Phase II trial of hypofractionated VMAT-based treatment for early stage breast cancer: 2-year toxicity and clinical results

Abstract

Background

To report toxicity and early clinical outcomes of hypofractionated simultaneous integrated boost (SIB) approach with Volumetric Modulated Arc Therapy (VMAT) as adjuvant treatment after breast-conserving surgery.

Methods

Patients presenting early-stage breast cancer were enrolled in a phase II trial. Eligibility criteria: age > 18 years old, invasive cancer or ductal carcinoma in situ (DCIS), Stage I-II (T < 3 cm and N ≤ 3), breast-conserving surgery without oncoplastic reconstruction. Any systemic therapy was allowed in neoadjuvant or adjuvant setting. All patients underwent VMAT-SIB technique to irradiate the whole breast and the tumor bed. Doses to whole breast and surgical bed were 40.5 Gy and 48 Gy, respectively, delivered in 15 fractions over 3 weeks. Acute and late skin toxicities were recorded. Cosmetic outcome was assessed as excellent/good or fair/poor.

Results

The present study focused on results of a cohort of 144 patients with a minimum follow-up of 24 months (median 37, range 24–55 months). Median age was 62 years old (range 30–88). All patients had an invasive carcinoma (no patients with DCIS were present in this subset). At one year, the highest reported skin toxicity was G1, in 14 % of the patients; this data dropped to 4 % at the last follow-up, after more than 2 years. Breast pain was recorded in 21.6 % of the patients 6 months after treatment, while it was present in 3.5 % of the patients at the last follow-up, showing a significant improvement with time. Correlation between liponecrosis and boost target volume was found not significant. Breast pain was correlated with breast volume. No pulmonary or cardiological toxicities were recorded. After an early evaluation of clinical outcomes, only one case presented disease relapse, as liver metastases.

Conclusions

The 3-week VMAT-SIB course as adjuvant treatment after breast-conserving surgery showed to be well tolerated and was associated with optimal local control. Long-term follow-up data are needed to assess late toxicity and clinical outcomes.

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Connectivity map identifies HDAC inhibition as a treatment option of high-risk hepatoblastoma.

Connectivity map identifies HDAC inhibition as a treatment option of high-risk hepatoblastoma.

Cancer Biol Ther. 2016 Sep 16;:0

Authors: Beck A, Eberherr C, Hagemann M, Cairo S, Häberle B, Vokuhl C, von Schweinitz D, Kappler R

Abstract
Hepatoblastoma (HB) is the most common liver tumor of childhood, usually occurring in children under the age of three years. The prognosis of patients presenting with distant metastasis, vascular invasion and advanced tumor stages remains poor and children that do survive often face severe late effects from the aggressive chemotherapy regimen. To identify potential new therapeutics for high risk HB we used a 1,000-gene expression signature as input for a Connectivity Map (CMap) analysis, which predicted histone deacetylase (HDAC) inhibitors as a promising therapy option. Subsequent expression analysis of primary HB and HB cell lines revealed a general overexpression of HDAC1 and HDAC2, which has been suggested to be predictive for the efficacy of HDAC inhibition. Accordingly, treatment of HB cells with the HDAC inhibitors SAHA and MC1568 resulted in a potent reduction of cell viability, induction of apoptosis, reactivation of epigenetically suppressed tumor suppressor genes, and the reversion of the 16-gene HB classifier towards the more favorable expression signature. Most importantly, the combination of HDAC inhibitors and cisplatin - a major chemotherapeutic agent of HB treatment - revealed a strong synergistic effect, even at significantly reduced doses of cisplatin. Our findings suggest that HDAC inhibitors skew HB cells towards a more favorable prognostic phenotype through changes in gene expression, thus indicating a targeted molecular mechanism that seems to enhance the anti-proliferative effects of conventional chemotherapy. Thus, adding HDAC inhibitors to the treatment regimen of high risk HB could potentially improve outcomes and reduce severe late effects.

PMID: 27635950 [PubMed - as supplied by publisher]

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Expression of steroid hormone receptors and its prognostic significance in urothelial carcinoma of the upper urinary tract.

Expression of steroid hormone receptors and its prognostic significance in urothelial carcinoma of the upper urinary tract.

Cancer Biol Ther. 2016 Sep 16;:0

Authors: Kashiwagi E, Fujita K, Yamaguchi S, Fushimi H, Ide H, Inoue S, Mizushima T, Reis LO, Sharma R, Netto GJ, Nonomura N, Miyamoto H

Abstract
To assess the expression status of steroid hormone receptors in upper urinary tract urothelial carcinoma (UUTUC), we immunohistochemically stained for androgen receptor (AR), estrogen receptor-α (ERα), ERβ, glucocorticoid receptor (GR), and progesterone receptor (PR) in 99 UUTUC specimens and paired non-neoplastic urothelial tissues. AR/ERα/ERβ/GR/PR was positive in 20%/18%/62%/63%/16% of tumors, which was significantly lower (except PR) than in benign urothelial tissues [57% (P<0.001)/40% (P = 0.001)/85% (P = 0.001)/84% (P = 0.002)/13% (P = 0.529)]. There were no significant associations between each receptor expression pattern and histopathological characteristic of the tumors including tumor grade/stage. Kaplan-Meier and log-rank tests revealed no significant prognostic value of each receptor expression in these 99 patients. However, patients with UUTUC positive for either ERα or PR had a significantly higher risk of disease-specific mortality (P = 0.025), compared with those with UUTUC negative for both. PR positivity alone in pT3 or pT4 tumors was also strongly associated with the risk of disease-specific mortality (P = 0.040). Multivariate analysis further identified the expression of ERα and/or PR as a strong predictor for disease-specific mortality in the entire cohort of the patients (hazard ratio, 2.434; P = 0.037). Thus, in accordance with previous observations in bladder specimens, significant decreases in the expression of AR/ERα/ERβ/GR in UUTUC, compared with that in non-neoplastic urothelium, were observed. Meanwhile, the negativity of both ERα and PR in UUTUC as well as the negativity of PR alone in deeply invasive tumor was suggested to serve as a prognosticator.

PMID: 27635763 [PubMed - as supplied by publisher]

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Clinicopathological Characteristics and Survival of ALK, ROS1 and RET rearrangements in Non-Adenocarcinoma Non-Small Cell Lung Cancer Patients.

Clinicopathological Characteristics and Survival of ALK, ROS1 and RET rearrangements in Non-Adenocarcinoma Non-Small Cell Lung Cancer Patients.

