In vivo pretargeted radioimmunotherapy using click chemistry

The pretargeting system based on the inverse electron demand Diels-Alder reaction (IEDDA) between trans-cyclooctene (TCO) and tetrazine (Tz) combines the favorable pharmacokinetic properties of radiolabeled small molecules with the affinity and specificity of antibodies. This strategy has proven to be an efficient method for the molecularly targeted delivery of pharmaceuticals, including isotopes for radiological imaging. Despite encouraging results from in vivo PET imaging studies, this promising system has yet to be thoroughly evaluated for pretargeted radioimmunotherapy (PRIT). Towards that end, we synthesized two novel 177Lu-labeled tetrazine-bearing radioligands. Next we compared the usefulness of our ligands for PRIT when paired with TCO-modified 5B1- a human, anti-CA19.9 mAb - in preclinical murine models of pancreatic cancer. The exemplary ligand, 177Lu-DOTA-PEG7-Tz, showed rapid (4.6 ± 0.8 %ID/g at 4h) and persistent (16.8 ± 3.9 %ID/g at 120h) uptake in tumors while concurrently clearing from blood and non-target tissues. Single-dose therapy studies using 5B1-TCO and varying amounts of 177Lu-DOTA-PEG7-Tz (400, 800, and 1200μCi) showed that our system elicits a dose-dependent therapeutic response in mice bearing human xenografts. Furthermore, dosimetry calculations suggest that our approach is amenable to clinical applications with its excellent dosimetric profile in organs of clearance (i.e. liver and kidneys) as well as in dose-limiting tissues, such as red marrow. This study established that a pretargeted methodology utilizing the IEDDA reaction can rapidly and specifically deliver a radiotherapeutic payload to tumor tissue, thus illustrating its excellent potential for clinical translation.

http://mct.aacrjournals.org/cgi/content/short/1535-7163.MCT-16-0503v1?rss=1

Radiosensitization by AZD6738

AZD6738 is an orally active ATR inhibitor (ATRi) currently in phase I clinical trials. We found in vitro growth inhibitory activity of this ATRi in a panel of human cancer cell lines. We demonstrated radiosensitization by AZD6738 to single radiation fractions in multiple cancer cell lines independent of both p53 and BRCA2 status by clonogenic assay. Radiosensitization by AZD6738 to clinically-relevant doses of fractionated radiation was demonstrated in vitro using a 3D tumor spheroid model and, in vivo, AZD6738 radiosensitized by abrogating the radiation-induced G2 cell cycle checkpoint and inhibiting homologous recombination. Mitosis with damaged DNA resulted in mitotic catastrophe as measured by micronucleus formation by live cell fluorescent-ubiquitination cell cycle imaging of cell cycle progression and nuclear morphology. Induction of micronuclei was significantly more prominent for AZD6738 compared to inhibition of the downstream kinase CHK1 alone at isoeffective doses. Micronuclei were characterized as acentric chromosomal fragments which displayed characteristics of increased DNA damage and cell cycle dyssynchrony when compared to the primary nucleus.

http://mct.aacrjournals.org/cgi/content/short/1535-7163.MCT-16-0239v1?rss=1

Radio-sensitizing effects of TAS-116

Hsp90 inhibitors have been investigated as cancer therapeutics in mono-therapy and to augment radiotherapy, however serious adverse effects of early generation Hsp90 inhibitors limited their development. TAS-116 is a novel Hsp90 inhibitor with lower adverse effects than other Hsp90 inhibitors, and here we investigated the radio-sensitizing effects of TAS-116 in low LET X-ray, and high LET carbon ion irradiated human cancer cells and mouse tumor xenografts. TAS-116 decreased cell survival of both X-ray and carbon ion-irradiated human cancer cell lines (HeLa and H1299 cells), and similar to other Hsp90 inhibitors, it did not affect radiosensitivity of non-cancerous human fibroblasts. TAS-116 increased the number of radiation-induced -H2AX foci, and delayed the repair of DNA double-strand breaks (DSBs). TAS-116 reduced the expression of proteins that mediate repair of DSBs by homologous recombination (RAD51) and non-homologous end joining (Ku, DNA-PKcs), and suppressed formation of RAD51 foci and phosphorylation/activation of DNA-PKcs. TAS-116 also decreased expression of the cdc25 cell cycle progression marker, markedly increasing G2/M arrest. Combined treatment of mouse tumor xenografts with carbon ions and TAS-116 showed promising delay in tumor growth compared to either individual treatment. These results demonstrate that TAS-116 radio-sensitizes human cancer cells to both X rays and carbon ions by inhibiting the two major DSB repair pathways, and these effects were accompanied by marked cell cycle arrest. The promising results of combination TAS-116 + carbon ion radiation therapy of tumor xenografts justify further exploration of TAS-116 as an adjunct to radiotherapy using low or high LET radiation.

http://mct.aacrjournals.org/cgi/content/short/1535-7163.MCT-16-0573v1?rss=1

Effect of an antipsychotic drug TFP on glioblastoma

Calcium (Ca2+) signaling is an important signaling process, implicated in cancer cell proliferation and motility of the deadly glioblastomas that aggressively invade neighboring brain tissue. We have previously demonstrated that caffeine blocks glioblastoma invasion and extends survival by inhibiting Ca2+ release channel Inositol 1,4,5-Trisphosphate Receptor (IP3R) Subtype 3. Trifluoperazine (TFP) is an FDA-approved antipsychotic drug for schizophrenia. Interestingly, TFP has been recently reported to show a strong anticancer effect on lung cancer, hepatocellular carcinoma and T-cell lymphoma. However, the possible anticancer effect of TFP on glioblastoma has not been tested. Here, we report that TFP potently suppresses proliferation, motility and invasion of glioblastoma cells in vitro, and tumor growth in in vivo xenograft mouse model. Unlike caffeine, TFP triggers massive and irreversible release of Ca2+ from intracellular stores by IP3R subtype 1 and 2 by directly interacting at the TFP binding site of a Ca2+ binding protein, Calmodulin subtype 2 (CaM2). TFP binding to CaM2 causes a dissociation of CaM2 from IP3R and subsequent opening of IP3R. Compared to the control neural stem cells, various glioblastoma cell lines showed enhanced expression of CaM2 and thus enhanced sensitivity to TFP. Based on these findings we propose TFP as a potential therapeutic drug for glioblastoma by aberrantly and irreversibly increasing Ca2+ in glioblastoma cells.

