Patients with ROS1 rearrangement-positive non-small-cell lung cancer benefit from pemetrexed-based chemotherapy

Abstract

ROS1 gene-rearrangement in non-small-cell lung cancer (NSCLC) patients has recently been identified as a driver gene and benefited from crizotinib treatment. However, no data are available for ROS1-positive NSCLC about chemotherapeutic options and prognostic data. We investigated pemetrexed-based treatment efficacy in ROS1 translocation NSCLC patients and determined the expression of thymidylate synthetase (TS) to provide a rationale for the efficacy results. We determined the ROS1 status of 1750 patients with lung adenocarcinoma. Patients' clinical and therapeutic profiles were assessed. In positive cases, thymidylate synthetase (TS) mRNA level was performed by RT-PCR. For comparison, we evaluated the TS mRNA status and pemetrexed-based treatment efficacy from 170 NSCLC patients with anaplastic lymphoma kinase (ALK) translocation (n = 46), EGFR mutation (n = 50), KRAS mutation (n = 32), and wild-type of EGFR/ALK/ROS1/KRAS (n = 42). Thirty-four ROS1 translocation patients were identified at two institutions. Among the 34 patients, 12 with advanced stage or recurrence were treated with pemetrexed-based first-line chemotherapy. The median progression-free survivals of pemetrexed-based first-line chemotherapy in ROS1 translocation, ALK translocation, EGFR mutation, KRAS mutation, and EGFR/ALK/ROS1/KRAS wild-type patients were 6.8, 6.7, 5.2, 4.2, and 4.5 months, respectively (P = 0.003). The TS mRNA level was lower in patients with ROS1-positive than ROS1-negative patients (264 ± 469 × 10⁻⁴ vs. 469 ± 615 × 10⁻⁴, P = 0.03), but similar with ALK-positive patients (264 ± 469 × 10⁻⁴ vs. 317 ± 524 × 10⁻⁴, P = 0.64). Patients diagnosed with ROS1 translocation lung adenocarcinoma may benefit from pemetrexed-based chemotherapy. TS mRNA level enables the selection of therapeutic options for ROS1 translocation patients.

This study determined 34 patients with ROS1 rearrangement positive from 1750 samples with lung cancer. They found PFS of pemetrexed-based chemotherapy in ROS1-positive patients is longer than ROS1-negative and the TS mRNA level was lower in patients with ROS1-positive than in ROS1-negative patients.

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Gallium-68 perfusion positron emission tomography/computed tomography to assess pulmonary function in lung cancer patients undergoing surgery

Abstract

Background

Pre-operative evaluation of lung cancer patients relies on calculation of predicted post-operative (PPO) lung function based on split lung function testing. Pulmonary perfusion (Q) PET/CT can now be performed by substituting Technetium-99 m labeling of macroaggregated albumin (MAA) with Gallium-68. This study compares Q PET/CT with current recommended methods of pre-operative lung function assessment.

Methods

Twenty-two patients planned for curative surgical resection (mean FEV1 77 %, SD 21 %; mean DLCO 66 %, SD 17 % predicted) underwent pre-operative Q PET/CT. Sixteen patients also underwent conventional lung scintigraphy. Lobar and lung split PPO lung function were calculated using Q PET/CT and current recommended methods, i.e. calculation based on anatomical segments for lobar function, and conventional perfusion scan for pneumonectomy. Bland-Altman statistics were used to calculate agreement between methods for PPO FEV1 and PPO DLCO.

Results

While mean split lobar functions were comparable, there was variation on an individual level between Q PET/CT and the anatomical method, with absolute difference over 5 % and 10 % in 37 % and 11 % of patients, respectively. For lobectomy the mean difference in PPO FEV1 was−1.2, but limits of agreement were−10 to 8.1 %. For DLCO, values were−1.1 % and−9.7 to 7.5 %, respectively. For pneumonectomy, PPO FEV1 values were−0.4 and−5.9 to 5.1 %. For DLCO, values were 0.3 % and−5.1 to 4.6 %.

Conclusions

While anatomic estimation provides "fixed" results, split lobar functions computed with Q PET/CT vary widely, reflecting the intra and inter-individual variability of regional lung function. Further studies to assess the role of Q PET/CT in predicting peri-operative risk in lung cancer patients planned for lobectomy are warranted.

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Antibody Drug Conjugates (ADCs): Changing the Treatment Landscape of Lymphoma

Opinion statement

While strides advancing cancer treatment have made it possible to cure some malignancies, the effort to strike an intricate balance between attaining higher efficacy and lower toxicity has been difficult to accomplish, especially with conventional chemotherapy agents. Introduction of antibody drug conjugates (ADCs) has brought us a step closer to this goal and made it possible to target the cancer cells and to minimize effects on normal tissue. Continued efforts have led to approval of two ADCs for cancer therapy, while many others are in various stages of clinical development. The design of ADCs allows them to be internalized into the cancer cells where the drug payload is released and leads to cell death. The key is to identify targets that are exclusively expressed on malignant cells with minimal or no expression on normal cells, which allows for selective killing of tumor cells. Development and approval of more potent ADCs could change the landscape of cancer therapy and possibly eliminate traditional chemotherapy agents from treatment algorithms. In this review, we discuss the ADCs that are being investigated in early and late stage clinical trials for the treatment of B cell non-Hodgkin lymphoma (NHL).

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Patients homozygous for DPYD c.1129-5923C>G/haplotype B3 have partial DPD deficiency and require a dose reduction when treated with fluoropyrimidines

Abstract

Purpose

Dihydropyrimidine dehydrogenase (DPD) is a critical determinant of 5-fluorouracil pharmacology, and reduced activity of DPD as a result of deleterious polymorphisms in the gene encoding DPD (DPYD) can result in severe treatment-related toxicity. Dosing recommendations to individualize treatment have been provided for three DPYD variants (DPYD*2A, c.2846A>T, and c.1679T>G). A fourth variant, c.1129-5923C>G/HapB3, has been shown to increase the risk of fluoropyrimidine-associated toxicity, but little is known about the functional effects of this variant.

Methods

By performing a large retrospective screen for DPYD variants, we identified three patients who were homozygous for c.1129-5923C>G/HapB3. We describe their clinical course of treatment and analyzed DPD activity and DPYD gene expression, to provide insight into the phenotypic effects of c.1129-5923C>G/HapB3.