Cancer Biol Ther. 2016 Sep 16;:0

Authors: Song Z, Yu X, Zhang Y

Abstract
BACKGROUND: ALK, ROS1 and RET rearrangements represent three most frequent fusion genes in non-small cell lung cancer (NSCLC). Rearrangements of these three genes exist predominantly in lung adenocarcinoma while rarely in non-adenocarcinoma. Our objective was to explore the frequency, clinicopathological characteristics and survival of ALK, ROS1 and RET rearrangements in non-adenocarcinoma NSCLC patients.
METHODS: ALK, ROS1 and RET rearrangements were screened by reverse transcriptase polymerase chain reaction (RT-PCR) in patients with completely resected non-adenocarcinoma NSCLC. All positive samples were confirmed with fluorescence in situ hybridization (FISH). Survival analysis was performed with Kaplan-Meier method and log-rank for comparison.
RESULTS: A total of 385 patients underwent complete resection, including squamous cell carcinoma (n = 245), adenosquamous carcinoma (n = 85) and large cell carcinoma (n = 55). Twelve of them were identified as harboring fusion genes, including ALK (n = 7), ROS1 (n = 3) and RET (n = 2) rearrangements. The fusion frequencies of adenosquamous, squamous cell and large cell carcinomas were 8.2%, 1.6% and 1.8% respectively. Their median age was 49.5 years and 3 of them had a smoking history. No survival difference existed between fusion gene positive and negative patients (36.7 vs.50.2 months, P = 0.21).
CONCLUSION: The frequencies of ALK, ROS1 and RET rearrangements are low in non-adenocarcinoma NSCLC patients. And their clinical characteristics are similar to those in lung adenocarcinoma. Fusions of the above three genes are not prognostic factor for non-adnocarcinoma NSCLC patients.

PMID: 27635639 [PubMed - as supplied by publisher]

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Clinician and Parent Perspectives on Educational Needs for Increasing Adolescent HPV Vaccination

Abstract

Human papillomavirus (HPV)-related morbidity and mortality remain a significant public health burden despite the availability of HPV vaccines for cancer prevention. We engaged clinicians and parents to identify barriers and opportunities related to adolescent HPV vaccination within a focused geographic region. This mixed-method study design used an interviewer-administered semi-structured interview with clinicians (n = 52) and a written self-administered survey with similar items completed by parents (n = 54). Items focused on experiences, opinions, and ideas about HPV vaccine utilization in the clinical setting, family, and patient perceptions about HPV vaccination and potential future efforts to increase vaccine utilization. Quantitative items were analyzed using descriptive statistics, while qualitative content was analyzed thematically. Suggested solutions for achieving higher rates of HPV vaccination noted by clinicians included public health education, the removal of stigma associated with vaccines, media endorsements, and targeting parents as the primary focus of educational messages. Parents expressed the need for more information about HPV-related disease, HPV vaccines, vaccine safety, sexual concerns, and countering misinformation on social media. Results from this mixed-method study affirm that educational campaigns targeting both health care professionals and parents represent a key facilitator for promoting HPV vaccination; disease burden and cancer prevention emerged as key themes for this messaging.

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Sulforaphane Regulates NFE2L2/Nrf2-Dependent Xenobiotic Metabolism Phase II and Phase III Enzymes Differently in Human Colorectal Cancer and Untransformed Epithelial Colon Cells.

Sulforaphane Regulates NFE2L2/Nrf2-Dependent Xenobiotic Metabolism Phase II and Phase III Enzymes Differently in Human Colorectal Cancer and Untransformed Epithelial Colon Cells.

Nutr Cancer. 2016 Sep 16;:1-11

Authors: Lubelska K, Wiktorska K, Mielczarek L, Milczarek M, Zbroińska-Bregisz I, Chilmonczyk Z

Abstract
Sulforaphane (SFN), a naturally occurring chemopreventive and anticancer agent, is a nuclear factor, erythroid 2-like 2 (NFE2L2/Nrf2) inducer. Nrf2 plays a critical role in coordinating the cell defense system by initiating the transcription of cytoprotective genes, including detoxification enzymes such as NAD(P)H quinone dehydrogenase 1 (NQO1) and transport proteins such as ATP-binding cassette, subfamily C (CFTR/MRP). Recently, the essential role of Nrf2 in tumor development and progression and in the development of multidrug resistance in cancer cells has been highlighted. The aim of this study was to compare the effect of SFN on the Nrf2 system and the Nrf2-target enzymes NQO1 and MRP in human untransformed epithelial colon CRL-1790 cells and in HT-29 and Caco-2 colorectal cancer cells to elucidate the role of SFN in cancer prevention and treatment. We have demonstrated that SFN has excellent cytoprotective properties in CRL-1790 cells, as it induced Nrf2-dependent expression of MRP1 and NQO1. SFN induced Nrf2 target enzyme activity in HT-29 and Caco-2 cancer cells but regulated the Nrf2/ARE signaling pathway differently in cancer and untransformed cells.

PMID: 27636860 [PubMed - as supplied by publisher]

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Association between Dietary Inflammatory Index and Gastric Cancer Risk in an Italian Case-Control Study.

Association between Dietary Inflammatory Index and Gastric Cancer Risk in an Italian Case-Control Study.

Nutr Cancer. 2016 Sep 16;:1-7

Authors: Shivappa N, Hébert JR, Ferraroni M, La Vecchia C, Rossi M

Abstract
BACKGROUND: In this study, we explored the association between the dietary inflammatory index (DII) and gastric cancer risk in an Italian case-control study.
MATERIALS AND METHODS: Cases were 230 patients with incident, histologically confirmed cases of gastric cancer from the Greater Milan area, Northern Italy. Controls were 547 frequency-matched subjects admitted to the same network of hospitals as cases for a wide spectrum of acute, non-neoplastic conditions. The DII was computed using a reproducible and valid 78-item food frequency questionnaire. Odds ratios (ORs) were estimated through logistic regression models conditioned on age and sex and adjusted for recognized confounding factors, including total energy intake.
RESULTS: Subjects with the most pro-inflammatory diet had a higher risk of gastric cancer compared to subjects with the most anti-inflammatory diet (ORQuartile4vs1 = 2.35, 95% confidence interval, 1.32, 4.20; P-trend = 0.004).
CONCLUSION: These results indicate that a pro-inflammatory diet, as indicated by higher DII score, was associated with increased risk of gastric cancer.

