Physical and mental health of breast cancer patients and survivors before and during successive SARS-CoV-2-infection waves.

PURPOSE: During the first SARS-CoV-2-infection wave, a deterioration in emotional well-being and increased need for mental health care were observed among patients treated or being treated for breast cancer. In this follow-up study, we assessed patient-reported quality of life (QoL), physical functioning, and psychosocial well-being during the second SARS-CoV-2-infection wave in a large, representative cohort. METHODS: This longitudinal cohort study was conducted within the prospective, multicenter UMBRELLA breast cancer cohort. To assess patient-reported QoL, physical functioning and psychosocial well-being, COVID-19-specific surveys were completed by patients during the first and second SARS-CoV-2-infection waves (April and November 2020, respectively). An identical survey was completed by a comparable reference population during the second SARS-CoV-2-infection waves. All surveys included the validated EORTC-QLQ-C30/BR23, HADS and "De Jong-Gierveld Loneliness" questionnaires. Pre-COVID-19 EORTC-QLQ-C30/BR23 and HADS outcomes were available from UMBRELLA. Response rates were 69.3% (n = 1106/1595) during the first SARS-CoV-2-infection wave and 50.9% (n = 822/1614) during the second wave. A total of 696 patients responded during both SARS-CoV-2-infection waves and were included in the analysis comparing patient-reported outcomes (PROs) during the second SARS-CoV-2-infection wave to PROs during the first wave. Moreover, PROs reported by all patients during the second SARS-CoV-2-infection wave (n = 822) were compared to PROs of a similar non-cancer reference population (n = 241) and to their pre-COVID-19 PROs. RESULTS: Patient-reported QoL, physical functioning, and psychosocial well-being of patients treated or being treated for breast cancer remained stable or improved from the first to the second SARS-CoV-2-infection wave. The proportion of emotional loneliness reduced from 37.6 to 29.9% of patients. Compared to a similar non-cancer reference population, physical, emotional, and cognitive functioning, future perspectives and symptoms of dyspnea and insomnia were worse in patients treated or being treated for breast cancer during the second SARS-CoV-2-infection wave. PROs in the second wave were similar to pre-COVID-19 PROs. CONCLUSION: Although patients scored overall worse than individuals without breast cancer, QoL, physical functioning, and psychosocial well-being did not deteriorate between the first and second wave. During the second wave, PROs were similar to pre-COVID-19 values. Overall, current findings are cautiously reassuring for future mental health of patients treated or being treated for breast cancer.

Differential Notch and TGFbeta signaling in primary colorectal tumors and their corresponding metastases.

BACKGROUND: Loss of epithelial morphology and the acquisition of mesenchymal characteristics may contribute to metastasis formation during colorectal tumorigenesis. The Wnt, Notch and TGFbeta signaling pathways control tissue homeostasis and tumor development in the gut. The relationship between the activity of these pathways and the expression of epithelial and mesenchymal markers was investigated in a series of primary colorectal tumors and their corresponding metastases. METHODS: Tissue samples of primary colorectal tumors, normal colonic mucosa, and regional and systemic metastases were processed for immunohistochemistry in a tissue microarray format. The expression of mesenchymal (vimentin, fibronectin) and epithelial (E-cadherin) markers was related to markers of Wnt (beta-catenin), Notch (HES1) and TGFbeta (phospho-SMAD2) signalling. In addition, the KRAS mutation status was assessed. RESULTS: When compared to normal mucosa, primary colorectal tumors showed a marked increase in the levels of cytoplasmic vimentin and nuclear beta-catenin, phospho-SMAD2 and HES1. Increased vimentin expression correlated with the presence of oncogenic KRAS and with nuclear beta-catenin. The corresponding liver, lymph node, brain and lung metastases did not express vimentin and displayed significantly lower levels of nuclear phospho-SMAD2 and HES1, while retaining nuclear beta-catenin. CONCLUSIONS: Primary colorectal carcinomas display aberrant expression of vimentin, and have activated Notch and TGFbeta signaling pathways. Surprisingly, many regional and distant metastases have lost nuclear HES1 and pSMAD2, suggesting that the activity of the Notch and TGFbeta pathways is reduced in secondary colorectal tumors.

Dual effect of Kras(D12) knockdown on tumorigenesis: increased immune-mediated tumor clearance and abrogation of tumor malignancy.

