Excision Of Primary Tumor Research Articles

Short and long-term results of sternectomy for sternal tumours.

We analyzed our experience in sternal resections (SRs) for primary or secondary neoplasm focusing on technical aspects of reconstruction, post-operative outcomes and long term survival. From January 2005 to December 2015, 36 patients (24 males, 67%) underwent surgical excision of primary (chondrosarcoma n=18 patients, 50%; osteosarcoma n=2, 6%; Ewing sarcoma n=1, 3%; other n=2, 6%) or secondary (breast cancer n=7, 19%; kidney carcinoma n=2, 6%) sternal tumour. We performed n=30 partial sternectomy and n=6 total sternectomy with en-bloc resection of the sternocostal cartilages in all patient and extended resection in 7 patients. Stability was obtained with prosthetic material, rigid and non-rigid and a muscular flap: rigid material [Strasbourg Thoracic Osteosynthesis System (STRATOS), MedXpert GmbH] and muscle flap n=11 (30.6%); polytetrafluoroethylene patch and muscle flap n=6 (16.7%); muscle flap alone n=19 (52.8%). The 30-day mortality rate was 0, overall complication rate was 19%. The median ICU stay was 1.5 days and mean hospital stay was 10.6±5.9 days. We obtained a complete (R0) resection in all patients. Overall survival (OS) at 5 and 10 years were 59% and 40%; in the group of primary neoplasm OS rate at 5 and 10 years was 79% and 54%. Disease free survival (DFS) rate at 5 years was 61%. Higher grading was identified as negative prognostic factor. Wide radical resections of anterior chest wall are basilar in a multimodality treatment for primary or metastatic neoplasm of the sternum. Stabilization with titanium bars and clips provides rigidity of chest wall with good functional results.

Long-Term Radiographic Findings After Balloon-based Accelerated Partial Breast Irradiation

Accelerated partial breast irradiation (APBI) offers patients the convenience of a shorter course of therapy with good clinical and cosmetic outcomes. While several retrospective institutional series have reported short term radiographic findings, including seroma, calcifications, and architectural distortion, less is known about long-term radiographic findings. The purpose of this study is to report long-term radiographic findings after treatment with balloon based APBI. Records of women treated with balloon based APBI from 2005-2012 at one institution were reviewed after IRB approval. All patients were treated with 34 Gy in 10 fractions. All patients had pre-treatment diagnostic imaging, with a minimum of 2 years of surveillance imaging. Post-treatment images of 129 patients were reviewed by one radiologist. The majority of surgical excisions were open cavity non-oncoplastic procedures. Univariate and multivariate analysis of factors leading to formation and resolution of seroma were performed in patients treated with lumpectomy and APBI. Median age at diagnosis was 62 years, and 89% were Stage 0-1. Median surgical excision volume was 108.9 cc (range 20.5-681.9). Number of margin re-excisions were 0, 1, 2+ in 36%, 40%, and 21% respectively. Median time from biopsy or segmental mastectomy to completion of RT was 1 month (range <1-4). Primary mode of imaging was mammogram. Median time from end of RT to first and last surveillance image was 6 and 54 months respectively. Median number of images was 7 (range 3-12). Time from end of RT to initial identification of seroma was 6.4 months (range 3-34). Seroma was identified in 98 (76%) patients, with median maximum diameter of 3.9 cm. Forty (41%) patients experienced resolution of seroma, at a median time of 29 months (range 6-74). Invasive or insitu pathology, body mass index, chemotherapy, multichannel device, and infection were not associated with formation or resolution of seroma. On univariate analysis, surgical excision volume was associated with seroma formation, and tumor stage and margin re-excision were significant on univariate and multivariate analysis. Seroma formation after APBI resolves around 2.5 years for many patients, but persists for others possibly due to primary tumor and surgical excision volumes. With revised criteria on the definition of positive margins, smaller volumes and fewer re-excisions may lead to decreased risk of seroma formation for future patients.

Extranodal spread of primary and secondary metastatic nodes: The dominant risk factor of survival in patients with head and neck squamous cell carcinoma.

