Radiolabeled F(ab′) 2 -cetuximab for theranostic purposes in colorectal and skin tumor-bearing mice models

Abstract

Purpose

This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, ¹¹¹In and ¹⁷⁷Lu, respectively.

Methods

We designed F(ab′)₂-fragments of cetuximab radiolabeled with ¹¹¹In and ¹⁷⁷Lu. ¹¹¹In-F(ab′)₂-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of ¹¹¹In-F(ab′)₂-cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on ¹⁷⁷Lu-F(ab′)₂-cetuximab was evaluated in SWISS nude mice bearing A431 tumors.

Results

Radiolabeling procedure did not change F(ab′)₂-cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. ¹¹¹In-DOTAGA-F(ab′)₂-cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab′)₂-cetuximab. SPECT imaging of ¹¹¹In-DOTAGA-F(ab′)₂-cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, ¹⁷⁷Lu-DOTAGA-F(ab′)₂-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses.

Conclusions

¹¹¹In-DOTAGA-F(ab′)₂-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. ¹⁷⁷Lu-DOTAGA-F(ab′)₂-cetuximab is an interesting theranostic tool allowing therapy and imaging.

https://ift.tt/2GucwkK

Improved recovery from limb ischaemia by delivery of an affinity-isolated heparan sulphate

Abstract

Peripheral arterial disease is a major cause of limb loss and its prevalence is increasing worldwide. As most standard-of-care therapies yield only unsatisfactory outcomes, more options are needed. Recent cell- and molecular-based therapies that have aimed to modulate vascular endothelial growth factor-165 (VEGF₁₆₅) levels have not yet been approved for clinical use due to their uncertain side effects. We have previously reported a heparan sulphate (termed HS7) tuned to avidly bind VEGF₁₆₅. Here, we investigated the ability of HS7 to promote vascular recovery in a murine hindlimb vascular ischaemia model. HS7 stabilised VEGF₁₆₅ against thermal and enzyme degradation in vitro, and isolated VEGF₁₆₅ from serum via affinity-chromatography. C57BL6 mice subjected to unilateral hindlimb ischaemia injury received daily intramuscular injections of respective treatments (n = 8) and were assessed over 3 weeks by laser Doppler perfusion, magnetic resonance angiography, histology and the regain of function. Mice receiving HS7 showed improved blood reperfusion in the footpad by day 7. In addition, they recovered hindlimb blood volume two- to fourfold faster compared to the saline group; the greatest rate of recovery was observed in the first week. Notably, 17% of HS7-treated animals recovered full hindlimb function by day 7, a number that grew to 58% and 100% by days 14 and 21, respectively. This was in contrast to only 38% in the control animals. These results highlight the potential of purified glycosaminoglycan fractions for clinical use following vascular insult, and confirm the importance of harnessing the activity of endogenous pro-healing factors generated at injury sites.

https://ift.tt/2rV4Lie

Solid Pseudopapillary Neoplasm of the Pancreas Clinicopathological Characteristics and Long-Term Outcome: a Single-Center Experience

Abstract

Solid pseudopapillary neoplasm is a rare tumor of the pancreas. These tumors are considered to have low malignant potential with good prognosis. Due to its rarity, details about clinical presentation and management of the disease are not very clear. This study aims to share our experience and to describe management of the disease. We retrospectively evaluated patients 13 patients diagnosed with SPT on histopathological examination of resected specimen. Data on their clinicopathological, management-related factors, and follow-up was collected. All the patients were females, with a median age of 20 years. Abdominal pain was the most common presentation. The mean tumor size was 6.5 cm and majority of tumors were located in the head region. R0 resection was obtained in all the patients. All patients were disease-free with a median follow-up of 68 months. Excellent prognosis can be achieved with a margin-negative resection in these tumors. Adjacent organ or vascular involvement is not a contraindication for surgical resection.

https://ift.tt/2rT2nJC

Recent Strategies and Paradigm Shift in Management of Hepatic Metastasis from Colorectal Cancer