http://mct.aacrjournals.org/cgi/content/short/1535-7163.MCT-16-0169-Tv1?rss=1

Favorable Preliminary Outcomes for Men with Low- and Intermediate-Risk Prostate Cancer Treated with 19 Gy Single Fraction High-Dose-Rate Brachytherapy

Publication date: Available online 9 November 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Daniel J. Krauss, Hong Ye, Alvaro A. Martinez, Beth Mitchell, Evelyn Sebastian, Amy Limbacher, Gary S. Gustafson
PurposeTo report toxicity and preliminary clinical outcomes of a prospective trial evaluating 19 Gy single fraction high-dose-rate (HDR) brachytherapy for men with low- and intermediate-risk prostate cancer.Materials and Methods63 patients were treated according to an IRB-approved prospective study of single fraction HDR brachytherapy. Eligible patients had tumor stage < T2a, PSA < 15, and Gleason score < 7. Patients with prostate gland volume > 50 cc and baseline American Urologic Association (AUA) symptom score > 12 were ineligible. Patients underwent trans-rectal ultrasound (TRUS)-guided trans-perineal implant of the prostate followed by single fraction HDR brachytherapy. Treatment was delivered via Ir-192 to a dose of 19 Gy prescribed to the prostate with no additional margin applied.Results58 patients were available for analysis. Five withdrew consent during the follow-up period. Median follow up was 2.9 years [range 0.3-5.2 years]. Median age was 61.4 years. Median gland volume at the time of treatment was 34.8 cc. 91% of patients had T1 disease, 71% had Gleason score < 6 (29% Gleason 7), and median pre-treatment PSA was 5.1 ng/mL. Acute and chronic grade 2 genitourinary toxicity incidence was 12.1% and 10.3%, respectively. No grade 3 urinary toxicity occurred. No patients experienced acute rectal toxicity > grade 2, and 2 experienced > grade 2 chronic GI toxicity. 3 patients have experienced biochemical failure yielding a 3-year cumulative incidence estimate of 6.8%.ConclusionsSingle fraction HDR brachytherapy is well-tolerated with favorable preliminary biochemical and clinical disease control rates.

Teaser

We present results of a prospective, non-randomized clinical trial of 19 Gy single-fraction HDR brachytherapy for low- and intermediate-risk prostate cancer patients. With 58 patients and a median follow up of nearly 3 years, we have demonstrated favorable biochemical control rates and a highly favorable toxicity profile. These results support further prospective study in this area.


http://rss.sciencedirect.com/action/redirectFile?&zone=main&currentActivity=feed&usageType=outward&url=http%3A%2F%2Fwww.sciencedirect.com%2Fscience%3F_ob%3DGatewayURL%26_origin%3DIRSSSEARCH%26_method%3DcitationSearch%26_piikey%3DS0360301616330966%26_version%3D1%26md5%3D8d1641e91a2fd11153e03d632d1c29a0

Direct comparison of respiration-correlated four-dimensional magnetic resonance imaging (4DMRI) reconstructed based on concurrent internal navigator and external bellows

Publication date: Available online 9 November 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Guang Li, Jie Wei, Devin Olek, Mo Kadbi, Neelam Tyagi, Kristen Zakian, James Mechalakos, Joseph O. Deasy, Margie Hunt
PurposeTo compare the image quality of amplitude-binned four-dimensional magnetic resonance imaging (4DMRI) reconstructed using two concurrent respiratory (navigator and bellows) waveforms.Methods and MaterialsA prospective, respiratory-correlated 4DMRI scanning program was employed to acquire T2-weighted single-breath 4DMRI image using an internal navigator and external bellows. After 10-second training of a surrogate signal, 2D MRI image acquisition was triggered at a level (bin) and anatomic location (slice) until the bin-slice table was filled for 4DMRI reconstruction. The bellows signal was always collected, even when the navigator trigger was used, to retrospectively reconstruct a bellows-rebinned 4DMRI. Ten volunteers participated in this IRB-approved 4DMRI study and four scans were acquired for each subject, including coronal and sagittal scans triggered by either navigator or bellows, and six 4DMRI images (navigator-triggered, bellows-rebinned, and bellows-triggered) were reconstructed. The simultaneously acquired waveforms and resulting 4DMRI image quality were compared using signal correlation, bin/phase shift, and binning motion artifacts. The consecutive bellows-triggered 4DMRI was used for indirect comparison.ResultsCorrelation coefficients between navigator and bellows signals were found to be patient-specific and inhalation-/exhalation-dependent, ranging from 0.1 to 0.9, due to breathing irregularities (>50% scans) and commonly-observed bin/phase shifts (-1.1±0.6 bin) in both 1D waveforms and diaphragm motion extracted from 4D images. The navigator-triggered 4DMRI contains much fewer binning motion artifacts at the diaphragm than bellows-rebinned and bellows-triggered 4DMRI. Coronal scans are faster than sagittal scans due to fewer slices and higher achievable acceleration factors.ConclusionNavigator-triggered 4DMRI contains substantially fewer binning motion artifacts than bellows-rebinned and bellows-triggered 4DMRI, primarily due to the deviation of the external from the internal surrogate. This study compares two concurrent surrogates during the same 4DMRI scan and their resulting 4DMRI quality. The navigator-triggered 4DMRI scanning protocol is preferred to the bellows-based, especially the coronal scans, for clinical respiratory motion simulation.

Teaser

Summary: This study presents direct comparison of two concurrent respiratory surrogates: internal navigator and external bellows, and their corresponding 4DMRI image quality. Sixty 4DMRI images in ten volunteers were reconstructed and compared. We found that phase shift is common in the concurrent 1D waveforms and motions extracted from 4DMRI images. Navigator-triggered 4DMRI image quality is far superior. This study provides better understanding of external-internal motion relationship, as well as potential use of 4DMRI in replacing 4DCT.


http://rss.sciencedirect.com/action/redirectFile?&zone=main&currentActivity=feed&usageType=outward&url=http%3A%2F%2Fwww.sciencedirect.com%2Fscience%3F_ob%3DGatewayURL%26_origin%3DIRSSSEARCH%26_method%3DcitationSearch%26_piikey%3DS0360301616334265%26_version%3D1%26md5%3D47f20cb74d9c4439f6521c5dc08630e6

Cancer in the elderly: Moving the needle toward evidence-based personalized oncology