Results

DPD activity could be measured in two patients and was 4.1 and 5.4 nmol/mg/h (DPD activity 41 and 55 % compared to controls, respectively). The fluoropyrimidine dose had to be reduced during treatment in both patients. In line with partial DPD deficiency in both patients, sequence analysis of DPD cDNA demonstrated a normal-sized (wild type) cDNA fragment of 486 bp, as well as a larger-sized (mutant) 530-bp fragment containing an aberrant 44-bp insertion in intron 10. Patient three tolerated treatment well, but DPD activity measurement was not possible as the patient had deceased at the time of performing the study.

Conclusions

The presented functional and clinical data indicate that the c.1129-5923C>G variant is both functionally and clinically relevant, and support an upfront dose reduction of the fluoropyrimidine starting dose in patients carrying c.1129-5923C>G homozygously.

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A phase II study of topotecan and cisplatin with sequential thoracic radiotherapy in elderly patients with small-cell lung cancer: Okayama Lung Cancer Study Group 0102

Abstract

Purpose

The treatment outcome in elderly patients with limited-disease small-cell lung cancer (LD-SCLC) remains poor. We carried out a phase II trial of split topotecan and cisplatin (TP) therapy and sequential thoracic radiotherapy for elderly LD-SCLC patients as a follow-up to our previous phase I trial.

Methods

In total, 30 patients aged 76 years or older, with untreated LD-SCLC were enrolled. Four courses of topotecan (1.0 mg/m², days 1–3) and cisplatin (20 mg/m², days 1–3) were administered, followed by thoracic radiotherapy (1.8 Gy/day, total of 45 Gy). The primary end point was the overall response rate (ORR).

Results

The trial was terminated early with 22 patients because of slow accrual. Their median age was 79 years. The median number of courses of chemotherapy administered was three, and the actual completion rate of the entire treatment course was 41 %. The ORR was 68 % with a 95 % confidence interval of 47–89 % (15/22 cases). The median progression-free survival and overall survival were 9.1 and 22.2 months, respectively. The main toxicity was myelosuppression, with grades 3–4 neutropenia (96 %), thrombocytopenia (50 %), and febrile neutropenia (32 %).

Conclusions

This regimen produced a favorable survival outcome, despite moderate-to-severe toxicity profiles. Further efforts are necessary to define an optimal regimen for elderly patients with limited SCLC.

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INGs are potential drug targets for cancer

Abstract

Purpose

The inhibitor of growth (ING) family consists of ING1, ING2, ING3, ING4 and ING5, which function as the type II tumor suppressors. INGs regulate cell proliferation, senescence, apoptosis, differentiation, angiogenesis, DNA repair, metastasis, and invasion by multiple pathways. In addition, INGs increase cancer cell sensitivity for chemotherapy and radiotherapy, while clinical observations show that INGs are frequently lost in some types of cancers. The aim of the study was to summarize the recent progress regarding INGs regulating tumor progression.

Methods

The literatures of INGs regulating tumor progression were searched and assayed.

Results

The regulating signaling pathways of ING1, ING2, ING3 or ING4 on tumor progression were shown. The mechanisms of INGs on tumor suppression were also assayed.

Conclusions

This review better summarized the signaling mechanism of INGs on tumor suppression, which provides a candidate therapy strategy for cancers.

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Differential somatostatin and CXCR4 chemokine receptor expression in MALT-type lymphoma of gastric and extragastric origin

Abstract

Purpose

Whereas the different somatostatin receptor (SSTR) subtypes and the chemokine receptor CXCR4 are known to be expressed in a wide variety of human malignancies, comprehensive data are still lacking for MALT-type lymphomas.

Methods

Overall, 55 cases of MALT-type lymphoma of both gastric and extragastric origin were evaluated for the SSTR subtype and CXCR4 expression by means of immunohistochemistry using novel monoclonal rabbit antibodies. The stainings were rated by means of the immunoreactive score and correlated with clinical data.

Results

While the CXCR4 was detected in 92 % of the cases investigated, the SSTR subtypes were much less frequently present. The SSTR5 was expressed in about 50 % of the cases, followed by the SSTR3, the SSTR2A, the SSTR4 and the SSTR1, which were present in 35, 27, 18 or 2 %, respectively, of the tumors only. Gastric lymphomas displayed a significantly higher SSTR3, SSTR4 and SSTR5 expression than extragastric tumors. A correlation between CXCR4 and Ki-67 expression was seen in gastric lymphomas, whereas primarily in extragastric tumors SSTR5 negativity was associated with poor patient outcome.

Conclusions

The CXCR4 may serve as a promising target for diagnostics and therapy of MALT-type lymphomas, while the SSTRs appear not suitable in this respect.

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Margin of Error for a Frameless Image-Guided Radiosurgery System: Direct Confirmation Based On Post-Treatment MRI Scans

Publication date: Available online 20 August 2016
Source:Practical Radiation Oncology
Author(s): Guozhen Luo, Joseph S. Neimat, Anthony Cmelak, Austin N. Kirschner, Albert Attia, Manuel Morales-Paliza, George X. Ding
PurposeTo report on radiosurgery delivery positioning accuracy in the treatment of tremor patients with frameless image-guided radiosurgery using the linear accelerator (LINAC) based ExacTrac system and to describe quality assurance (QA) procedures used.MethodsBetween 2010 and 2015, twenty patients underwent radiosurgical thalamotomy targeting the ventral intermediate nucleus for the treatment of severe tremor. The median prescription dose was 140Gy (range 120–145Gy) in a single fraction. The median maximum dose was 156Gy (range 136–162Gy). All treatment planning was performed with the iPlan system using a 4-mm circular cone with multiple arcs. Before each treatment QA procedures were performed including the imaging system. As a result of the extremely high dose delivered in a single fraction, a well-defined circular mark developed on the post-treatment MRI. Eight out of these twenty patients were selected to evaluate treatment localization errors because their circular marks were available in post treatment MRI. In this study the localization error is defined as the distance between the center of the intended target and the center of the post-treatment mark.ResultsThe mean error of distance was found to be 1.1mm (range 0.4mm to 1.5mm). The mean errors for the left–right, anterior–posterior, and superior–inferior directions are 0.5mm, 0.6mm, and 0.7mm, respectively.ConclusionsThe result reported in this study includes all tremor patients treated at our institution when their post treatment MRI data were available for study. It represents a direct confirmation of target positioning accuracy in radiosurgery with a LINAC-based frameless system and its limitations. This level of accuracy is only achievable with an appropriate QA program in place for a LINAC-based frameless radiosurgery system.