PMID: 27636679 [PubMed - as supplied by publisher]

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Diet Quality of Breast Cancer Survivors after a Six-Month Weight Management Intervention: Improvements and Association with Weight Loss.

Diet Quality of Breast Cancer Survivors after a Six-Month Weight Management Intervention: Improvements and Association with Weight Loss.

Nutr Cancer. 2016 Sep 16;:1-8

Authors: Christifano DN, Fazzino TL, Sullivan DK, Befort CA

Abstract
PURPOSE: Obesity and diet quality are two distinct lifestyle factors associated with morbidity and mortality among breast cancer survivors. The purposes of this study were to examine diet quality changes during a weight loss intervention among breast cancer survivors and to examine whether diet quality change was an important factor related to weight loss.
METHODS: Participants were overweight/obese breast cancer survivors (n = 180) participating in a weight loss intervention. Diet quality scores were calculated using the Healthy Eating Index (HEI)-2010. Paired sample t-tests were run to examine change in diet quality, and a latent difference model was constructed to examine whether change in diet quality was associated with weight change.
RESULTS: Participants significantly improved diet quality (P = 0.001) and lost 13.2 ± 5.8% (mean ± SD) of their weight (P = 0.001). Six-month HEI score was significantly associated with weight loss, controlling for baseline BMI (P = 0.003). Improvement in diet quality was also significantly associated with weight loss (P = 0.01).
CONCLUSION: Our findings indicate that a weight loss intervention can result in both clinically significant weight loss and improvement in diet quality, and that improved diet quality is predictive of weight loss. Both weight loss and diet quality are implicated in longevity and quality of life for breast cancer survivors.

PMID: 27635676 [PubMed - as supplied by publisher]

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Seed Oil of Brucea javanica Induces Cell Cycle Arrest and Apoptosis via Reactive Oxygen Species-Mediated Mitochondrial Dysfunction in Human Lung Cancer Cells.

Seed Oil of Brucea javanica Induces Cell Cycle Arrest and Apoptosis via Reactive Oxygen Species-Mediated Mitochondrial Dysfunction in Human Lung Cancer Cells.

Nutr Cancer. 2016 Sep 16;:1-10

Authors: Wang D, Qu X, Zhuang X, Geng G, Hou J, Xu N, Li W, Hu T, Chen YS

Abstract
Brucea javanica oil (BJO), a traditional herbal medicine extracted from the seeds of B. javanica, has been clinically used to treat non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in combination with chemotherapy or radiotherapy in China. However, how BJO exerts this antitumor effect is still largely unknown. Here, effects of BJO on the growth of NSCLC and SCLC cell lines were investigated by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenytetrazolium Bromide (MTT) assay, and the results showed that BJO inhibited the proliferation of A549 cells (NSCLC) and H446 cells (SCLC). Further studies revealed that BJO induced G0/G1 arrest partly via regulating p53 and cyclin D1 in these two cell lines. BJO also has pro-apoptotic effect on H446 and A549 cells through mitochondria/caspase-mediated pathway, which was initiated by the accumulation of intracellular reactive oxygen species (ROS). These findings thus revealed the molecular mechanisms underlying the antitumor effect of BJO on SCLC and NSCLC, which may benefit the further clinical application of BJO.

PMID: 27635476 [PubMed - as supplied by publisher]

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Association between XRCC3 Thr241Met polymorphism and nasopharyngeal carcinoma risk: evidence from a large-scale case-control study and a meta-analysis

Abstract

The X-ray repair cross-complementing group 3 (XRCC3) Thr241Met polymorphism (rs861539, C > T) has drawn wide attentions as its association with cancer risk and its involvement in DNA repair. Several studies have attempted to link rs861539 to nasopharyngeal cancer (NPC) risk; however, the sample sizes of these studies are small and the results are controversial. To investigate the relationship of rs861539 and NPC susceptibility, we conducted a large-scale case-control study involving 4001 NPC cases and 2967 controls of southern Chinese. Logistic regression analysis revealed significant association for rs861539 and NPC risk under the recessive model (TT vs. CT + CC) with adjustment of age and gender (odds ratio, OR = 2.72; 95 % CI 1.10–6.72; P = 0.03). Further, meta-analysis involving 4457 NPC cases and 4132 controls from four studies showed consistent association of TT carriers and NPC risk (OR = 3.12; 95 % CI 1.58–6.13; P = 0.001). Taken together, our findings based on large-scale sample size suggested rs861539 at XRCC3 to be associated with NPC risk through recessive model.

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Clinician and Parent Perspectives on Educational Needs for Increasing Adolescent HPV Vaccination

Abstract

Human papillomavirus (HPV)-related morbidity and mortality remain a significant public health burden despite the availability of HPV vaccines for cancer prevention. We engaged clinicians and parents to identify barriers and opportunities related to adolescent HPV vaccination within a focused geographic region. This mixed-method study design used an interviewer-administered semi-structured interview with clinicians (n = 52) and a written self-administered survey with similar items completed by parents (n = 54). Items focused on experiences, opinions, and ideas about HPV vaccine utilization in the clinical setting, family, and patient perceptions about HPV vaccination and potential future efforts to increase vaccine utilization. Quantitative items were analyzed using descriptive statistics, while qualitative content was analyzed thematically. Suggested solutions for achieving higher rates of HPV vaccination noted by clinicians included public health education, the removal of stigma associated with vaccines, media endorsements, and targeting parents as the primary focus of educational messages. Parents expressed the need for more information about HPV-related disease, HPV vaccines, vaccine safety, sexual concerns, and countering misinformation on social media. Results from this mixed-method study affirm that educational campaigns targeting both health care professionals and parents represent a key facilitator for promoting HPV vaccination; disease burden and cancer prevention emerged as key themes for this messaging.

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Comparative protein profiling of B16 mouse melanoma cells susceptible and non-susceptible to alphavirus infection: Effect of the tumor microenvironment.

Comparative protein profiling of B16 mouse melanoma cells susceptible and non-susceptible to alphavirus infection: Effect of the tumor microenvironment.