Publication date: Available online 9 November 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Martine Extermann




http://rss.sciencedirect.com/action/redirectFile?&zone=main&currentActivity=feed&usageType=outward&url=http%3A%2F%2Fwww.sciencedirect.com%2Fscience%3F_ob%3DGatewayURL%26_origin%3DIRSSSEARCH%26_method%3DcitationSearch%26_piikey%3DS0360301616334277%26_version%3D1%26md5%3Daef2c1a30c1250c94c142570f7bf260c

Responding to the quality imperative to embed mental health care into ambulatory oncology

The calls by the Institute of Medicine to fully integrate psychosocial care into oncology practice are closer to being implemented. Because of the multiple challenges faced across the cancer care continuum, it is recommended that multidimensional approaches that extend beyond the assessment of depression and anxiety and consider physical symptoms and practical concerns be considered as part of systematic psychosocial screening in oncology practice. See also pages 000-000.

http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fcncr.30402

Optimized glucuronide-monomethylauristatin E linker for ADCs

The emergence of antibody-drug conjugates (ADCs) such as brentuximab vedotin and ado-trastuzumab emtansine has led to increased efforts to identify new payloads and develop improved drug-linker technologies. Most antibody payloads impart significant hydrophobicity to the ADC, resulting in accelerated plasma clearance and suboptimal in vivo activity, particularly for conjugates with high drug-to-antibody ratios (DAR). We recently reported on the incorporation of a discrete PEG24 polymer as a side chain in a beta-glucuronidase-cleavable monomethylauristatin E (MMAE) linker to provide homogeneous DAR 8 conjugates with decreased plasma clearance and increased antitumor activity in xenograft models relative to a non-PEGylated control. In this work, we optimized the drug-linker by minimizing the size of the PEG side chain and incorporating a self-stabilizing maleimide to prevent payload de-conjugation in vivo. Multiple PEG-glucuronide-MMAE linkers were prepared with PEG size up to 24 ethylene oxide units, and homogeneous DAR 8 ADCs were evaluated. A clear relationship was observed between PEG length and conjugate pharmacology when tested in vivo. Longer PEG chains resulted in slower clearance, with a threshold length of PEG8 beyond which clearance was not impacted. Conjugates bearing PEG of sufficient length to minimize plasma clearance provided a wider therapeutic window relative to faster clearing conjugates bearing shorter PEGs. A lead PEGylated glucuronide-MMAE linker was identified incorporating a self-stabilizing maleimide and a PEG12 side chain emerged from these efforts, enabling highly potent, homogeneous DAR 8 conjugates and is under consideration for future ADC programs.

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In vivo pretargeted radioimmunotherapy using click chemistry

The pretargeting system based on the inverse electron demand Diels-Alder reaction (IEDDA) between trans-cyclooctene (TCO) and tetrazine (Tz) combines the favorable pharmacokinetic properties of radiolabeled small molecules with the affinity and specificity of antibodies. This strategy has proven to be an efficient method for the molecularly targeted delivery of pharmaceuticals, including isotopes for radiological imaging. Despite encouraging results from in vivo PET imaging studies, this promising system has yet to be thoroughly evaluated for pretargeted radioimmunotherapy (PRIT). Towards that end, we synthesized two novel 177Lu-labeled tetrazine-bearing radioligands. Next we compared the usefulness of our ligands for PRIT when paired with TCO-modified 5B1- a human, anti-CA19.9 mAb - in preclinical murine models of pancreatic cancer. The exemplary ligand, 177Lu-DOTA-PEG7-Tz, showed rapid (4.6 ± 0.8 %ID/g at 4h) and persistent (16.8 ± 3.9 %ID/g at 120h) uptake in tumors while concurrently clearing from blood and non-target tissues. Single-dose therapy studies using 5B1-TCO and varying amounts of 177Lu-DOTA-PEG7-Tz (400, 800, and 1200μCi) showed that our system elicits a dose-dependent therapeutic response in mice bearing human xenografts. Furthermore, dosimetry calculations suggest that our approach is amenable to clinical applications with its excellent dosimetric profile in organs of clearance (i.e. liver and kidneys) as well as in dose-limiting tissues, such as red marrow. This study established that a pretargeted methodology utilizing the IEDDA reaction can rapidly and specifically deliver a radiotherapeutic payload to tumor tissue, thus illustrating its excellent potential for clinical translation.

from Cancer via ola Kala on Inoreader http://mct.aacrjournals.org/cgi/content/short/1535-7163.MCT-16-0503v1?rss=1
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Radiosensitization by AZD6738

AZD6738 is an orally active ATR inhibitor (ATRi) currently in phase I clinical trials. We found in vitro growth inhibitory activity of this ATRi in a panel of human cancer cell lines. We demonstrated radiosensitization by AZD6738 to single radiation fractions in multiple cancer cell lines independent of both p53 and BRCA2 status by clonogenic assay. Radiosensitization by AZD6738 to clinically-relevant doses of fractionated radiation was demonstrated in vitro using a 3D tumor spheroid model and, in vivo, AZD6738 radiosensitized by abrogating the radiation-induced G2 cell cycle checkpoint and inhibiting homologous recombination. Mitosis with damaged DNA resulted in mitotic catastrophe as measured by micronucleus formation by live cell fluorescent-ubiquitination cell cycle imaging of cell cycle progression and nuclear morphology. Induction of micronuclei was significantly more prominent for AZD6738 compared to inhibition of the downstream kinase CHK1 alone at isoeffective doses. Micronuclei were characterized as acentric chromosomal fragments which displayed characteristics of increased DNA damage and cell cycle dyssynchrony when compared to the primary nucleus.

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Radio-sensitizing effects of TAS-116

Hsp90 inhibitors have been investigated as cancer therapeutics in mono-therapy and to augment radiotherapy, however serious adverse effects of early generation Hsp90 inhibitors limited their development. TAS-116 is a novel Hsp90 inhibitor with lower adverse effects than other Hsp90 inhibitors, and here we investigated the radio-sensitizing effects of TAS-116 in low LET X-ray, and high LET carbon ion irradiated human cancer cells and mouse tumor xenografts. TAS-116 decreased cell survival of both X-ray and carbon ion-irradiated human cancer cell lines (HeLa and H1299 cells), and similar to other Hsp90 inhibitors, it did not affect radiosensitivity of non-cancerous human fibroblasts. TAS-116 increased the number of radiation-induced -H2AX foci, and delayed the repair of DNA double-strand breaks (DSBs). TAS-116 reduced the expression of proteins that mediate repair of DSBs by homologous recombination (RAD51) and non-homologous end joining (Ku, DNA-PKcs), and suppressed formation of RAD51 foci and phosphorylation/activation of DNA-PKcs. TAS-116 also decreased expression of the cdc25 cell cycle progression marker, markedly increasing G2/M arrest. Combined treatment of mouse tumor xenografts with carbon ions and TAS-116 showed promising delay in tumor growth compared to either individual treatment. These results demonstrate that TAS-116 radio-sensitizes human cancer cells to both X rays and carbon ions by inhibiting the two major DSB repair pathways, and these effects were accompanied by marked cell cycle arrest. The promising results of combination TAS-116 + carbon ion radiation therapy of tumor xenografts justify further exploration of TAS-116 as an adjunct to radiotherapy using low or high LET radiation.