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Inherent Functional Dependence Among Cochlear Dose Surrogates for Stereotactic Radiosurgery of Vestibular Schwannomas

Publication date: Available online 20 August 2016
Source:Practical Radiation Oncology
Author(s): Lijun Ma, Steve E. Braunstein, Philip V. Theodosopoulos, Michael W. McDermott, Penny K. Sneed
PurposeVarious cochlear dose surrogates have been reported as associated with hearing outcome in studies of stereotactic radiosurgery (SRS) for vestibular schwannomas. In this study, we investigated whether an inherent functional relationship exits among these reported surrogates.Methods and MaterialsA cohort of 85 serial patient cases treated with single-fraction stereotactic radiosurgery from 1997–2013 at our institution was analyzed. For all the cases, the mean prescription dose was 12.5±0.3Gy (range, 12–13Gy) and mean target volume 1.32±1.51mL (range, 0.80–8.77mL). The mean cochlea volume was 0.078±0.016mL (range, 0.048–0.131mL; median, 0.076mL). Correlation analysis among mean cochlear dose, point maximum dose and modiolus dose was performed and also parameterized with new variables such as the Effective Dose Radius (EDR) as derived from a general dose fall-off model.ResultsWeak correlation via linear regression was found between the point maximum dose and the mean cochlear dose (R²=0.719) as well as the modiolus dose (R²=0.568). However, when parameterized with EDR, a near perfect correlation (p<0.0001) via linear regression was found between the EDR for the point maximum dose and the EDR for the mean cochlear dose (R²=0.996), and with the EDR for the modiolus dose (R²=0.993). Such a result led to a functional formula relating these dose surrogates, yielding dose equivalence results such as: 12Gy point maximum dose is equivalent to mean cochlear dose of 5.6±0.1Gy (95% CL), or modiolous dose of 6.0±0.2Gy (95% CL).ConclusionsAn inherent functional relationship was found among point maximum, modiolus, and mean cochlear doses for SRS of vestibular schwannomas. As such, clinical hearing outcome can be interchangeably analyzed or reported via any of these dose surrogates.



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43th ISOBM Annual Congress of International Society of Oncology and BioMarkers, September 1-6, 2016 Chicago, USA

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MiR-384 regulated IRS1 expression and suppressed cell proliferation of human hepatocellular carcinoma

Abstract

Acquired evidence indicated that microRNAs (miRNAs) played essential roles in cancer development, including hepatocellular carcinoma (HCC). Functions and mechanisms of miRNAs involved in HCC remain largely unknown. Here, we found that miR-384 was significantly downregulated in HCC cells and tissues by RT-PCR. Gain and loss of function studies revealed that miR-384 significantly suppressed HCC cell proliferation. Insulin receptor substrate 1(IRS1) was identified as a direct and functional target of miR-384. Moreover, miR-384 decreased IRS1 expression, subsequently downregulating cyclin D1 and upregulating p21 and p-Rb expression. In addition, promotion of cell proliferation caused by miR-384-in was counteracted by silencing IRS1 expression with siRNAs. Taken together, our data provided convincing evidence that miR-384 exerted suppressive effect on HCC cell proliferation through the direct inhibition of IRS1 expression, suggesting miR-384 may serve as a potential therapeutic target for HCC.

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Depletion of STYK1 inhibits intrahepatic cholangiocarcinoma development both in vitro and in vivo

Abstract

Intrahepatic cholangiocarcinoma (ICC) has been reported to be the second most common primary hepatic carcinoma worldwide, and very limited therapies are currently available. Serine threonine tyrosine kinase (STYK1), a member of the receptor tyrosine kinase family, exhibits tumorigenicity in many types of cancers and is a potential therapeutic target for ICC. In this study, STYK1 was knocked down in the ICC cell lines HCCC-9810 and RBE via a lentivirus-mediated system using short hairpin RNA (shRNA). Next, cell proliferation, colony formation, cell cycle progression, tumor formation in nude mice, migration and invasion, and the expression levels of cell cycle proteins in Lv-sh STYK1- or Lv-sh Con-infected cells were analyzed by CCK-8 assay, colony formation evaluation, flow cytometry, tumor formation evaluation, wound scratch assay, transwell assay, and western blotting. The results indicated that depletion of STYK1 inhibits ICC development both in vitro and in vivo.

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SPARC expression in patients with high-risk localized soft tissue sarcoma treated on a randomized phase II trial of neo/adjuvant chemotherapy

Abstract

Background

Treatment for localized soft tissue sarcoma includes surgery and radiation, while the role of chemotherapy is controversial. Biomarkers that could predict therapeutic response or prognosticate overall survival (OS) are needed to define patients most likely to benefit from systemic treatment. Serum protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that has been evaluated as a potential biomarker in numerous malignancies given its involvement in cell adhesion, proliferation, migration, and tissue remodeling.

Methods

Using primary biopsy and resection specimens from patients with high-risk localized, soft tissue sarcoma treated on a neo/adjuvant chemotherapy study, SPARC expression was assessed and compared to patient and tumor characteristics, treatment, and outcomes. Survival functions were estimated using the Kaplan–Meier method and compared using the log-rank test. The Cox model was used for multivariate analysis.

Results

Fifty patients had primary tumor specimens available. High, low, and no SPARC expression was found in 22, 13, and 15 patients, respectively. There was no significant difference in time to recurrence or OS between patients in these three groups. Comparing lack of SPARC expression with any SPARC expression, there was no significant difference in time to recurrence in patients without SPARC expression (n = 15) compared to patients with SPARC expression (n = 35). Likewise, there was no statistically significant difference in OS in patients without SPARC expression versus patients whose tumors expressed SPARC.

Conclusions

Although we did not find a statistically significant difference in time to recurrence and OS in patients with high-risk soft tissue sarcoma, we did identify a trend toward improved time to recurrence and OS in patients whose tumors lacked SPARC expression. However, SPARC did not demonstrate the ability to discern which high-risk patients may have a worse prognosis or greater benefit from chemotherapy.

Trial registration

The trial was registered on September 13, 2005 with ClinicalTrials.gov, number http://ift.tt/2b6Ig4z.

