (PFS12m). Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to progression (TTP), overall survival (OS) and adverse events (AEs). 48 patients received anti-EGFR-ILs-dox 50 mg/m$^{2}$ iv, on day one of a 28 days-cycle until progression. The Kaplan-Meier estimate for PFS12m was 13% (one-sided 90% CI 7%, 95% CI [5%, 25%]), median PFS was 3.5 months (95% CI 1.9, 5.4). The trial has not reached its primary endpoint. There were no new toxicity signals. Based on these results, anti-EGFR-ILs-dox should not be further developed for TNBC. It remains an open question whether anti-EGFR-ILs-dox would offer more opportunities in other EGFR-expressing malignancies, where targeting this receptor has already shown anticancer effects.Trial registration: This trial was registered at clinicaltrials.gov: NCT02833766. Registered 14/07/2016

Group-based body psychotherapy improves appreciation of body awareness in post-treatment cancer patients: A non-randomized clinical trial

IntroductionCancer-related impairments often co-occur with bodily disturbances. Body psychotherapy (BPT) can improve bodily wellbeing, yet evidence in cancer survivors is scarce. Hence, we aimed to evaluate whether blended group BPT alleviates bodily disturbances in post-treatment cancer patients.MethodsWe conducted a bi-center study (registered in ClinicalTrials.gov, under No. NCT03707548), applying a pre-post convergent parallel design of weekly group BPT interspersed with smartphone-based ambulatory interventions using a waiting-period comparator. We included patients with completed curatively intended treatment for malignant neoplasms, suffering from bodily disturbances. The primary outcome was body image disturbances. Secondary outcomes were experiencing and appreciating body awareness, mental wellbeing, and health-related quality of life.ResultsForty patients (mean age 51.7 years) attended group BPT. Mixed-effect linear regression models contrasting intervention with the waiting period did not show statistically significant differences regarding the primary outcome [Pre-post difference contrasts: 1.44, 95% confidence interval (CI): −1.51 to 4.93, p = 0.339]. However, patients showed greater improvements in appreciating body awareness, measured by the “Body Mindfulness Questionnaire” (BMQ), from pre- to post-intervention as compared to the waiting period (pre-post difference contrasts: 7.31 95% CI: 4.15–10.47, Bonferroni-Holm corrected q = 0.0002).DiscussionWe found no evidence that blended group BPT was effective in improving body image disturbances in post-treatment cancer patients, but found indications for an increase in body awareness appreciation.Clinical trial registrationClinicalTrials.gov, identifier NCT03707548

Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells

Circulating tumor cells (CTCs) are shed from solid cancers in the form of single or clustered cells, and the latter display an extraordinary ability to initiate metastasis. Yet, the biological phenomena that trigger the shedding of CTC clusters from a primary cancerous lesion are poorly understood. Here, when dynamically labeling breast cancer cells along cancer progression, we observe that the majority of CTC clusters are undergoing hypoxia, while single CTCs are largely normoxic. Strikingly, we find that vascular endothelial growth factor (VEGF) targeting leads to primary tumor shrinkage, but it increases intra-tumor hypoxia, resulting in a higher CTC cluster shedding rate and metastasis formation. Conversely, pro-angiogenic treatment increases primary tumor size, yet it dramatically suppresses the formation of CTC clusters and metastasis. Thus, intra-tumor hypoxia leads to the formation of clustered CTCs with high metastatic ability, and a pro-angiogenic therapy suppresses metastasis formation through prevention of CTC cluster generation

Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study

BACKGROUND We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. METHODS In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. RESULTS Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1-4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1-158) months, 34 (range: 1-118) months and 29 (range: 1-113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). CONCLUSIONS Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. (ClinicalTrials.gov number NCT00978211)