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Effect of an antipsychotic drug TFP on glioblastoma

Calcium (Ca2+) signaling is an important signaling process, implicated in cancer cell proliferation and motility of the deadly glioblastomas that aggressively invade neighboring brain tissue. We have previously demonstrated that caffeine blocks glioblastoma invasion and extends survival by inhibiting Ca2+ release channel Inositol 1,4,5-Trisphosphate Receptor (IP3R) Subtype 3. Trifluoperazine (TFP) is an FDA-approved antipsychotic drug for schizophrenia. Interestingly, TFP has been recently reported to show a strong anticancer effect on lung cancer, hepatocellular carcinoma and T-cell lymphoma. However, the possible anticancer effect of TFP on glioblastoma has not been tested. Here, we report that TFP potently suppresses proliferation, motility and invasion of glioblastoma cells in vitro, and tumor growth in in vivo xenograft mouse model. Unlike caffeine, TFP triggers massive and irreversible release of Ca2+ from intracellular stores by IP3R subtype 1 and 2 by directly interacting at the TFP binding site of a Ca2+ binding protein, Calmodulin subtype 2 (CaM2). TFP binding to CaM2 causes a dissociation of CaM2 from IP3R and subsequent opening of IP3R. Compared to the control neural stem cells, various glioblastoma cell lines showed enhanced expression of CaM2 and thus enhanced sensitivity to TFP. Based on these findings we propose TFP as a potential therapeutic drug for glioblastoma by aberrantly and irreversibly increasing Ca2+ in glioblastoma cells.

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Favorable Preliminary Outcomes for Men with Low- and Intermediate-Risk Prostate Cancer Treated with 19 Gy Single Fraction High-Dose-Rate Brachytherapy

Publication date: Available online 9 November 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Daniel J. Krauss, Hong Ye, Alvaro A. Martinez, Beth Mitchell, Evelyn Sebastian, Amy Limbacher, Gary S. Gustafson
PurposeTo report toxicity and preliminary clinical outcomes of a prospective trial evaluating 19 Gy single fraction high-dose-rate (HDR) brachytherapy for men with low- and intermediate-risk prostate cancer.Materials and Methods63 patients were treated according to an IRB-approved prospective study of single fraction HDR brachytherapy. Eligible patients had tumor stage < T2a, PSA < 15, and Gleason score < 7. Patients with prostate gland volume > 50 cc and baseline American Urologic Association (AUA) symptom score > 12 were ineligible. Patients underwent trans-rectal ultrasound (TRUS)-guided trans-perineal implant of the prostate followed by single fraction HDR brachytherapy. Treatment was delivered via Ir-192 to a dose of 19 Gy prescribed to the prostate with no additional margin applied.Results58 patients were available for analysis. Five withdrew consent during the follow-up period. Median follow up was 2.9 years [range 0.3-5.2 years]. Median age was 61.4 years. Median gland volume at the time of treatment was 34.8 cc. 91% of patients had T1 disease, 71% had Gleason score < 6 (29% Gleason 7), and median pre-treatment PSA was 5.1 ng/mL. Acute and chronic grade 2 genitourinary toxicity incidence was 12.1% and 10.3%, respectively. No grade 3 urinary toxicity occurred. No patients experienced acute rectal toxicity > grade 2, and 2 experienced > grade 2 chronic GI toxicity. 3 patients have experienced biochemical failure yielding a 3-year cumulative incidence estimate of 6.8%.ConclusionsSingle fraction HDR brachytherapy is well-tolerated with favorable preliminary biochemical and clinical disease control rates.

Teaser

We present results of a prospective, non-randomized clinical trial of 19 Gy single-fraction HDR brachytherapy for low- and intermediate-risk prostate cancer patients. With 58 patients and a median follow up of nearly 3 years, we have demonstrated favorable biochemical control rates and a highly favorable toxicity profile. These results support further prospective study in this area.


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Direct comparison of respiration-correlated four-dimensional magnetic resonance imaging (4DMRI) reconstructed based on concurrent internal navigator and external bellows

Publication date: Available online 9 November 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Guang Li, Jie Wei, Devin Olek, Mo Kadbi, Neelam Tyagi, Kristen Zakian, James Mechalakos, Joseph O. Deasy, Margie Hunt
PurposeTo compare the image quality of amplitude-binned four-dimensional magnetic resonance imaging (4DMRI) reconstructed using two concurrent respiratory (navigator and bellows) waveforms.Methods and MaterialsA prospective, respiratory-correlated 4DMRI scanning program was employed to acquire T2-weighted single-breath 4DMRI image using an internal navigator and external bellows. After 10-second training of a surrogate signal, 2D MRI image acquisition was triggered at a level (bin) and anatomic location (slice) until the bin-slice table was filled for 4DMRI reconstruction. The bellows signal was always collected, even when the navigator trigger was used, to retrospectively reconstruct a bellows-rebinned 4DMRI. Ten volunteers participated in this IRB-approved 4DMRI study and four scans were acquired for each subject, including coronal and sagittal scans triggered by either navigator or bellows, and six 4DMRI images (navigator-triggered, bellows-rebinned, and bellows-triggered) were reconstructed. The simultaneously acquired waveforms and resulting 4DMRI image quality were compared using signal correlation, bin/phase shift, and binning motion artifacts. The consecutive bellows-triggered 4DMRI was used for indirect comparison.ResultsCorrelation coefficients between navigator and bellows signals were found to be patient-specific and inhalation-/exhalation-dependent, ranging from 0.1 to 0.9, due to breathing irregularities (>50% scans) and commonly-observed bin/phase shifts (-1.1±0.6 bin) in both 1D waveforms and diaphragm motion extracted from 4D images. The navigator-triggered 4DMRI contains much fewer binning motion artifacts at the diaphragm than bellows-rebinned and bellows-triggered 4DMRI. Coronal scans are faster than sagittal scans due to fewer slices and higher achievable acceleration factors.ConclusionNavigator-triggered 4DMRI contains substantially fewer binning motion artifacts than bellows-rebinned and bellows-triggered 4DMRI, primarily due to the deviation of the external from the internal surrogate. This study compares two concurrent surrogates during the same 4DMRI scan and their resulting 4DMRI quality. The navigator-triggered 4DMRI scanning protocol is preferred to the bellows-based, especially the coronal scans, for clinical respiratory motion simulation.