Activating mutations in the human KRAS proto-oncogene are acquired during the earliest stages of colorectal cancer development. If mutant KRAS is to be used as a target for therapy in colorectal cancer, tumor growth should depend on its continued presence. Here, we report that stable knockdown of Kras(D12) in murine C26 colorectal cancer cells by RNA interference resulted in loss of transformed properties in vitro. The incidence of subcutaneous tumor formation was reduced by 60% and the lag time was increased sevenfold. Kras(D12)-knockdown tumors grew noninvasively and did not cause morbidity. Remarkably, some of the Kras(D12)-knockdown tumors regressed spontaneously, which rendered these mice resistant to parental C26 tumor growth. In immune-deficient hosts, the incidence of tumor formation by Kras(D12)-knockdown cells was 100%. None of these tumors regressed spontaneously. We conclude that the reduced incidence of tumor formation by Kras(D12)-knockdown cells is due to tumor cell clearance by the host immune system, but not to an intrinsic inability of these cells to grow out as tumors. Interestingly, Kras(D12) knockdown resulted in increased production of interleukin 18 (Il-18), an immune-stimulatory cytokine that has been implicated in limiting colorectal tumor formation. Thus, mutant Kras(D12) suppresses Il-18 production in colorectal tumor cells, which may contribute to evasion of the local immune system during tumor development.

Multipolar radiofrequency ablation of large hepatic metastases of endocrine tumours.

Radiofrequency ablation (RFA) is a reliable method of creating thermally induced coagulation necrosis. Local recurrence after RFA of hepatic metastases is directly dependent on tumour size related to the free margin of ablation. To produce larger coagulation volumes a bipolar radiofrequency device was developed that allows the simultaneous activation of three active needles. This technique was used at laparotomy in a patient with liver metastases of an endocrine tumour. Coagulation size up to 12 cm in diameter could be created. The postoperative recovery of the patient was uncomplicated. No local recurrence was seen after 13 months of follow-up with computed tomography scan. The use of simultaneously operated multiple radiofrequency electrodes in a multipolar mode expands the treatment options for patients with large and unresectable intrahepatic metastases.

Liver metastases of neuroendocrine tumours; early reduction of tumour load to improve life expectancy.

BACKGROUND: Neuroendocrine tumours frequently metastasize to the liver. Although generally slowly progressing, hepatic metastases are the major cause of carcinoid syndrome and ultimately lead to liver dysfunction, cardiac insufficiency and finally death. METHODS: A literature review was performed to define the optimal treatment strategy and work-up in patients with neuroendocrine hepatic metastases. Based on this, an algorithm for the management of these patients was established. RESULTS: Platelet serotonin and chromogranin A are useful biomarkers for detection and follow-up of neuroendocrine tumour. Helical computed tomography and somatostatin receptor scintigraphy are the most sensitive diagnostic modalities. Surgical debulking is an accepted approach for reducing hormonal symptoms and to establish better conditions for medical treatment, but is frequently impossible due to the extent of disease. A novel approach is the local ablation of tumour by thermal coagulation using therapies such as radiofrequency ablation (RFA) or laser induced thermotherapy (LITT). These techniques preserve normal liver tissue. There is a tendency to destroy metastases early in the course of disease, thereby postponing or eliminating the surgically untreatable stage. This can be combined with postoperative radioactive octreotide to eliminate small multiple metastases. In patients with extensive metastases who are not suitable for local destruction, systemic therapy by octreotide, 131I-MIBG treatment or targeted chemo- and radiotherapy should be attempted. A final option for selective patients is orthotopic liver transplantation. CONCLUSION: Treatment for patients with neuroendocrine hepatic metastases must be tailored for each individual patient. When local ablative therapies are used early in the course of the disease, the occurrence of carcinoid syndrome with end stage hepatic disease can be postponed or prevented.

Multiple fiber laser-induced thermotherapy for ablation of large intrahepatic tumors.

OBJECTIVE: The aim of this study was to test three techniques used simultaneously to increase lesion size. BACKGROUND DATA: Laser-induced thermotherapy (LITT) is a method of local tumor ablation, which may prolong survival in patients with unresectable liver metastases. The main limitation has been the production of lesions with sufficient tumor-free margin. METHODS: LITT treatment was performed with water-cooled, multiple fiber application and hepatic blood flow occlusion in six patients with unresectable intrahepatic metastases. Response was measured by computed tomography scan. RESULTS: In all patients, tumors were effectively ablated. In two patients with colorectal metastases, lesions up to 8.6 cm could be created. CONCLUSION: The use of watercooled multiple fiber application and hepatic inflow occlusion makes LITT an effective ablative method, expanding the treatment options for patients with large intrahepatic masses.

Synergistic effect of interstitial laser coagulation and doxorubicin in a murine tumor recurrence model of solitary colorectal liver metastasis.