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Environmental, maternal, and reproductive risk factors for childhood acute lymphoblastic leukemia in Egypt: a case-control study

Abstract

Background

Acute lymphocytic leukemia (ALL) is the most common pediatric cancer. The exact cause is not known in most cases, but past epidemiological research has suggested a number of potential risk factors. This study evaluated associations between environmental and parental factors and the risk for ALL in Egyptian children to gain insight into risk factors in this developing country. Methods: We conducted a case-control design from May 2009 to February 2012. Cases were recruited from Children's Cancer Hospital, Egypt (CCHE). Healthy controls were randomly selected from the general population to frequency-match the cumulative group of cases by sex, age groups (<1; 1 – 5; >5 – 10; >10 years) and region of residence (Cairo metropolitan region, Nile Delta region (North), and Upper Egypt (South)). Mothers provided answers to an administered questionnaire about their environmental exposures and health history including those of the father. Odds ratios (ORs) and 95 % confidence intervals (CI) were calculated using logistic regression with adjustment for covariates.

Results

Two hundred ninety nine ALL cases and 351 population-based controls frequency-matched for age group, gender and location were recruited. The risk of ALL was increased with the mother's use of medications for ovulation induction (OR_adj = 2.5, 95 % CI =1.2 –5.1) and to a lesser extend with her age (OR_adj = 1.8, 95 % CI = 1.1 – 2.8, for mothers ≥ 30 years old). Delivering the child by Cesarean section, was also associated with increased risk (OR_adj = 2.01, 95 % CI =1.24–2.81).

Conclusions

In Egypt, the risk for childhood ALL appears to be associated with older maternal age, and certain maternal reproductive factors.

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Use of non-steroidal anti-inflammatory drugs and risk of breast cancer: The Spanish Multi-Case-control (MCC) study

Abstract

Background

The relationship between non-steroidal anti-inflammatory drug (NSAID) consumption and breast cancer has been repeatedly studied, although the results remain controversial. Most case-control studies reported that NSAID consumption protected against breast cancer, while most cohort studies did not find this effect. Most studies have dealt with NSAIDs as a whole group or with specific drugs, such aspirin, ibuprofen, or others, but not with NSAID subgroups according to the Anatomical Therapeutic Chemical Classification System; moreover, scarce attention has been paid to their effect on different tumor categories (i.e.: ductal/non-ductal, stage at diagnosis or presence of hormonal receptors).

Methods

In this case-control study, we report the NSAID – breast cancer relationship in 1736 breast cancer cases and 1895 healthy controls; results are reported stratifying by the women's characteristics (i.e.: menopausal status or body mass index category) and by tumor characteristics.

Results

In our study, NSAID use was associated with a 24 % reduction in breast cancer risk (Odds ratio [OR] = 0.76; 95 % Confidence Interval [CI]: 0.64–0.89), and similar results were found for acetic acid derivatives, propionic acid derivatives and COXIBs, but not for aspirin. Similar results were found in postmenopausal and premenopausal women. NSAID consumption also protected against hormone + or HER2+ cancers, but not against triple negative breast cancers. The COX-2 selectivity showed an inverse association with breast cancer (i.e. OR < 1), except in advanced clinical stage and triple negative cancers.

Conclusion

Most NSAIDs, but not aspirin, showed an inverse association against breast cancer; this effect seems to be restricted to hormone + or HER2+ cancers.

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Is there any role of intravenous iron for the treatment of anemia in cancer?

Abstract

Background

Anemia is a major cause of morbidity in patients with cancer resulting in poor physical performance, prognosis and therapy outcome. The aim of this study is to assess the efficacy of intravenous (iv) iron administration for the correction of anemia, for the prevention of exacerbation of anemia, for decreasing blood transfusion rates, and for the survival of cancer patients.

Methods

Patients with different solid tumor diagnosis who received iv iron during their cancer treatment were evaluated retrospectively. Sixty-three patients with hemoglobin (Hgb) levels between ≥ 9 g/dL, and ≤ 10 g/dL, and no urgent need for red blood cell transfusion were included in this retrospective analysis. The aim of cancer treatment was palliative for metastatic patients (36 out of 63), or adjuvant or curative for patients with localized disease (27 out of 63). All the patients received 100 mg of iron sucrose which was delivered intravenously in 100 mL of saline solution, infused within 30 min, 5 infusions every other day. Complete blood count, serum iron, and ferritin levels before and at every 1 to 3 months subsequently after iv iron administration were followed regularly.

Results

Initial mean serum Hgb, serum ferritin and serum iron levels were 9.33 g/dL, 156 ng/mL, and 35.9 μg/dL respectively. Mean Hgb, ferritin, and iron levels 1 to 3 months, and 6 to 12 months after iv iron administration were 10.4 g/dL, 11.2 g/dL, 298.6 ng/mL, 296.7 ng/mL, and 71.6 μg/dL, 67.7 μg/dL respectively with a statistically significant increase in the levels (p < 0.001). Nineteen patients (30 %) however had further decrease in Hgb levels despite iv iron administration, and blood transfusion was necessary in 18 of these 19 patients (28.5 %). The 1-year overall survival rates differed in metastatic cancer patients depending on their response to iv iron; 61.1 % in responders versus 35.3 % in non-responders, (p = 0.005), furthermore response to iv iron correlated with tumor response to cancer treatment, and this relation was statistically significant, (p < 0.001).

Conclusions

Iv iron administration in cancer patients undergoing active oncologic treatment is an effective and safe measure for correction of anemia, and prevention of worsening of anemia. Amelioration of anemia and increase in Hgb levels with iv iron administration in patients with disseminated cancer is associated with increased tumor response to oncologic treatment and overall survival. Response to iv iron may be both a prognostic and a predictive factor for response to cancer treatment and survival.