Cancer Biol Ther. 2016 Aug 11;:1-16

Authors: Vasilevska J, De Souza GA, Stensland M, Skrastina D, Zhulenvovs D, Paplausks R, Kurena B, Kozlovska T, Zajakina A

Abstract
Alphavirus vectors are promising tools for cancer treatment. However, relevant entry mechanisms and interactions with host cells are still not clearly understood. The first step toward a more effective therapy is the identification of novel intracellular alterations that could be associated with cancer aggressiveness and could affect the therapeutic potential of these vectors. In this study, we observed that alphaviruses efficiently infected B16 mouse melanoma tumors/tumor cells in vivo, whereas their transduction efficiency in B16 cells under in vitro conditions was blocked. Therefore, we further aimed to understand the mechanisms pertaining to the differential transduction efficacy of alphaviruses in B16 tumor cells under varying growth conditions. We hypothesized that the tumor microenvironment might alter gene expression in B16 cells, leading to an up-regulation of the expression of virus-binding receptors or factors associated with virus entry and replication. To test our hypothesis, we performed a proteomics analysis of B16 cells cultured in vitro and of B16 cells isolated from tumors, and we identified 277 differentially regulated proteins. A further in-depth analysis to identify the biological and molecular functions of the detected proteins revealed a set of candidate genes that could affect virus infectivity. Importantly, we observed a decrease in the expression of interferon α (IFN-α) in tumor-isolated cells that resulted in the suppression of several IFN-regulated genes, thereby abrogating host cell antiviral defense. Additionally, differences in the expression of genes that regulate cytoskeletal organization caused significant alterations in cell membrane elasticity. Taken together, our findings demonstrated favorable intracellular conditions for alphavirus transduction/replication that occurred during tumor transformation. These results pave the way for optimizing the development of strategies for the application of alphaviral vectors as a potent cancer therapy.

PMID: 27636533 [PubMed - as supplied by publisher]

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Fusion proteins in head and neck neoplasms: Clinical implications, genetics, and future directions for targeting.

Fusion proteins in head and neck neoplasms: Clinical implications, genetics, and future directions for targeting.

Cancer Biol Ther. 2016 Aug 15;:1-8

Authors: Escalante DA, Wang H, Fundakowski CE

Abstract
Fusion proteins resulting from chromosomal rearrangements are known to drive the pathogenesis of a variety of hematological and solid neoplasms such as chronic myeloid leukemia and non-small-cell lung cancer. Efforts to elucidate the role they play in these malignancies have led to important diagnostic and therapeutic triumphs, including the famous development of the tyrosine kinase inhibitor dasatinib targeting the BCR-ABL fusion. Until recently, there has been a paucity of research investigating fusion proteins harbored by head and neck neoplasms. The discovery and characterization of novel fusion proteins in neoplasms originating from the thyroid, nasopharynx, salivary glands, and midline head and neck structures offer substantial contributions to our understanding of the pathogenesis and biological behavior of these neoplasms, while raising new therapeutic and diagnostic opportunities. Further characterization of these fusion proteins promises to facilitate advances on par with those already achieved with regard to hematologic malignancies in the precise, molecularly guided diagnosis and treatment of head and neck neoplasms. The following is a subsite specific review of the clinical implications of fusion proteins in head and neck neoplasms and the future potential for diagnostic targeting.

PMID: 27636353 [PubMed - as supplied by publisher]

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A retrospective analysis of the role of adjuvant radiotherapy in the treatment of cutaneous melanoma.

A retrospective analysis of the role of adjuvant radiotherapy in the treatment of cutaneous melanoma.

Cancer Biol Ther. 2016 Aug 15;:1-5

Authors: Baker A, Camacho F, Andrews G, Mackley H

Abstract
Melanoma is a significant clinical problem, with rising rates of incidence. Surgery is the mainstay of treatment. The role of adjuvant radiotherapy in the control of locoregionally advanced cutaneous melanoma is controversial. A retrospective study of the Surveillance, Epidemiology, and End Results (SEER) database was performed. Patients with locoregionally confined cutaneous melanoma treated surgically between 2004 and 2009 were evaluated, with cancer-specific and all-cause mortality as primary end points. Propensity score matching was used to match 319 radiotherapy patients with 319 non-radiotherapy controls, stratifying by head and neck (HN) and non-head and neck (NHN) primary. Surgery was primarily by wide excision in both the radiotherapy (51.72%) and non-radiotherapy (53.91%) groups. The majority had nodal disease (82.13% vs. 82.44%). White (91.22% vs. 90.59%) males (70.21% vs. 68.96%) predominated. Average ages at diagnosis were 62.27 (SD 15.93) and 63.02 (SD 16.03). Using Cox proportional hazards models, radiation conferred decreased survival in all-cause (HR 1.44, p < 0.0003), and cancer specific mortality (HR 1.57, p < 0.0002) in combined analysis. The NHN group showed significantly decreased 6-year cancer specific survival (HR 2.05, p < 0.0001) for radiated patients. The HN group showed a non-significant hazard with radiotherapy (HR 1.19, p = 0.307). Meaningful differences not captured in the SEER database may exist between cohorts. Based on available SEER data, routine use of adjuvant radiotherapy should be viewed with caution and reserved for high-risk patients. Future trials evaluating patient quality of life may clarify the benefit of adjuvant radiotherapy in high-risk melanoma populations.

PMID: 27636187 [PubMed - as supplied by publisher]

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Downregulation of a novel human gene, ROGDI, increases radiosensitivity in cervical cancer cells.

Downregulation of a novel human gene, ROGDI, increases radiosensitivity in cervical cancer cells.

Cancer Biol Ther. 2016 Aug 12;:1-9

Authors: Chen YF, Cho JJ, Huang TH, Tseng CN, Huang EY, Cho CL

Abstract
ROGDI is a protein that contains a leucine zipper domain and may be involved in cell proliferation. In addition, ROGDI is associated with genome stability by regulating the activity of a DNA damage marker, γ-H2AX. The role of ROGDI in tumor radiosensitization has not been investigated. Previous studies have indicated that radiosensitivity is associated with DNA repair and the cell cycle. In general, the G2/M DNA damage checkpoint is more sensitive to radiation, whereas the G1/S phase transition is more resistant to radiation. Inhibition of cyclin-dependent kinases (CDKs) can lead to a halt of cell cycle progression and a stay at different phases or checkpoints. Our data show that the downregulation of ROGDI led to a decreased expression of CDK 1, 2, cyclin A, B and resulted in a G2/M phase transition block. In addition, the downregulation of ROGDI increased cell accumulation at the G2 phase as detected using flow cytometry and decreased cell survival as revealed by clonogenic assay in HeLa and C33A cells following irradiation. These findings suggest that the downregulation of ROGDI can mediate radiosensitivity by blocking cells at G2/M, the most radiosensitive phase of the cell cycle, as well as exerting deleterious effects in the form of DNA damage, as shown by increased γ-H2AX activation.