BACKGROUND: Interstitial laser coagulation (ILC) is gaining acceptance for treatment of unresectable colorectal liver metastases. However, local recurrence rates are still high. To overcome this problem, we investigated the potential of additional systemic therapy after ILC in a murine model. METHODS: Single C26 colon carcinoma nodules (approximately 1 mm3) expressing firefly luciferase were implanted in the left liver lobe of 32 BALB/c mice. Seven days after implantation, tumors were treated with either ILC alone (neodymium-yttrium aluminum garnet; 6 W/cm; 800 J/cm) or ILC followed by 1 mg/kg of doxorubicin intravenously. Controls received either doxorubicin alone or sham treatment. Tumor load was measured by in vivo bioluminescent imaging. RESULTS: Solitary colorectal liver metastases developed over 7 days after tumor implantation in the liver. Extrahepatic disease was not observed. The ILC dose was set to ablate the liver metastases with recurrent tumor growth in 9 of 16 mice after 7 days. After ILC plus doxorubicin, complete tumor destruction occurred without recurrence (0 of 14). Sham treatment or treatment with doxorubicin alone showed an exponential increase in tumor load. CONCLUSIONS: A murine tumor recurrence model after local ablative treatment of solitary liver metastasis was developed. The combination of ILC and doxorubicin had a strong synergistic effect that led to complete tumor remission in all animals treated.

Ischemia/reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model.

Mortality in colorectal cancer is associated with the development of liver metastases. Surgical removal of these tumors is the only hope for cure, but recurrence is common. During liver surgery, ischemia/reperfusion (I/R) often occurs as a result of hemorrhage or vascular clamping. Although the adverse effects of I/R on postoperative liver function are well documented, the influence of I/R on the outgrowth of residual micrometastases is unknown. We used a highly standardized mouse model of partial hepatic I/R to study the effects of I/R on the outgrowth of preestablished colorectal micrometastases. Five days following intrasplenic injection of C26 colon carcinoma cells, the vascular structures of the left lobe were clamped for 45 minutes under hemodynamically stable conditions. Tissue glutathione, plasma liver enzymes, hepatocellular necrosis, and tumor growth were assessed over time. I/R caused oxidative stress and early liver tissue damage. The outgrowth of micrometastases in occluded liver lobes was accelerated five- to sixfold compared with nonoccluded lobes and was associated with areas of necrotic liver tissue surrounded by inflammatory cells and apoptotic hepatocytes. Accelerated tumor growth and tissue necrosis were completely prevented by occluding blood flow intermittently. In contrast, ischemic preconditioning or treatment with the antioxidants alpha-tocopherol or ascorbic acid failed to protect against late tissue necrosis and tumor growth, although early hepatocellular damage was largely prevented by these methods. In conclusion, I/R is a strong stimulus of recurrent intrahepatic tumor growth. Measures to prevent I/R-induced late tissue necrosis cross-protect against this phenomenon.

In vitro and in vivo studies of a VEGF121/rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors.

Vascular endothelial growth factor (VEGF) plays a key role in the growth and metastasis of solid tumors. We generated a fusion protein containing VEGF(121) linked by a flexible G(4)S tether to the toxin gelonin (rGel) and expressed this as a soluble protein in bacteria. Purified VEGF(121)/rGel migrated as an 84-kDa homodimer under nonreducing conditions. VEGF(121)/rGel bound to purified, immobilized Flk-1, and the binding was competed by VEGF(121). Both VEGF(121)/rGel and VEGF(121) stimulated cellular kinase insert domain receptor (KDR) phosphorylation. The VEGF(121)/rGel fusion construct was highly cytotoxic to endothelial cells overexpressing the KDR/Flk-1 receptor. The IC(50) of the construct on dividing endothelial cells expressing 10(5) or more KDR/Flk-1 receptors per cell was 0.5-1 nM, as compared with 300 nM for rGel itself. Dividing endothelial cells overexpressing KDR were approximately 60-fold more sensitive to VEGF(121)/rGel than were nondividing cells. Endothelial cells overexpressing FLT-1 were not sensitive to the fusion protein. Human melanoma (A-375) or human prostate (PC-3) xenografts treated with the fusion construct demonstrated a reduction in tumor volume to 16% of untreated controls. The fusion construct localized selectively to PC-3 tumor vessels and caused thrombotic damage to tumor vessels with extravasation of red blood cells into the tumor bed. These studies demonstrate the successful use of VEGF(121)/rGel fusion construct for the targeted destruction of tumor vasculature in vivo.