Teaser

Summary: This study presents direct comparison of two concurrent respiratory surrogates: internal navigator and external bellows, and their corresponding 4DMRI image quality. Sixty 4DMRI images in ten volunteers were reconstructed and compared. We found that phase shift is common in the concurrent 1D waveforms and motions extracted from 4DMRI images. Navigator-triggered 4DMRI image quality is far superior. This study provides better understanding of external-internal motion relationship, as well as potential use of 4DMRI in replacing 4DCT.


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Cancer in the elderly: Moving the needle toward evidence-based personalized oncology

Publication date: Available online 9 November 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Martine Extermann




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Responding to the quality imperative to embed mental health care into ambulatory oncology

The calls by the Institute of Medicine to fully integrate psychosocial care into oncology practice are closer to being implemented. Because of the multiple challenges faced across the cancer care continuum, it is recommended that multidimensional approaches that extend beyond the assessment of depression and anxiety and consider physical symptoms and practical concerns be considered as part of systematic psychosocial screening in oncology practice. See also pages 000-000.

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Screening for depression in cancer patients receiving radiotherapy: Feasibility and identification of effective tools in the NRG Oncology RTOG 0841 trial

BACKGROUND

Brief tools are needed to screen oncology outpatients for depressive symptoms.

METHODS

Patients starting radiotherapy for the first diagnosis of any tumor completed distress screening tools, including the 9-item Patient Health Questionnaire (PHQ-9), the 2-item Patient Health Questionnaire (PHQ-2), the National Comprehensive Cancer Network Distress Thermometer (NCCN-DT), and the Hopkins Symptom Checklist (HSCL) (25-item version). Patients exceeding validated cutoff scores and a systematic sample of patients whose screening was negative completed the Structured Clinical Interview for DSM-IV (SCID) mood disorder modules via telephone.

RESULTS

Four hundred sixty-three patients from 35 community-based radiation oncology sites and 2 academic radiation oncology sites were recruited. Sixty-six percent of the 455 eligible patients (n = 299) were women, and the eligible patients had breast (45%), gastrointestinal (11%), lung (10%), gynecologic (6%), or other cancers (27%). Seventy-five (16.5%) exceeded screening cutoffs for depressive symptoms. Forty-two of these patients completed the SCID. Another 37 patients whose screening was negative completed the SCID. Among the 79 patients completing the SCID, 8 (10.1%) met the criteria for major depression, 2 (2.5%) met the criteria for dysthymia, and 6 (7.6%) met the criteria for an adjustment disorder. The PHQ-2 demonstrated good psychometric properties for screening for mood disorders with a cutoff score of ≥3 (receiver operating characteristic area under the curve [AUC], 0.83) and was comparable to the PHQ-9 ( > 9; AUC = 0.85). The NCCN-DT did not detect depression (AUC = 0.59).

CONCLUSIONS

The PHQ-2 demonstrated good psychometric properties for screening for mood disorders, which were equivalent to the PHQ-9 and superior to the NCCN-DT. These findings support using the PHQ-2 to identify patients in need of further assessment for depression, which has a low prevalence but is a clinically significant comorbidity. These findings could inform the implementation of distress screening accreditation standards. Cancer 2016. © 2016 American Cancer Society.

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Case 34-2016: A 17-Year-Old Boy with Myopia and Craniofacial and Skeletal Abnormalities

Presentation of Case. Dr. Angela E. Lin: A 17-year-old boy was referred to the medical genetics clinic of this hospital because of high myopia (i.e. severe nearsightedness) and craniofacial and other skeletal abnormalities. As a child, the patient had had difficulty with articulation and had…

http://www.nejm.org/doi/full/10.1056/NEJMcpc1610096?rss=searchAndBrowse

Bilateral ovarian pedicle ligation as an alternative to ovariectomy and ovarian response to eCG treatment

Abstract

Ovariectomy (OVE) is a standard technique used for dog spaying. If blood circulation to the ovaries is blocked, ovarian tissue is destroyed without being removed from the body. In this study, 12 adult female dogs were selected. Dogs were assigned to treatment (N = 7) and control (N = 5) groups. Blood samples and vaginal cytology were taken and checked for estrus cycle for 3 weeks. After that, both ovarian pedicles of dogs in the treatment group were ligated and in the control group, laparotomy was performed only. Blood sampling and vaginal cytology smears were taken from both groups once a week for the next 8 weeks. All dogs received eCG (20 IU/kg, IM) 1 month post surgery for 5 consecutive days. On the 5th day after eCG treatment, they received a single dose of hCG (500 IU/cases IM). After 8 weeks, ovariohysterectomy was performed and the ovaries of all dogs were sent to the pathology laboratory for pathological examination. In serum samples, estrogen and progesterone were assayed with ELISA kits. Based on the results, five dogs were in the anestrous from the beginning to the end of study. Other dogs were cyclic. Estrogen and progesterone levels were not significantly changed due to ovarian activity (P > 0.05). There was a significant difference between blood levels of estrogen after eCG induction. The difference in progesterone between ligated and sham operated group was significant (P = 0.01). Ultrasonographical evaluation showed excessive fluid accumulation in ovarian bursa and giant follicles on ovaries of the ligated groups 1 month post ligation. Histopathological findings showed hemorrhage and necrosis in ovarian tissues. However, developing follicles and corpus luteums were seen too. In conclusion, the results of the present study showed that despite the severe changes in ovarian tissue following ovarian pedicle ligation, minor perfusions still exist and supply the ovaries so that hormone response and follicular development can occur.

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Surgical management of complex residual masses following systemic chemotherapy for metastatic testicular germ cell tumours

This report describes the outcome of 25 patients with metastatic testicular germ cell tumours who underwent postchemotherapy resection of very complex resdual masses including vascular reconstruction of the Aorta and inferior vena cava, replacement of vertebral bodies and pancreaticoduodenal surgery.