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Stereotactic Radiosurgery for poor performance status patients: A cost-effectiveness dilemma for radiation oncologist in public healthcare system

Publication date: Available online 20 August 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Paolo Tini, Valerio Nardone, PierPaolo Pastina, Giuseppe Battaglia, Lucio Sebaste, Luigi Pirtoli




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Painting Dose: the ART of Radiation

Publication date: Available online 20 August 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Hannah J. Roberts, Anthony L. Zietman, Jason A. Efstathiou
The discovery of X-rays in 1895 captivated society like no other scientific advance. Radiation instantly became the subject not only of numerous scientific papers, but also of circus bazaars, poetry, fiction, costume design, comics, and marketing for household items. Its spread was "viral". What is not well known, however, is its incorporation into visual art, despite the long tradition of medicine and surgery as a subject in art. Using a number of contemporary search methods, we identified five examples of paintings or sculpture that thematically feature radiotherapy. All were by artists who had had an exhibited career in art: Georges Chicotot, Marcel Duchamp, David Alfaro Siqueiros, Robert Pope, and Cookie Kerxton. Each artist portrays radiation differently, ranging from traditional healer, to mysterious danger, to futuristic propaganda, to the emotional challenges of undergoing cancer therapy. This range captures radiation's complex role as both a therapy and a hazard. While some of these artists, however, are now world-famous, none of these examples are as well known as their surgical counterparts. Radiation's penetration into popular culture was rapid and pervasive, yet its role as a thematic subject in art never fully caught on, perhaps due to a lack of understanding of the technology, radiation's intangibility, or perhaps even a suppressive effect of society's ambivalent relationship with it. These five artists have established a rich foundation upon which pop culture and art can further develop with time to reflect the extraordinary progress of modern radiation therapy.



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Analysis of Lung Tumor Motion in a Large Sample: Patterns and Factors Influencing Precise ITV Delineation

Publication date: Available online 20 August 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Lukas Knybel, Jakub Cvek, Lukas Molenda, Natalie Stieberova, David Feltl
Purpose/Objective: To evaluate lung tumor motion during respiration and describe factors affecting the range and variability of motion in patients treated with stereotactic ablative radiotherapy.MethodsLog file analysis from online respiratory tumor tracking was performed in 145 patients. Geometrical tumor location in the lungs, tumor volume and origin (primary or metastatic), gender, and tumor motion amplitudes in the superior-inferior (SI), latero-lateral (LL), and anterior-posterior (AP) directions were recorded. Tumor motion variability during treatment was described using intra/interfraction amplitude variability and tumor motion baseline changes. Tumor movement dependent on the tumor volume, position, and origin and gender were evaluated using statistical regression and correlation analysis.ResultsAfter analyzing >500 hours of data, the highest rates of motion amplitudes, intra/interfraction variation, and tumor baseline changes were in the SI direction (6.0±2.2 mm, 2.2±1.8 mm, 1.1±0.9 mm, and −0.1±2.6 mm). Mean motion amplitudes in the lower/upper geometrical halves of the lungs were significantly different (p<0.001). Motion amplitude >15 mm was observed only in the lower geometrical quarter of the lungs. Higher tumor motion amplitude generated higher intrafraction variation (R=0.86, p<0.001). Interfraction variation and baseline change >3 mm indicated tumors contacting mediastinal structures or parietal pleura. On univariate analysis, neither gender nor tumor origin (primary vs. metastatic) were independent predictive factors of different movement patterns. Metastatic lesions in women, but not men, showed significantly higher mean amplitudes (p=0.03) and variability (primary, 2.7 mm; metastatic, 4.9 mm; p=0.002) than primary tumors.ConclusionOnline tracking showed significant irregularities in lung tumor movement during respiration. Motion amplitude was significantly lower in upper lobe tumors; higher interfraction amplitude variability indicated tumors in contact with mediastinal structures, though adhesion to parietal pleura did not necessarily reduce tumor motion amplitudes. The most variable lung tumors were metastatic lesions in women.

Teaser

Understanding patterns of tumor motion and involving them in treatment planning is important for performing precise lung radiotherapy. Data from online tumor tracking was used to evaluate respiratory motions of lung tumors and describe factors affecting range of motion and motion variability during radiotherapy.


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MR image-guided radiation therapy (MR-IGRT) for external beam accelerated partial breast irradiation (APBI): Evaluation of delivered dose and intra-fractional cavity motion

Publication date: Available online 20 August 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sahaja Acharya, Benjamin W. Fischer-Valuck, Thomas Mazur, Austen Curcuru, Karl Sona, Rojano Kashani, Olga Green, Laura Ochoa, Sasa Mutic, Imran Zoberi, H. Harold Li, Maria A. Thomas
Purpose/Objective: To utilize MR-image guided radiation therapy (MR-IGRT) for accelerated partial breast irradiation (APBI) to: (1) determine intra-fractional motion of the breast surgical cavity and (2) assess delivered dose versus planned dose.Materials/MethodsThirty women with breast cancer (Stages 0-I) who underwent breast conserving surgery were enrolled in a prospective registry evaluating APBI using a 0.35 T MR-IGRT system. CTV was defined as the surgical cavity plus a 1 cm margin (excluding chest wall, pectoral muscles, and 5 mm from skin). No additional margin was added for PTV. A volumetric MRI was acquired prior to each fraction and patients were setup to the surgical cavity as visualized on MRI. To determine the delivered dose for each fraction, the electron density map and contours from the CT simulation were transferred to the pre-treatment MRI via rigid registration. Intra-fractional motion of the surgical cavity was determined by applying a tracking algorithm to the cavity contour as visualized on cine MR.ResultsMedian PTV volume was reduced by 52% when utilizing no PTV margin compared to a 1 cm PTV margin used conventionally. The mean difference between planned and delivered dose to the PTV (V95) was 0.6% ± 0.1%. The mean cavity displacement in the anterior-posterior (AP) and superior-inferior (SI) directions was 0.6 ± 0.4 mm and 0.6 ± 0.3 mm, respectively. The mean margin required for at least 90% of the cavity to be contained by the margin for 90% of the time was 0.7 mm (5^th-95^th percentile: 0-2.7 mm).ConclusionMinimal intra-fractional motion was observed and the mean difference between planned and delivered dose was less than 1%. Assessment of efficacy and cosmesis of this MR-guided APBI approach is underway.

Teaser

We utilize MR-image guided radiation therapy (MR-IGRT) for accelerated partial breast irradiation (APBI) to: (1) determine intra-fractional motion of the breast surgical cavity and (2) assess delivered dose versus planned dose. Our results indicate there is minimal intrafractional motion and there is good agreement between delivered and planned dose. Assessment of efficacy and cosmesis of this MR-guided APBI approach is underway.