PMID: 27636029 [PubMed - as supplied by publisher]

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Connectivity map identifies HDAC inhibition as a treatment option of high-risk hepatoblastoma.

Connectivity map identifies HDAC inhibition as a treatment option of high-risk hepatoblastoma.

Cancer Biol Ther. 2016 Sep 16;:0

Authors: Beck A, Eberherr C, Hagemann M, Cairo S, Häberle B, Vokuhl C, von Schweinitz D, Kappler R

Abstract
Hepatoblastoma (HB) is the most common liver tumor of childhood, usually occurring in children under the age of three years. The prognosis of patients presenting with distant metastasis, vascular invasion and advanced tumor stages remains poor and children that do survive often face severe late effects from the aggressive chemotherapy regimen. To identify potential new therapeutics for high risk HB we used a 1,000-gene expression signature as input for a Connectivity Map (CMap) analysis, which predicted histone deacetylase (HDAC) inhibitors as a promising therapy option. Subsequent expression analysis of primary HB and HB cell lines revealed a general overexpression of HDAC1 and HDAC2, which has been suggested to be predictive for the efficacy of HDAC inhibition. Accordingly, treatment of HB cells with the HDAC inhibitors SAHA and MC1568 resulted in a potent reduction of cell viability, induction of apoptosis, reactivation of epigenetically suppressed tumor suppressor genes, and the reversion of the 16-gene HB classifier towards the more favorable expression signature. Most importantly, the combination of HDAC inhibitors and cisplatin - a major chemotherapeutic agent of HB treatment - revealed a strong synergistic effect, even at significantly reduced doses of cisplatin. Our findings suggest that HDAC inhibitors skew HB cells towards a more favorable prognostic phenotype through changes in gene expression, thus indicating a targeted molecular mechanism that seems to enhance the anti-proliferative effects of conventional chemotherapy. Thus, adding HDAC inhibitors to the treatment regimen of high risk HB could potentially improve outcomes and reduce severe late effects.

PMID: 27635950 [PubMed - as supplied by publisher]

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Expression of steroid hormone receptors and its prognostic significance in urothelial carcinoma of the upper urinary tract.

Expression of steroid hormone receptors and its prognostic significance in urothelial carcinoma of the upper urinary tract.

Cancer Biol Ther. 2016 Sep 16;:0

Authors: Kashiwagi E, Fujita K, Yamaguchi S, Fushimi H, Ide H, Inoue S, Mizushima T, Reis LO, Sharma R, Netto GJ, Nonomura N, Miyamoto H

Abstract
To assess the expression status of steroid hormone receptors in upper urinary tract urothelial carcinoma (UUTUC), we immunohistochemically stained for androgen receptor (AR), estrogen receptor-α (ERα), ERβ, glucocorticoid receptor (GR), and progesterone receptor (PR) in 99 UUTUC specimens and paired non-neoplastic urothelial tissues. AR/ERα/ERβ/GR/PR was positive in 20%/18%/62%/63%/16% of tumors, which was significantly lower (except PR) than in benign urothelial tissues [57% (P<0.001)/40% (P = 0.001)/85% (P = 0.001)/84% (P = 0.002)/13% (P = 0.529)]. There were no significant associations between each receptor expression pattern and histopathological characteristic of the tumors including tumor grade/stage. Kaplan-Meier and log-rank tests revealed no significant prognostic value of each receptor expression in these 99 patients. However, patients with UUTUC positive for either ERα or PR had a significantly higher risk of disease-specific mortality (P = 0.025), compared with those with UUTUC negative for both. PR positivity alone in pT3 or pT4 tumors was also strongly associated with the risk of disease-specific mortality (P = 0.040). Multivariate analysis further identified the expression of ERα and/or PR as a strong predictor for disease-specific mortality in the entire cohort of the patients (hazard ratio, 2.434; P = 0.037). Thus, in accordance with previous observations in bladder specimens, significant decreases in the expression of AR/ERα/ERβ/GR in UUTUC, compared with that in non-neoplastic urothelium, were observed. Meanwhile, the negativity of both ERα and PR in UUTUC as well as the negativity of PR alone in deeply invasive tumor was suggested to serve as a prognosticator.

PMID: 27635763 [PubMed - as supplied by publisher]

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Clinicopathological Characteristics and Survival of ALK, ROS1 and RET rearrangements in Non-Adenocarcinoma Non-Small Cell Lung Cancer Patients.

Clinicopathological Characteristics and Survival of ALK, ROS1 and RET rearrangements in Non-Adenocarcinoma Non-Small Cell Lung Cancer Patients.

Cancer Biol Ther. 2016 Sep 16;:0

Authors: Song Z, Yu X, Zhang Y

Abstract
BACKGROUND: ALK, ROS1 and RET rearrangements represent three most frequent fusion genes in non-small cell lung cancer (NSCLC). Rearrangements of these three genes exist predominantly in lung adenocarcinoma while rarely in non-adenocarcinoma. Our objective was to explore the frequency, clinicopathological characteristics and survival of ALK, ROS1 and RET rearrangements in non-adenocarcinoma NSCLC patients.
METHODS: ALK, ROS1 and RET rearrangements were screened by reverse transcriptase polymerase chain reaction (RT-PCR) in patients with completely resected non-adenocarcinoma NSCLC. All positive samples were confirmed with fluorescence in situ hybridization (FISH). Survival analysis was performed with Kaplan-Meier method and log-rank for comparison.
RESULTS: A total of 385 patients underwent complete resection, including squamous cell carcinoma (n = 245), adenosquamous carcinoma (n = 85) and large cell carcinoma (n = 55). Twelve of them were identified as harboring fusion genes, including ALK (n = 7), ROS1 (n = 3) and RET (n = 2) rearrangements. The fusion frequencies of adenosquamous, squamous cell and large cell carcinomas were 8.2%, 1.6% and 1.8% respectively. Their median age was 49.5 years and 3 of them had a smoking history. No survival difference existed between fusion gene positive and negative patients (36.7 vs.50.2 months, P = 0.21).
CONCLUSION: The frequencies of ALK, ROS1 and RET rearrangements are low in non-adenocarcinoma NSCLC patients. And their clinical characteristics are similar to those in lung adenocarcinoma. Fusions of the above three genes are not prognostic factor for non-adnocarcinoma NSCLC patients.