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Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early breast cancer: a subanalysis of data from the randomized phase III GeparSepto trial

In a large cohort of patients with HER2-positive early breast cancer (n=396), a dual HER2-targeted combination of pertuzumab and trastuzumab, together with 8 cycles of taxane-epirubicin-cyclophosphamide neoadjuvant chemotherapy, was well tolerated and achieved high rates of pathological complete response.

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Letter to the Editor

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A Randomized Trial of TLR-2 agonist CADI-05 targeting desmocollin-3 for advanced non-small-cell lung cancer

Patients with advanced NSCLC (N=221) were randomized to Cisplatin-Paclitaxel or Cisplatin-Paclitaxel plus CADI-05, a TLR-2 agonist targeting desmocollin-3. Addition of CADI-05, improved median survival in Squamous cell subset (127 days, hazard ratio, 0.55; P=0.046) and in those receiving four cycles of chemotherapy (66 days, hazard ratio, 0.64; P=0.04) without adding systemic side effects.

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Causes of death among cancer patients

We analyzed deaths among cancer patients from 1973 to 2012. Patients with cancer of the lung, pancreas, and brain are most likely to die of their cancer. Second cancers are important causes of death for patients with lymphoma and cancers of the oropharynx, testis, larynx. Patients with breast and prostate cancer are at highest risk of non-cancer death.

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Research needs in breast cancer

Although important advances have been made in some areas of breast cancer research leading to improvements in therapies and outcomes over the last few decades, other areas have not benefited to the same degree. We summarize the short and medium-term clinical research needs in breast cancer deemed as priorities by a panel of experts, in an attempt to focus and accelerate future research in the most needed areas.

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Reply to "Is the pursuit of a higher impact factor fully justified?"

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Characterizing CD137 Upregulation on NK cells in Patients Receiving Monoclonal Antibody Therapy

Proper patient stratification based on predictive biomarkers can improve outcome in cancer immunotherapy.We describe clinical and pathologic prognostic factors that predict CD137 expression on natural killer cells after treatment with monoclonal antibodies. Our efforts constitute the first step in developing a nomogram that predicts outcome and individualizes CD137-targeted therapies for patients.

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Industry Corner: perspectives and controversies

In therapeutic indications such as NSCLC, where there is a clear unmet medical need, delayed access to new therapies following regulatory approval is a significant challenge. Nintedanib meets a medical need in NSCLC; however, patients across Europe are not gaining equal access to this new therapy due to varying reimbursement procedures.

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Surgical management of complex residual masses following systemic chemotherapy for metastatic testicular germ cell tumours

This report describes the outcome of 25 patients with metastatic testicular germ cell tumours who underwent postchemotherapy resection of very complex resdual masses including vascular reconstruction of the Aorta and inferior vena cava, replacement of vertebral bodies and pancreaticoduodenal surgery.

http://annonc.oxfordjournals.org/cgi/content/short/mdw605v1?rss=1

Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early breast cancer: a subanalysis of data from the randomized phase III GeparSepto trial

In a large cohort of patients with HER2-positive early breast cancer (n=396), a dual HER2-targeted combination of pertuzumab and trastuzumab, together with 8 cycles of taxane-epirubicin-cyclophosphamide neoadjuvant chemotherapy, was well tolerated and achieved high rates of pathological complete response.

http://annonc.oxfordjournals.org/cgi/content/short/mdw610v1?rss=1

Letter to the Editor

http://annonc.oxfordjournals.org/cgi/content/short/mdw572v1?rss=1

A Randomized Trial of TLR-2 agonist CADI-05 targeting desmocollin-3 for advanced non-small-cell lung cancer

Patients with advanced NSCLC (N=221) were randomized to Cisplatin-Paclitaxel or Cisplatin-Paclitaxel plus CADI-05, a TLR-2 agonist targeting desmocollin-3. Addition of CADI-05, improved median survival in Squamous cell subset (127 days, hazard ratio, 0.55; P=0.046) and in those receiving four cycles of chemotherapy (66 days, hazard ratio, 0.64; P=0.04) without adding systemic side effects.

http://annonc.oxfordjournals.org/cgi/content/short/mdw608v1?rss=1

Causes of death among cancer patients

We analyzed deaths among cancer patients from 1973 to 2012. Patients with cancer of the lung, pancreas, and brain are most likely to die of their cancer. Second cancers are important causes of death for patients with lymphoma and cancers of the oropharynx, testis, larynx. Patients with breast and prostate cancer are at highest risk of non-cancer death.

http://annonc.oxfordjournals.org/cgi/content/short/mdw604v1?rss=1

Research needs in breast cancer

Although important advances have been made in some areas of breast cancer research leading to improvements in therapies and outcomes over the last few decades, other areas have not benefited to the same degree. We summarize the short and medium-term clinical research needs in breast cancer deemed as priorities by a panel of experts, in an attempt to focus and accelerate future research in the most needed areas.

http://annonc.oxfordjournals.org/cgi/content/short/mdw571v1?rss=1

Reply to "Is the pursuit of a higher impact factor fully justified?"

http://annonc.oxfordjournals.org/cgi/content/short/mdw614v1?rss=1

Characterizing CD137 Upregulation on NK cells in Patients Receiving Monoclonal Antibody Therapy

Proper patient stratification based on predictive biomarkers can improve outcome in cancer immunotherapy.We describe clinical and pathologic prognostic factors that predict CD137 expression on natural killer cells after treatment with monoclonal antibodies. Our efforts constitute the first step in developing a nomogram that predicts outcome and individualizes CD137-targeted therapies for patients.

http://annonc.oxfordjournals.org/cgi/content/short/mdw570v1?rss=1

Industry Corner: perspectives and controversies

In therapeutic indications such as NSCLC, where there is a clear unmet medical need, delayed access to new therapies following regulatory approval is a significant challenge. Nintedanib meets a medical need in NSCLC; however, patients across Europe are not gaining equal access to this new therapy due to varying reimbursement procedures.

http://annonc.oxfordjournals.org/cgi/content/short/mdw569v1?rss=1

Bevacizumab versus anti–epidermal growth factor receptor in first-line metastatic colorectal cancer. A meta-analysis: The last building block?