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Targeting phosphatidylinositol 4-kinase IIIα for radiosensitization: a potential model of drug repositioning using anti-HCV agent

Publication date: Available online 20 August 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jeanny Kwon, Dan Hyo Kim, Ji Min Park, Young Hee Park, Yeo Hyun Hwang, Hong-Gyun Wu, Kyung Hwan Shin, In Ah Kim
PurposePhosphatidylinositol 4-kinase (PI4K) is responsible for the generation of PI4-phosphate (PI4P), a common upstream substrate of both the PLC/PKC and PI3K/Akt pathways. Inhibition of PI4K is expected to inactivate these PI4P-dependent pathways simultaneously. Therefore, we investigated that which isotype of PI4K may affect a radiosensitivity and examined whether anti-hepatitis C viral (HCV) agents, some of which have been shown to inhibit PI4K IIIα activity, could be repositioned or not as a radiosensitizer in human cancer cells.Methods and MaterialsU251, BT474, HepG2 cell lines and NHA were used. RNAi, clonogenic assays, western blotting, immunofluorescence, annexin V assay, lysotracker staining, and β-galactosidase assay were performed.ResultsOf the four PI4K isotypes, specific inhibition of IIIα increased the radiosensitivity. For pharmacologic inhibition of PI4K IIIα, we screened 9 anti-HCV agents by IC50 assay. Simeprevir was selected and its inhibition of PI4K IIIα activity was confirmed. Combination of simeprevir treatment and radiation significantly attenuated expression of p-PKC and p-Akt and increased radiation-induced cell death in tested cell lines. Pretreatment with simeprevir prolonged γH2AX foci formation and downregulation of p-DNA-PKcs, indicating impairment of nonhomologous end-joining repair. Cells pretreated with simeprevir exhibited mixed modes of cell death, including apoptosis and autophagy.ConclusionThese data demonstrate that targeting PI4K IIIα using an anti-HCV agent is a viable approach to enhance the therapeutic efficacy of radiotherapy in various human cancers, such as glioma, breast, and hepatocellular carcinoma.

Teaser

Targeting PI4K IIIα by siRNA showed a significant radiosensitizing effect on human cancer cells. The anti-HCV agent simeprevir had an inhibitory effect of PI4K IIIα, resulting in radiosensitization by inhibiting prosurvival signaling and DNA damage repair. Inhibition of PI4K IIIα via simeprevir represents an attractive approach for simultaneously inhibiting both the PI3K/Akt and PLC/PKC pathways and a viable approach to enhance the therapeutic efficacy of radiotherapy in various human cancers.


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Learning, technology and intellectual property: a survey of the philosophies and preferences of our trainees and peers

Abstract

Background

Increasing workloads threaten the quality of teaching in academic radiology practices. There is a wealth of unfiltered educational resources for radiology on the internet. As a digital native, today's radiology trainee may have differing opinions from teachers about learning and intellectual property.

Objective

To identify the preferences and philosophies regarding learning, technology and intellectual property toward the future development of an innovative radiology curriculum.

Materials and methods

An electronic survey with 22 questions was sent to 2,010 members of the Society for Pediatric Radiology and 100 radiology trainees.

Results

Three hundred sixty-one of the 2,110 surveys were returned. All questions were completed in 342 surveys. Fifty-three respondents were trainees (residents and fellows) and 289 respondents were radiologists (teachers). Time needed for a single learning activity in both groups is <30 min, but teachers spend less time (P=0.007). The preferred learning environments were point-of-care and outside work hours for both groups. Ideal lecture durations were 31-45 min for trainees and 21-30 min for teachers (P=0.001). Adoption of new technology showed late majority and laggard trends for both groups (P=0.296). Interest in gadgets was greater in trainees (17%) than teachers (2%) (P<0.001). Interest in lecture recording was greater in trainees (84%) than teachers (61%) (P=0.008). More trainees (61%) than teachers (42%) would not charge money for educational materials (P=0.028); 27% versus 13%, respectively, disagreed with dissemination of those materials beyond the institution (P=0.013).

Conclusion

While millennial trainees are adult learners with a stronger comfort with technology, learning styles of trainees and teachers are more similar than was previously believed. Trainees and teachers hold conflicting philosophies about intellectual property. Results herein speak favorably for revising our teaching portfolio to include practical learning materials of short duration available at point-of-care.

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Patients homozygous for DPYD c.1129-5923C>G/haplotype B3 have partial DPD deficiency and require a dose reduction when treated with fluoropyrimidines

Abstract

Purpose

Dihydropyrimidine dehydrogenase (DPD) is a critical determinant of 5-fluorouracil pharmacology, and reduced activity of DPD as a result of deleterious polymorphisms in the gene encoding DPD (DPYD) can result in severe treatment-related toxicity. Dosing recommendations to individualize treatment have been provided for three DPYD variants (DPYD*2A, c.2846A>T, and c.1679T>G). A fourth variant, c.1129-5923C>G/HapB3, has been shown to increase the risk of fluoropyrimidine-associated toxicity, but little is known about the functional effects of this variant.

Methods

By performing a large retrospective screen for DPYD variants, we identified three patients who were homozygous for c.1129-5923C>G/HapB3. We describe their clinical course of treatment and analyzed DPD activity and DPYD gene expression, to provide insight into the phenotypic effects of c.1129-5923C>G/HapB3.

Results

DPD activity could be measured in two patients and was 4.1 and 5.4 nmol/mg/h (DPD activity 41 and 55 % compared to controls, respectively). The fluoropyrimidine dose had to be reduced during treatment in both patients. In line with partial DPD deficiency in both patients, sequence analysis of DPD cDNA demonstrated a normal-sized (wild type) cDNA fragment of 486 bp, as well as a larger-sized (mutant) 530-bp fragment containing an aberrant 44-bp insertion in intron 10. Patient three tolerated treatment well, but DPD activity measurement was not possible as the patient had deceased at the time of performing the study.

Conclusions

The presented functional and clinical data indicate that the c.1129-5923C>G variant is both functionally and clinically relevant, and support an upfront dose reduction of the fluoropyrimidine starting dose in patients carrying c.1129-5923C>G homozygously.

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A phase II study of topotecan and cisplatin with sequential thoracic radiotherapy in elderly patients with small-cell lung cancer: Okayama Lung Cancer Study Group 0102

Abstract

Purpose

The treatment outcome in elderly patients with limited-disease small-cell lung cancer (LD-SCLC) remains poor. We carried out a phase II trial of split topotecan and cisplatin (TP) therapy and sequential thoracic radiotherapy for elderly LD-SCLC patients as a follow-up to our previous phase I trial.