PMID: 27635639 [PubMed - as supplied by publisher]

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Sensitizing ovarian cancer cells to chemotherapy by interfering with pathways that are involved in the formation of cancer stem cells

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The long noncoding RNA H19 promotes cell proliferation via E2F-1 in pancreatic ductal adenocarcinoma

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A retrospective analysis of the role of adjuvant radiotherapy in the treatment of cutaneous melanoma

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Fusion proteins in head and neck neoplasms: Clinical implications, genetics, and future directions for targeting

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Downregulation of a novel human gene, ROGDI, increases radiosensitivity in cervical cancer cells

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Comparative protein profiling of B16 mouse melanoma cells susceptible and non-susceptible to alphavirus infection: Effect of the tumor microenvironment

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Preradiation Chemotherapy for Adult High-risk Medulloblastoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4397).

Objectives: To assess the long-term outcomes and objective response (OR) to preradiation chemotherapy and radiation in adult high-risk medulloblastoma. Materials and Methods: In this prospective phase II trial, adults with high-risk medulloblastoma were treated with 3 cycles of preradiation cisplatin, etoposide, cyclophosphamide, and vincristine followed by craniospinal radiation (CSI). OR, progression-free survival (PFS), overall survival (OS), and toxicities were assessed. Results: Eleven patients were enrolled over a 6-year period. Six (55%) had subarachnoid metastases. Two (18%) had an OR to preradiation chemotherapy. Two (18%) progressed while on chemotherapy. Completion of CSI was not compromised. The OR rate after chemotherapy and radiation was 45% (5/11). Nonevaluable patients at both time-points weakened the response data conclusions. Median PFS was 43.8 months. Five-year PFS was 27%. Five-year OS was 55%. Nonmetastatic (M0) and metastatic (M+) patients had similar outcomes. Conclusions: The OR to this preradiation chemotherapy regimen is lower than anticipated from the adult and pediatric literature raising a question about comparative efficacy of chemotherapy in different age groups. The OS achieved is similar to retrospective adult series, but worse than pediatric outcomes. Although this regimen can be administered without compromising delivery of CSI, our results do not provide support for the use of this neoadjuvant chemotherapy for adult medulloblastoma. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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In Memoriam: A. Robert Kagan, MD.

No abstract available

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Concurrent Radiotherapy and Triweekly Carboplatin for the Definitive Treatment of Locally Advanced Laryngeal Carcinoma.

Purpose of the Study: In 2003, our institution adopted triweekly carboplatin (tCb) area under the curve (AUC) 5 as an alternative to high-dose cisplatin (100 mg/m2) for select patients receiving definitive concurrent chemoradiation for locally advanced laryngeal carcinoma (LALC). Here, we present our experience and outcomes with this definitive concurrent chemoradiation regimen. Methods: From January 2003 through December 2013, 53 patients with stage III (60%) or IVA (40%) LALC were treated with tCb AUC 5 and concurrent radiotherapy to 70 Gy without neoadjuvant chemotherapy. Reasons for using carboplatin instead of cisplatin in these patients were: age 70 and older (21%), poor renal function (6%), presence of 1 or more major comorbid condition(s) (36%), and per discretion of the treating medical oncologist (38%). Primary disease site was glottis in 22 (42%) patients and supraglottis in 31 (58%) patients. Results: Median follow-up time was 63 months for surviving patients. Out of the 53 patients, 43 (81%) received all 3 cycles of carboplatin and all patients received their intended dose of radiotherapy. Although 17 (32%) patients required a feeding tube during treatment, only 2 (4%) required it long term. There were no acute treatment-related grade 4 or 5 hematologic toxicities. On last follow-up, 14 (26%) patients had died of intercurrent disease. For the subgroup of "RTOG 9111 eligible" patients in our cohort (n=46), 5-year estimates of overall survival, disease-free survival, laryngectomy-free survival, larynx preservation, and locoregional control were: 49%, 42%, 39%, 80%, and 63%, respectively. Conclusions: In patients with LALC who are suboptimal candidates for high-dose cisplatin, our experience suggests that tCb AUC 5 with concurrent radiotherapy provides acceptable outcomes with tolerable toxicity. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Evaluating Candidacy for Hypofractionated Radiation Therapy, Accelerated Partial Breast Irradiation, and Endocrine Therapy After Breast Conserving Surgery: A Surveillance Epidemiology and End Results (SEER) Analysis.

Purpose/Objective(s): After breast conserving surgery, adjuvant radiation therapy represents the standard of care for most patients. However, multiple options exist beyond standard fractionated whole breast irradiation including hypofractionated whole breast irradiation (HFRT), accelerated partial breast irradiation (APBI), and endocrine therapy (ET) alone, which can limit treatment duration, and potentially reduce morbidity and cost. Limited data are available on the percentage of patients eligible for these alternatives; therefore, a Surveillance Epidemiology and End Results (SEER) analysis was performed to assess candidacy for these alternative options in women with early stage breast cancer. Materials and Methods: Women treated for breast cancer between the years of 2010 and 2012 were identified in the SEER database. Patients with unknown staging, metastatic disease, T3/T4 disease, and >=N1 disease were excluded. Patients were defined as eligible for HFRT based on the American Society for Radiation Oncology (ASTRO) consensus guidelines and randomised trial testing intensity modulated and partial organ radiotherapy following breast conservation surgery for early breast cancer (IMPORT LOW) trial criteria, APBI based on the ASTRO, American Brachytherapy Society and the Groupe Europeen de Curietherapie of European Society for Therapeutic Radiotherapy and Oncology (GEC-ESTRO) consensus guidelines, and GEC-ESTRO APBI and IMPORT LOW trial criteria, and ET alone based on the Cancer and Leukemia Group B 9343 and Post-operative Radiotherapy in Minimum Risk Elderly II inclusion criteria. Results: A total of 108,484 women with early stage breast cancer who met the aforementioned inclusion criteria were identified. Of these patients, 86,896 (80.1%) were eligible for HFRT based on ASTRO consensus guidelines and 81,459 (75.0%) based on IMPORT LOW trial criteria. Regarding APBI, 44,797 (41.2%), 81,020 (74.6%), 81,020 (74.6%) were eligible according to ASTRO, ABS, GEC-ESTRO consensus guidelines, respectively, 97,301 (89.7%) patients according to the GEC-ESTRO trial criteria, and 81,459 (75.0%) patients according to the IMPORT LOW trial criteria. For ET alone, 23,006 (21.2%) were eligible according to Cancer and Leukemia Group B 9343 criteria and 42,104 (38.8%) according to Post-operative Radiotherapy in Minimum Risk Elderly II criteria. Conclusions: This SEER analysis demonstrates that a substantial proportion of women with early stage breast cancer are eligible for HFRT, APBI, or ET alone after breast conserving surgery according to consensus guidelines and prospective trial criteria. With incorporation of additional pathologic, dosimetric, and chemotherapy data, quality assurance pathways may use such data to help ensure patients are receiving appropriate risk stratified treatment recommendations. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Stereotactic Ablative Radiotherapy (SABR) for Large Renal Tumors: A Retrospective Case Series Evaluating Clinical Outcomes, Toxicity, and Technical Considerations.