Publication date: December 2016
Source:European Journal of Cancer, Volume 69
Author(s): Michel Ducreux, Jean-Pierre Pignon




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Role of tumour-free margin distance for loco-regional control in vulvar cancer—a subset analysis of the Arbeitsgemeinschaft Gynäkologische Onkologie CaRE-1 multicenter study

Publication date: December 2016
Source:European Journal of Cancer, Volume 69
Author(s): Linn Woelber, Lis-Femke Griebel, Christine Eulenburg, Jalid Sehouli, Julia Jueckstock, Felix Hilpert, Nikolaus de Gregorio, Annette Hasenburg, Atanas Ignatov, Peter Hillemanns, Sophie Fuerst, Hans-Georg Strauss, Klaus H. Baumann, Falk C. Thiel, Alexander Mustea, Werner Meier, Philipp Harter, Pauline Wimberger, Lars Christian Hanker, Barbara Schmalfeldt, Ulrich Canzler, Tanja Fehm, Alexander Luyten, Martin Hellriegel, Jens Kosse, Christoph Heiss, Peer Hantschmann, Peter Mallmann, Berno Tanner, Jacobus Pfisterer, Barbara Richter, Petra Neuser, Sven Mahner
Aim of the studyA tumour-free pathological resection margin of ≥8 mm is considered state-of-the-art. Available evidence is based on heterogeneous cohorts. This study was designed to clarify the relevance of the resection margin for loco-regional control in vulvar cancer.MethodsAGO-CaRE-1 is a large retrospective study. Patients (n = 1618) with vulvar cancer ≥ FIGO stage IB treated at 29 German gynecologic-cancer-centres 1998–2008 were included. This subgroup analysis focuses on solely surgically treated node-negative patients with complete tumour resection (n = 289).ResultsOf the 289 analysed patients, 141 (48.8%) had pT1b, 140 (48.4%) pT2 and 8 (2.8%) pT3 tumours. One hundred twenty-five (43.3%) underwent complete vulvectomy, 127 (43.9%) partial vulvectomy and 37 (12.8%) radical local excision. The median minimal resection margin was 5 mm (1 mm–33 mm); all patients received groin staging, in 86.5% with full dissection. Median follow-up was 35.1 months. 46 (15.9%) patients developed recurrence, thereof 34 (11.8%) at the vulva, after a median of 18.3 months. Vulvar recurrence rates were 12.6% in patients with a margin <8 mm and 10.2% in patients with a margin ≥8 mm. When analysed as a continuous variable, the margin distance had no statistically significant impact on local recurrence (HR per mm increase: 0.930, 95% CI: 0.849–1.020; p = 0.125). Multivariate analyses did also not reveal a significant association between the margin and local recurrence neither when analysed as continuous variable nor categorically based on the 8 mm cutoff. Results were consistent when looking at disease-free-survival and time-to-recurrence at any site (HR per mm increase: 0.949, 95% CI: 0.864–1.041; p = 0.267).ConclusionsThe need for a minimal margin of 8 mm could not be confirmed in the large and homogeneous node-negative cohort of the AGO-CaRE database.



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FAS and FASL genetic polymorphisms impact on clinical outcome of malignant pleural mesothelioma

https://www.dovepress.com/fas-and-fasl-genetic-polymorphisms-impact-on-clinical-outcome-of-malig-peer-reviewed-article-OTT

Cancer Immunotherapy: from the lab to clinical applications. Potential impact on cancer centres’ organisation

Linda Cairns, Sandrine Aspeslagh, Andrea Anichini, Jon Amund Kyte, Christian Blank, Paolo Ascierto, Nicolle Rekers, Per Thor Straten and Ahmad Awada

http://ecancer.org//journal/10/691-cancer-immunotherapy-from-the-lab-to-clinical-applications-potential-impact-on-cancer-centres-organisation.php

Cancer Immunotherapy: from the lab to clinical applications. Potential impact on cancer centres’ organisation

Linda Cairns, Sandrine Aspeslagh, Andrea Anichini, Jon Amund Kyte, Christian Blank, Paolo Ascierto, Nicolle Rekers, Per Thor Straten and Ahmad Awada

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Atypical presentation of appendicitis

A woman aged 64 years presented as an emergency with a mass in the right iliac fossa, clinically within the abdominal wall, but an otherwise soft abdomen. Systemically, she was quite well with normal vital signs. Blood tests revealed raised inflammatory markers, and an abdominal CT scan demonstrated a perforated appendix with associated large subcutaneous abscess. This represents a rare presentation of a common condition, demonstrating how appendicitis can still be a challenging problem for the clinician. The patient underwent incision and drainage of the abscess, resulting in the formation of an enterocutaneous fistula (ECF). This was managed with enteral nutritional support, wound dressings and antibiotics. Following normal CT imaging, an ileocaecal resection was planned in the expectation that the ECF would persist. The operation was postponed due to intercurrent illness, during which time her symptoms and the ECF fully resolved.

http://casereports.bmj.com/cgi/content/short/2016/nov10_1/bcr2016217293?rss=1

Intracranial venous thrombosis in a man taking clomiphene citrate

Clomiphene citrate is widely used by the female population for the management of a wide array of medical conditions especially those related to ovulation, but its use in male population remains controversial. Efficacy of clomiphene is not well established in male hypogonadism and infertility. Its side effects and complications are also poorly studied or reported. We present a case of a man with infertility issues for which he started receiving clomiphene citrate 3 weeks before presenting with progressive symptoms of headache, vomiting, transient blurred vision and diplopia, which eventually turned out to be the symptoms of intracranial venous thrombosis. After excluding the common causes of intracranial venous thrombosis and hypercoagulable state, clomiphene citrate seems the most likely culprit.

http://casereports.bmj.com/cgi/content/short/2016/nov10_1/bcr2016217403?rss=1

Radiomics based targeted radiotherapy planning (Rad-TRaP): a computational framework for prostate cancer treatment planning with MRI

Abstract

Background

Radiomics or computer – extracted texture features have been shown to achieve superior performance than multiparametric MRI (mpMRI) signal intensities alone in targeting prostate cancer (PCa) lesions. Radiomics along with deformable co-registration tools can be used to develop a framework to generate targeted focal radiotherapy treatment plans.

Methods

The Rad-TRaP framework comprises three distinct modules. Firstly, a module for radiomics based detection of PCa lesions on mpMRI via a feature enabled machine learning classifier. The second module comprises a multi-modal deformable co-registration scheme to map tissue, organ, and delineated target volumes from MRI onto CT. Finally, the third module involves generation of a radiomics based dose plan on MRI for brachytherapy and on CT for EBRT using the target delineations transferred from the MRI to the CT.