Methods

In total, 30 patients aged 76 years or older, with untreated LD-SCLC were enrolled. Four courses of topotecan (1.0 mg/m², days 1–3) and cisplatin (20 mg/m², days 1–3) were administered, followed by thoracic radiotherapy (1.8 Gy/day, total of 45 Gy). The primary end point was the overall response rate (ORR).

Results

The trial was terminated early with 22 patients because of slow accrual. Their median age was 79 years. The median number of courses of chemotherapy administered was three, and the actual completion rate of the entire treatment course was 41 %. The ORR was 68 % with a 95 % confidence interval of 47–89 % (15/22 cases). The median progression-free survival and overall survival were 9.1 and 22.2 months, respectively. The main toxicity was myelosuppression, with grades 3–4 neutropenia (96 %), thrombocytopenia (50 %), and febrile neutropenia (32 %).

Conclusions

This regimen produced a favorable survival outcome, despite moderate-to-severe toxicity profiles. Further efforts are necessary to define an optimal regimen for elderly patients with limited SCLC.

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Curcumin Changes the Polarity of Tumor-Associated Microglia and Eliminates Glioblastoma

Abstract

Glioblastoma (GBM) is one of the most pernicious forms of cancer and currently chances of survival from this malady are extremely low. We have used the non-invasive strategy of intranasal (IN) delivery of a glioblastoma-directed adduct of curcumin (CC), CC-CD68Ab, into the brain of mouse GBM GL261-implanted mice to study the effect of CC on tumor remission and on the phenotype of the tumor-associated microglial cells (TAMs). The treatment caused tumor remission in 50% of GL261-implanted GBM mice. A similar rescue rate was also achieved through intraperitoneal infusion of a lipid-encapsulated formulation of CC, Curcumin Phytosome, into the GL261-implanted GBM mice. Most strikingly, both forms of CC elicited a dramatic change in the tumor-associated Iba1+ TAMs, suppressing the tumor-promoting Arginase1^high, iNOS^low M2-type TAM population while inducing the Arginase1^low, iNOS^high M1-type tumoricidal microglia. Concomitantly, we observed a marked induction and activation of microglial NF-kB and STAT1, which are known to function in coordination to cause induction of iNOS. Therefore, our novel findings indicate that appropriately delivered CC can directly kill GBM cells and also repolarize the TAMs to the tumoricidal M1 state. This article is protected by copyright. All rights reserved.

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Heparan Sulfate Proteoglycans Mediate Renal Carcinoma Metastasis

Abstract

The surface proteoglycan/glycoprotein layer (glycocalyx) on tumor cells has been associated with cellular functions that can potentially enable invasion and metastasis. In addition, aggressive tumor cells with high metastatic potential have enhanced invasion rates in response to interstitial flow stimuli in vitro. Our previous studies suggest that heparan sulfate (HS) in the glycocalyx plays an important role in this flow mediated mechanostransduction and upregulation of invasive and metastatic potential. In this study, highly metastatic renal cell carcinoma cells were genetically modified to suppress HS production by knocking down its synthetic enzyme NDST1. Using modified Boyden chamber and microfluidic assays, we show that flow-enhanced invasion is suppressed in HS deficient cells. To assess the ability of these cells to metastasize in vivo, parental or knockdown cells expressing fluorescence reporters were injected into kidney capsules in SCID mice. Histological analysis confirmed that there was a large reduction (95%) in metastasis to distant organs by tumors formed from the NDST1 knockdown cells compared to control cells with intact HS. The ability of these cells to invade surrounding tissue was also impaired. The substantial inhibition of metastasis and invasion upon reduction of HS suggests an active role for the tumor cell glycocalyx in tumor progression. This article is protected by copyright. All rights reserved.

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Evaluation the Survival of Patients with Gastric Cancer Treated with Adjuvant or Palliative Chemotherapy

Abstract

Aim

Our aim was to evaluate impact of chemotherapy (5-fluorouracil plus docetaxel and cisplatin) on the survival of gastric cancer cases.

Method

Seventy-nine patients were eligible to take part in this study between November 2006 and April 2013, who received 5-fluorouracil (700 mg/m², 21-h infusion within 5 days), cisplatin (60 mg/m² on day 3), and Docetaxel (60 mg/m² on day 2). Radiotherapy was added to the treatment only in the cases with entire stomach body cancer (positive margin) and with giant ulcer (above 50 mm) in proximal gastric cancer.

Results

Twenty-four patients were female and 55 were male. The median age was 54. In this study, 54 % of the tumors were located in the proximal and 46 % in the distal of stomach. Seventy five percent of patients were at stage I–III (adjuvant chemotherapy), and 25 % at stage IV (palliative chemotherapy). Ninety-one percent of the patients at stages I–II, 68.3 % of the patients at stage III, and one out of 20 patients at stage IV were alive at the end of follow-up. Median disease-free survival for the patients at stages I–III was 63 months, and the overall survival for all patients was 50 months.

Conclusion

The results of our study indicate that the survival of the patients with stomach cancer increases with chemotherapy. Radiotherapy was used for our patients with gastric cancer in specific cases.

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Salivary and serum IL-10, TNF-α, TGF-β, VEGF levels in oropharyngeal squamous cell carcinoma and correlation with HPV and EBV infections

Abstract

Background

Each year approximately 6,000 new cases of head and neck cancer are registered in Poland. Human papillomavirus (HPV) and Epstein-Barr virus (EBV) have been associated with tumour formation. Cytokines have been shown to play an important role both in inflammation and carcinogenesis and they can be detected in saliva and serum with ELISA assays. Salivary biomarkers may be used as markers of early cancer detection.

The aim of this study was the analysis of the serum and salivary levels of IL-10, TNF-α, TGF-β and VEGF in patients with oropharyngeal cancer and in healthy individuals. The level of these biomarkers was also analyzed in HPV- and EBV-related cases.

Methods

The study involved 78 patients with histopathologically confirmed oropharyngeal squamous cell carcinoma and 40 healthy controls. Serum and salivary levels of IL-10, TNF-α, TGF-β and VEGF were analyzed both in patients and in healthy individuals by ELISA method using Diaclone SAS commercially available kits (France). EBV DNA was detected by the nested PCR for amplification of EBNA-2. HPV detection and genotyping was performed using the INNO-LiPA HPV Genotyping Extraassay (Innogenetics N. V, Gent, Belgium). The obtained results were subjected to statistical analysis using Mann–Whitney and Kruskal Wallis tests. Test values of p < 0.05 were considered statistically significant.