Abstract

The liver is the most common site for metastasis from colorectal cancers (CRCs). There are so many new armamentarium, which have increased the life expectancy and progression-free survival. There are various available guidelines, such as NCCN, ESMO, and ASCO, which provide an insight into the latest modalities and new protocols. We have tried to elucidate into paradigm shift of the management.

https://ift.tt/2Gtkg6h

Cancers, Vol. 10, Pages 148: p53-Autophagy-Metastasis Link

Cancers, Vol. 10, Pages 148: p53-Autophagy-Metastasis Link

Cancers doi: 10.3390/cancers10050148

Authors: Tatiana V. Denisenko Anastasia D. Pivnyuk Boris Zhivotovsky

The tumor suppressor p53 as the "guardian of the genome" plays an essential role in numerous signaling pathways that control the cell cycle, cell death and in maintaining the integrity of the human genome. p53, depending on the intracellular localization, contributes to the regulation of various cell death pathways, including apoptosis, autophagy and necroptosis. Accumulated evidence suggests that this function of p53 is closely involved in the process of cancer development. Here, present knowledge concerning a p53-autophagy-metastasis link, as well as therapeutic approaches that influence this link, are discussed.

https://ift.tt/2k9RrDt

A systematic review of the risk factors for clinical response to opioids for all-age patients with cancer-related pain and presentation of the paediatric STOP pain study

Abstract

Background

Inter-patient variability in response to opioids is well known but a comprehensive definition of its pathophysiological mechanism is still lacking and, more importantly, no studies have focused on children. The STOP Pain project aimed to evaluate the risk factors that contribute to clinical response and adverse drug reactions to opioids by means of a systematic review and a clinical investigation on paediatric oncological patients.

Methods

We conducted a systematic literature search in EMBASE and PubMed up to the 24th of November 2016 following Cochrane Handbook and PRISMA guidelines. Two independent reviewers screened titles and abstracts along with full-text papers; disagreements were resolved by discussion with two other independent reviewers. We used a data extraction form to provide details of the included studies, and conducted quality assessment using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.

Results

Young age, lung or gastrointestinal cancer, neuropathic or breakthrough pain and anxiety or sleep disturbance were associated to a worse response to opioid analgesia. No clear association was identified in literature regarding gender, ethnicity, weight, presence of metastases, biochemical or hematological factors. Studies in children were lacking. Between June 2011 and April 2014, the Italian STOP Pain project enrolled 87 paediatric cancer patients under treatment with opioids (morphine, codeine, oxycodone, fentanyl and tramadol).

Conclusions

Future studies on cancer pain should be designed with consideration for the highlighted factors to enhance our understanding of opioid non-response and safety. Studies in children are mandatory.

Trial registration

CRD42017057740.

https://ift.tt/2Gw9Bb4

The impact of contour variation on tumour control probability in anal cancer

Abstract

Background

While intensity modulated radiotherapy (IMRT) has been widely adopted for the treatment of anal cancer (AC), the added contour complexity poses potential risks. This study investigates the impact of contour variation on tumour control probability (TCP) when using IMRT for AC.

Methods

Nine Australian centres contoured a single computed tomography dataset of a patient with AC. The same optimised template-based IMRT planning protocol was applied to each contour set to generate nine representative treatment plans and their corresponding dose volume histograms. A geometric analysis was performed on all contours. The TCP was calculated for each plan using the linear quadratic and logitEUD model.

Results

The median concordance index (CI) for the bladder, head and neck of femur, bone marrow, small bowel and external genitalia was 0.94, 0.88, 0.84, 0.65 and 0.65, respectively. The median CI for the involved nodal, primary tumour and elective clinical target volumes were 0.85, 0.77 and 0.71, respectively. Across the nine plans, the TCP was not significantly different. Variation in TCP between plans increased as tumour cell load increased or radiation dose decreased.

Conclusions

When using IMRT for AC, contour variations generated from a common protocol within the limits of minor deviations do not appear to have a significant impact on TCP. Contouring variations may be more critical with increasing tumour cell load or reducing radiotherapy dose.

https://ift.tt/2IRftkg