Results

Rad-TRaP framework was evaluated using a retrospective cohort of 23 patient studies from two different institutions. 11 patients from the first institution were used to train a radiomics classifier, which was used to detect tumor regions in 12 patients from the second institution. The ground truth cancer delineations for training the machine learning classifier were made by an experienced radiation oncologist using mpMRI, knowledge of biopsy location and radiology reports. The detected tumor regions were used to generate treatment plans for brachytherapy using mpMRI, and tumor regions mapped from MRI to CT to generate corresponding treatment plans for EBRT. For each of EBRT and brachytherapy, 3 dose plans were generated - whole gland homogeneous ( \(\mathbb {P}^{\text {WH}}\) ) which is the current clinical standard, radiomics based focal ( \(\mathbb {P}^{\text {RF}}\) ), and whole gland with a radiomics based focal boost ( \(\mathbb {P}^{\text {WF}}\) ). Comparison of \(\mathbb {P}^{\text {RF}}\) against conventional \(\mathbb {P}^{\text {WH}}\) revealed that targeted focal brachytherapy would result in a marked reduction in dosage to the OARs while ensuring that the prescribed dose is delivered to the lesions. \(\mathbb {P}^{\text {WF}}\) resulted in only a marginal increase in dosage to the OARs compared to \(\mathbb {P}^{\text {WH}}\) . A similar trend was observed in case of EBRT with \(\mathbb {P}^{\text {RF}}\) and \(\mathbb {P}^{\text {WF}}\) compared to \(\mathbb {P}^{\text {WH}}\) .

Conclusions

A radiotherapy planning framework to generate targeted focal treatment plans has been presented. The focal treatment plans generated using the framework showed reduction in dosage to the organs at risk and a boosted dose delivered to the cancerous lesions.

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Radiomics based targeted radiotherapy planning (Rad-TRaP): a computational framework for prostate cancer treatment planning with MRI

Abstract

Background

Radiomics or computer – extracted texture features have been shown to achieve superior performance than multiparametric MRI (mpMRI) signal intensities alone in targeting prostate cancer (PCa) lesions. Radiomics along with deformable co-registration tools can be used to develop a framework to generate targeted focal radiotherapy treatment plans.

Methods

The Rad-TRaP framework comprises three distinct modules. Firstly, a module for radiomics based detection of PCa lesions on mpMRI via a feature enabled machine learning classifier. The second module comprises a multi-modal deformable co-registration scheme to map tissue, organ, and delineated target volumes from MRI onto CT. Finally, the third module involves generation of a radiomics based dose plan on MRI for brachytherapy and on CT for EBRT using the target delineations transferred from the MRI to the CT.

Results

Rad-TRaP framework was evaluated using a retrospective cohort of 23 patient studies from two different institutions. 11 patients from the first institution were used to train a radiomics classifier, which was used to detect tumor regions in 12 patients from the second institution. The ground truth cancer delineations for training the machine learning classifier were made by an experienced radiation oncologist using mpMRI, knowledge of biopsy location and radiology reports. The detected tumor regions were used to generate treatment plans for brachytherapy using mpMRI, and tumor regions mapped from MRI to CT to generate corresponding treatment plans for EBRT. For each of EBRT and brachytherapy, 3 dose plans were generated - whole gland homogeneous ( \(\mathbb {P}^{\text {WH}}\) ) which is the current clinical standard, radiomics based focal ( \(\mathbb {P}^{\text {RF}}\) ), and whole gland with a radiomics based focal boost ( \(\mathbb {P}^{\text {WF}}\) ). Comparison of \(\mathbb {P}^{\text {RF}}\) against conventional \(\mathbb {P}^{\text {WH}}\) revealed that targeted focal brachytherapy would result in a marked reduction in dosage to the OARs while ensuring that the prescribed dose is delivered to the lesions. \(\mathbb {P}^{\text {WF}}\) resulted in only a marginal increase in dosage to the OARs compared to \(\mathbb {P}^{\text {WH}}\) . A similar trend was observed in case of EBRT with \(\mathbb {P}^{\text {RF}}\) and \(\mathbb {P}^{\text {WF}}\) compared to \(\mathbb {P}^{\text {WH}}\) .

Conclusions

A radiotherapy planning framework to generate targeted focal treatment plans has been presented. The focal treatment plans generated using the framework showed reduction in dosage to the organs at risk and a boosted dose delivered to the cancerous lesions.

http://link.springer.com/10.1186/s13014-016-0718-3

Genetic variation rs7930 in the miR-4273-5p target site is associated with a risk of colorectal cancer

https://www.dovepress.com/genetic-variation-rs7930-in-the-mir-4273-5p-target-site-is-associated--peer-reviewed-article-OTT

Hürthle cell carcinoma: current perspectives

https://www.dovepress.com/huumlrthle-cell-carcinoma-current-perspectives-peer-reviewed-article-OTT

Cell membrane modulation as adjuvant in cancer therapy

Publication date: Available online 9 November 2016
Source:Cancer Treatment Reviews
Author(s): Sara Zalba, Timo L.M. ten Hagen
Cancer is a complex disease involving numerous biological processes, which can exist in parallel, can be complementary, or are engaged when needed and as such can replace each other. This redundancy in possibilities cancer cells have, are fundamental to failure of therapy. However, intrinsic features of tumor cells and tumors as a whole provide also opportunities for therapy. Here we discuss the unique and specific makeup and arrangement of cell membranes of tumor cells and how these may help treatment. Interestingly, knowledge on cell membranes and associated structures is present already for decades, while application of membrane modification and manipulation as part of cancer therapy is lagging. Recent developments of scientific tools concerning lipids and lipid metabolism, opened new and previously unknown aspects of tumor cells and indicate possible differences in lipid composition and membrane function of tumor cells compared to healthy cells. This field, coined Lipidomics, demonstrates the importance of lipid components in cell membrane in several illnesses. Important alterations in cancer, and specially in resistant cancer cells compared to normal cells, opened the door to new therapeutic strategies. Moreover, the ability to modulate membrane components and/or properties has become a reality. Here, developments in cancer-related Lipidomics and strategies to interfere specifically with cancer cell membranes and how these affect cancer treatment are discussed. We hypothesize that combination of lipid or membrane targeted strategies with available care to improve chemotherapy, radiotherapy and immunotherapy will bring the much needed change in treatment in the years to come.



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