Results

The level of tested cytokines was higher in patients than in controls both in serum (IL-10: 2.3 pg/ml vs 1.65 pg/ml, p = 0.0003; TGF-β: 11.3 ng/ml vs 7.8 ng/ml, p = 0.0005; VEGF: 614 pg/ml vs 210 pg/ml, p = 0.0004; TNF-α: 15.0 ng/ml vs 12.90 ng/ml, p = 0.1397) as well as in saliva (IL-10: 5.9 pg/ml vs 2.5 pg/ml, p = 0.00002; TGF-β: 24.1 ng/ml vs 14.8 ng/ml, p = 0.00002; VEGF: 4321 pg/ml vs 280 pg/ml, p = 0.0000; TNF-α: 23.1 ng/ml vs 11.3 ng/ml, p = 0.00002).

EBV DNA was detected in 51.3 % of patients and 20 % of controls, HPV DNA was present in 30.8 % of patients and 2,5 % of controls.

The level of IL-10 was statistically higher in patients infected with EBV, HPV and co-infected with EBV/HPV. The level of TNF-α was significantly higher in patients infected with EBV, while TGF-β in patients with HPV infection and EBV/HPV co-infection.

Conclusion

Detection of salivary cytokines may be very helpful in early diagnosis, treatment and prognosis of OSCC.

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FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome

Abstract

Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C>T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple-negative breast cancer patients. To investigate the association of the mutation with disease prognosis, we studied tumor phenotype, treatment outcome, and patient survival in 3933 invasive breast cancer patients, including 101 FANCM c.5101C>T mutation carriers and 3832 non-carriers. We also examined association of the mutation with nuclear immunohistochemical staining of DNA repair markers in 1240 breast tumors. The FANCM c.5101C>T mutation associated with poor 10-year breast cancer-specific survival (hazard ratio (HR)=1.66, 95% confidence interval (CI) 1.09 – 2.52, P=0.018), with a more pronounced survival effect among familial cases (HR=2.93, 95% CI 1.5 – 5.76, P=1.80x10⁻³). Poor disease outcome of the carriers was also found among the estrogen receptor (ER) positive subgroup of patients (HR=1.8, 95% CI 1.09 – 2.98, P=0.021). Reduced survival was seen especially among patients who had not received radiotherapy (HR=3.43, 95% CI 1.6 – 7.34, P=1.50x10⁻³) but not among radiotherapy treated patients (HR=1.35, 95% CI 0.82 – 2.23, P=0.237). Significant interaction was found between the mutation and radiotherapy (P=0.040). Immunohistochemical analyses show that c.5101C>T carriers have reduced PAR-activity. Our results suggest that FANCM c.5101C>T nonsense mutation carriers have a reduced breast cancer survival but postoperative radiotherapy may diminish this survival disadvantage. This article is protected by copyright. All rights reserved.

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Male pattern baldness and risk of incident skin cancer in a cohort of men

Abstract

We examined the association between male-pattern baldness and risk of incident skin cancer, including invasive melanoma, invasive squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) in a prospective analysis, based on 36,032 participants from the Health Professionals' Follow-up Study. In 1992, participants reported their status of male-pattern baldness at age 45 years by choosing from five crown-view pictograms based on Norwood's classification. Diagnosis of skin cancers was reported biennially and information on melanoma and SCC was pathologically confirmed. We identified 327 melanoma cases, 1324 SCC cases, and 8438 BCC cases during the follow-up. Male-pattern baldness was not significantly associated with risk of incident melanoma, but was significantly associated with increased risk of SCC and BCC. The multivariate-adjusted hazard ratio (HR) (95% confidence interval, CI) for the highest category of baldness (frontal plus severe vertex baldness) was 1.33 (1.06-1.68) for SCC (P_trend=0.001) and 1.23 (1.12-1.35) for BCC(P_trend<0.0001), compared with no baldness. Analyses by body sites found significant associations between frontal plus moderate to severe vertex baldness and risk of melanoma (HR=1.83, 95% CI: 1.01-3.34) and SCC (HR=1.30, 95% CI: 1.02-1.66) at head and neck. The associations were particularly stronger for scalp melanoma (HR=7.15, 95% CI: 1.29-39.42) and scalp SCC (HR=7.09, 95% CI: 3.84-13.08), but not for non-scalp head and neck sites. Information on body sites was not available for BCC. In conclusion, male pattern baldness may be associated with increased risk of skin cancer, but the associations may only exist for those occurring at head and neck, particularly at scalp. This article is protected by copyright. All rights reserved.

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Higher expression of XPF is a critical factor in intrinsic chemotherapy resistance of human renal cell carcinoma

Abstract

Human renal cancer is extremely resistant to chemotherapy and radiation therapy. This clinical characteristic reduces the efficacy of chemotherapeutic agents in the treatment of recurrence or metastasis following surgical resection. Understanding the mechanism of chemotherapy resistance in renal cell carcinoma remains a significant challenge. In this study, we have shown that varied level of XPF expression was organ-tissue specific by comparing human renal cancer, bladder cancer, testicular cancer and their normal tissue counterparts, respectively. The expression of XPF was significantly higher in renal cancer than in bladder cancer and testicular cancer and correlated with the clinical characteristic of their chemotherapeutics sensitivity. These novel findings proposed that the intrinsic chemoresistance of human renal cell carcinomas might be derived from the high level of XPF expression. In a panel of 5 cancer cell lines, decreasing cisplatin sensitivity correlated with increasing levels of XPF expression. Knockdown of XPF expression not only increased sensitivity of renal carcinoma cells to cisplatin treatment by affecting the DNA damage response, including DNA repair, cell cycle regulation and apoptosis, but also increased senescence of renal cancer cell. Furthermore, experiment in vivo confirmed that silenced XPF significantly increased the sensitivity and survival following treatment with cisplatin in xenograft mice bearing renal cell tumor. These findings firstly uncover a partial mechanism of intrinsic chemoresistance in renal cancer and may provide a new approach to break through the obstacle of intrinsic chemoresistance by targeting the XPF protein with a potential new inhibitor. This article is protected by copyright. All rights reserved.

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