Objectives: Metastatic renal cell carcinoma represents a clinical scenario where aggressive treatment to the primary tumor (ie, cytoreductive nephrectomy) is associated with a survival benefit. We hypothesized that stereotactic ablative radiotherapy (SABR) could be a safe alternative local modality for inoperable metastatic renal cell carcinoma patients. Our study objectives were to report on technical considerations, toxicity, and clinical outcomes of our institutional experience with renal SABR. Materials and Methods: Patients who underwent renal SABR at our institution between January 2008 and June 2015 were reviewed. Toxicity was quantified using the Common Terminology Criteria for Adverse Events version 4.0. Radiographic response was evaluated using the Response Evaluation Criteria in Solid Tumors classification. Median overall survival and follow-up were calculated using the Kaplan-Meier and reverse Kaplan-Meier methods, respectively. Results: We identified 11 patients that met study criteria. SABR was directed to the tumor or whole kidney in 5 fractions to a dose of 25 to 40 Gy. Median tumor diameter and planning target volume were 9.5 cm (range, 7.5 to 24.4) and 819.3 cm3 (range, 313.4 to 5704.3), respectively. Median follow-up was 3.9 years (95% confidence interval, 0.6-4.9). Five cases of grade 1 toxicity were reported. In the patient with the largest target, grade 2 diarrhea and probable grade 3 nausea were observed. In patients with available follow-up imaging (7/11), stable disease (n=5), partial response (n=1), and progressive disease (n=1) were observed. Median overall survival was 20.4 months (95% confidence interval, 2.30-N/A). Conclusions: In this small cohort, renal SABR was delivered with minimal toxicity. A prospective study is underway at our institution to determine maximum tolerable and optimal dosing (NCT02264548). Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Patient-reported Urinary, Bowel, and Sexual Function After Hypofractionated Intensity-modulated Radiation Therapy for Prostate Cancer: Results From a Randomized Trial.

Objectives: Hypofractionated prostate radiotherapy may increase biologically effective dose delivered while shortening treatment duration, but information on patient-reported urinary, bowel, and sexual function after dose-escalated hypofractionated radiotherapy is limited. We report patient-reported outcomes (PROs) from a randomized trial comparing hypofractionated and conventional prostate radiotherapy. Methods: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity-modulated radiation therapy (CIMRT, 75.6 Gy in 1.8 Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4 Gy fractions). Questionnaires assessing urinary, bowel, and sexual function were completed pretreatment and at 2, 3, 4, and 5 years after treatment. Results: Of 203 eligible patients, 185 were evaluable for PROs. A total of 173 completed the pretreatment questionnaire (82 CIMRT, 91 HIMRT) and 102 completed the 2-year questionnaire (46 CIMRT, 56 HIMRT). Patients who completed PROs were similar to those who did not complete PROs (all P>0.05). Patient characteristics, clinical characteristics, and baseline symptoms were well balanced between the treatment arms (all P>0.05). There was no difference in patient-reported bowel (urgency, control, frequency, or blood per rectum), urinary (dysuria, hematuria, nocturia, leakage), or sexual symptoms (erections firm enough for intercourse) between treatment arms at 2, 3, 4, and 5 years after treatment (all P>0.01). Concordance between physician-assessed toxicity and PROs varied across urinary and bowel domains. Discussion: We did not detect an increase in patient-reported urinary, bowel, and sexual symptom burden after dose-escalated intensity-modulated prostate radiation therapy using a moderate hypofractionation regimen (72 Gy in 2.4 Gy fractions) compared with conventionally fractionated radiation. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Decreased Risk of Radiation Pneumonitis With Coincident Concurrent Use of Angiotensin-converting Enzyme Inhibitors in Patients Receiving Lung Stereotactic Body Radiation Therapy.

Objectives: Angiotensin-converting enzyme inhibitors (ACEi) have demonstrated decreased rates of radiation-induced lung injury in animal models and clinical reports have demonstrated decreased pneumonitis in the setting of conventionally fractionated radiation to the lung. We tested the role of ACEi in diminishing rates of symptomatic (grade >=2) pneumonitis in the setting of lung stereotactic body radiation therapy (SBRT). Methods: We analyzed patients treated with thoracic SBRT to 48 to 60 Gy in 4 to 5 fractions from 2006 to 2014. We reviewed pretreatment and posttreatment medication profiles to document use of ACEi, angiotensin receptor blockers, bronchodilators, aspirin, PDE-5 inhibitors, nitrates, and endothelin receptor antagonists. Pneumonitis was graded posttreatment based on Common Terminology Criteria for Adverse Events Version 4.0. Univariate and multivariate analysis was performed and time to development of pneumonitis was evaluated by the Kaplan-Meier method. Results: A total of 189 patients were evaluated with a median follow-up of 24.8 months. The overall 1-year rate of symptomatic pneumonitis was 13.2%. The 1-year rate of symptomatic pneumonitis was 4.2% for ACEi users versus 16.3% in nonusers (P=0.03). On univariate analysis, the odds of developing grade 2 or greater pneumonitis were significantly lower for patients on ACEi (P=0.03). On multivariate analysis, after controlling for clinicopathologic characteristics and dosimetric endpoints, there was a significant association between ACEi use and decreased risk of clinical pneumonitis (P=0.04). Angiotensin receptor blockers or other bronchoactive medications did not show significant associations with development of pneumonitis. Conclusions: Incidental concurrent use of ACEi demonstrated efficacy in diminishing rates of symptomatic pneumonitis in the setting of lung SBRT. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Impact of completion axillary lymph node dissection in patients with breast cancer and isolated tumour cells or micrometastases in sentinel nodes

Publication date: November 2016
Source:European Journal of Cancer, Volume 67
Author(s): G. Houvenaeghel, J.M. Boher, F. Reyal, M. Cohen, J.R. Garbay, J.M. Classe, R. Rouzier, S. Giard, C. Faure, H. Charitansky, C. Tunon de Lara, E. Daraï, D. Hudry, P. Azuar, P. Gimbergues, R. Villet, P. Sfumato, E. Lambaudie
BackgroundOmission of completion axillary lymph node dissection (ALND) is a standard practice in patients with breast cancer (BC) and negative sentinel nodes (SNs) but has shown insufficient evidence to be recommended in those with SN invasion.MethodsA retrospective analysis of a cohort of patients with BC and micrometastases (Mic) or isolated tumour cells (ITCs) in SN. Factors associated with ALND were identified, and patients with ALND were matched to patients without ALND. Overall survival (OS) and recurrence-free survival (RFS) were estimated in the overall population, in Mic and in ITC cohorts.FindingsAmong 2009 patients analysed, 1390 and 619 had Mic and ITC in SN, respectively. Factors significantly associated with ALND were SN status, histological type, age, number of SN harvested and absence of adjuvant chemotherapy. After a median follow-up of 60.4 months, ALND omission was independently associated with reduced OS (hazard ratio [HR] 2.41, 90 confidence interval [CI] 1.36–4.27, p = 0.0102), but not with increased RFS (HR 1.21, 90 CI 0.74–2.0, p = 0.52) in the overall population. In matched patients, the increased risk of death in case of ALND omission was found only in the Mic cohort (HR 2.88, 90 CI 1.46–5.69), not in the ITC cohort. The risk of recurrence was also significantly increased in the subgroup of matched Mic patients (HR 1.56, 90 CI 0.90–2.73).InterpretationA separate analysis of Mic and ITC groups, matched for the determinants of ALND, suggested that patients with Mic had increased recurrence rates and shorter OS when ALND was not performed. Our results are consistent with those of previous studies for patients with ITC but not for those with Mic. Randomised controlled clinical trials are still warranted to show with a high level of evidence if ALND can be safely omitted in patients with micrometastatic disease in SN.



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Neutrophil-to-lymphocyte ratio as a prognostic marker in locally advanced nasopharyngeal carcinoma: A pooled analysis of two randomised controlled trials

Publication date: November 2016
Source:European Journal of Cancer, Volume 67
Author(s): Melvin Lee Kiang Chua, Sze Huey Tan, Grace Kusumawidjaja, Ma Than Than Shwe, Shie Lee Cheah, Kam Weng Fong, Yoke Lim Soong, Joseph Tien Seng Wee, Terence Wee Kiat Tan
PurposeTo assess the prognostic value of neutrophil-to-lymphocyte ratio (NLR) in patients with International Union Against Cancer (UICC)–staged III/IVA,B nasopharyngeal carcinoma (NPC), who were enrolled into two randomised controlled trials of concurrent/adjuvant chemotherapy when added to radiotherapy (SQNP01), and induction chemotherapy when added to chemoradiotherapy (NCC0901).Material and methodsA post hoc analysis of pooled cohorts from SQNP01 (N = 221) and NCC0901 (N = 172) was performed. We employed a threshold of pre-treatment NLR = 3.0 (median) to stratify patients. Survival outcomes were compared using log-rank test. Multivariable Cox regression analyses were performed to assess association between NLR and overall survival (OS), disease-free survival (DFS), distant metastasis–free survival (DMFS), and locoregional recurrence–free survival (LRFS).ResultsHigh NLR (≥3.0) was associated with advanced T-status (p = 0.002), N-status (p = 0.002), overall UICC stage (p = 0.004), and high pre-treatment Epstein–Barr virus DNA titre (p = 0.001). High NLR was not associated with OS (0.94 [0.67–1.32], p = 0.7), DFS (0.98 [0.73–1.33], p = 0.9), DMFS (1.02 [0.66–1.57], p = 0.9), and LRFS (1.37 [0.84–2.22], p = 0.2) on univariable and multivariable analyses, while conventional clinical indices (T-status, N-status, and overall UICC stage) were prognostic of clinical outcomes. High NLR also did not predict for a treatment effect with the experimental arms in both trials.ConclusionOur pooled analyses that were confined to a homogenous patient population of locally advanced NPC do not suggest that NLR adds prognostic value to conventional clinical indices in identifying patients with unfavourable disease.



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Associations between childhood height and morphologically different variants of melanoma in adulthood

Publication date: November 2016
Source:European Journal of Cancer, Volume 67
Author(s): Kathrine Damm Meyle, Michael Gamborg, Lisbet Rosenkrantz Hölmich, Jennifer Lyn Baker
Aim of the studyMelanoma subtypes have different aetiological characteristics. Child height is positively associated with adult melanoma; however, a clarification of associations with specific melanoma variants is necessary for an improved understanding of risk factors underlying the histologic entities. This study investigated associations between childhood height and future development of cutaneous melanoma variants.MethodA cohort study of 316,193 individuals from the Copenhagen School Health Records Register, with measured heights at ages 7–13 years who were born from 1930 to 1989. Melanoma cases were identified via linkage to the national Danish Cancer Registry and subdivided into subtypes. Cox proportional hazards regressions were performed.ResultsA total of 2223 cases of melanoma distributed as 60% superficial spreading melanoma (SSM), 27.5% melanoma not otherwise specified (NOS), 8.5% nodular melanoma (NM), and 2% lentigo maligna melanoma (LMM). The remaining rare melanoma forms were not analysed. Childhood height was positively and significantly associated with SSM, melanoma NOS, and NM, but not LMM, in adulthood. Per height z-score at age 13 years, the hazard ratios were 1.20 (95% confidence intervals [CI]: 1.13–1.27) for SSM, 1.19 (95% CI: 1.09–1.29) for melanoma NOS, and 1.21 (95% CI: 1.04–1.41) for NM. Further, growth patterns were linked to the melanoma variants with persistently tall children having an increased risk of developing SSM, melanoma NOS, or NM.ConclusionChildhood height is positively associated with the majority of the melanoma variants. These results suggest that the underlying processes contributing to childhood height and growth patterns interconnect early-life events with the predisposition to melanomagenesis in adulthood.



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