Extranodal spread (ENS) in patients with head and neck squamous cell carcinoma (HNSCC) can greatly influence the prognostic outcomes. However, the relative risks of ENS in the primary (1st) and secondary (2nd) metastatic nodes (mets) are not well documented. We retrospectively analyzed the hazard ratios (HRs) of ENS in the 1st and 2nd mets from 516 HNSCC patients who had undergone primary tumor excision. The impact of clinically and/or histologically confirmed ENS-positive mets on prognosis in terms of cancer-specific survival was analyzed. Cox proportional hazard regression analysis indicated that ENS-positive 1st met (adjusted HR = 3.15; 95% CI, 1.40–7.56; p = 0.006) and ENS-positive 2nd met (adjusted HR = 4.03; 95% CI, 1.41–16.96; p = 0.007) significantly and independently predicted poor prognosis; however, other variables including primary site, met size or numbers, and met location in the contralateral side of the primary lesion, did not. Cumulative incidence function and Cox analyses indicated that differences in ENS profiles of 1st and 2nd mets stratified HNSCC patients with varying risks of poor outcome; HRs relative to patients with ENS-positive 1st met (-)/ENS-positive 2nd met (-) were 4.02 (95% CI, 1.78–8.24; p = 0.002), 8.29 (95% CI, 4.58–14.76; p <0.001), and 25.80 (95% CI, 10.15–57.69; p <0.001) for patients with ENS-positive 1st met (+)/ENS-positive 2nd met (-), ENS-positive 1st met (-)/ENS-positive 2nd met (+), and ENS-positive 1st met (+)/ENS-positive 2nd met (+) patients, respectively. Kaplan-Meier analysis indicated that the 2nd met that appeared in the neck side with a history of 1st met and neck dissection had a higher risk of ENS than the 2nd met in the neck side without the history (p = 0.003). These results suggested that ENS is a dominant prognostic predictor of HNSCC patients, with double-positive ENS in the 1st and 2nd mets predicting the most devastating outcome.

Expression of far upstream element-binding protein 1 correlates with c-Myc expression in sacral chordomas and is associated with tumor progression and poor prognosis

The far upstream element (FUSE)-binding protein 1 (FUBP1), a well-known transcriptional regulator of the proto-oncogene c-Myc, has been demonstrated by previous work to be aberrantly expressed in a variety of tumors and plays a critical role in tumor progression; however, its expression and function in relatively rare and aggressive chordomas remains unclear. In this retrospective study, we reviewed clinicopathologic characteristics of 40 patients diagnosed with sacral chordoma, and analyzed 40 tumor and 20 distant normal tissues obtained from patients during the primary surgical tumor excision. Using immunohistochemistry, we observed an up-regulation in the expression of FUBP1 and c-Myc in sacral chordomas compared with the normal tissues (P = 0.001 for both). Additionally, positive correlations of FUBP1 expression with c-Myc (γ = 0.651, P < 0.001) and the cell proliferation index Ki-67 expression (γ = 0.447, P = 0.004) were indicated using Spearman's rank correlation coefficient. Increased expression of FUBP1 was significantly associated with tumor invasion into the surrounding muscles (P = 0.002). Kaplan-Meier curves demonstrated the association between FUBP1 levels and the patients' local recurrence-free survival (LRFS) (P < 0.001) but not with the overall survival (OS) (P = 0.070). The independent prognostic significance of FUBP1 levels for the LRFS was indicated by multivariate analysis (HR = 4.272; 95% CI, 1.133–16.112; P = 0.032). Our findings demonstrate an association between FUBP1 levels and chordoma progression and prognosis, suggesting that FUBP1 can be used as a biomarker and a potential therapeutic target.

REGATTA trial: its achievement and the issues unsolved

In gastric cancer patients with distant metastases, the standard treatment is systematic chemotherapy that targets the circulating cancer cells throughout the body (1). As the life expectancy of such patients is very short, aggressive surgical treatments are considered unreasonable owing to the relatively high risk of postoperative morbidities that may delay chemotherapy. Several studies have shown that primary tumor excision improves the prognosis of these patients owing to favorable short-term outcomes after surgery as well as the reduction in tumor burden; hence, adjuvant chemotherapy becomes more amenable (2). However, whether removal of the primary cancer is beneficial for patients with distant metastases remains unclear.

Resistance to Taxanes in Triple-Negative Breast Cancer Associates with the Dynamics of a CD49f+ Tumor-Initiating Population.

SummaryTaxanes are a mainstay of treatment for breast cancer, but resistance often develops followed by metastatic disease and mortality. Aiming to reveal the mechanisms underlying taxane resistance, we used breast cancer patient-derived orthoxenografts (PDX). Mimicking clinical behavior, triple-negative breast tumors (TNBCs) from PDX models were more sensitive to docetaxel than luminal tumors, but they progressively acquired resistance upon continuous drug administration. Mechanistically, we found that a CD49f+ chemoresistant population with tumor-initiating ability is present in sensitive tumors and expands during the acquisition of drug resistance. In the absence of the drug, the resistant CD49f+ population shrinks and taxane sensitivity is restored. We describe a transcriptional signature of resistance, predictive of recurrent disease after chemotherapy in TNBC. Together, these findings identify a CD49f+ population enriched in tumor-initiating ability and chemoresistance properties and evidence a drug holiday effect on the acquired resistance to docetaxel in triple-negative breast cancer.

Long term radiographic findings of breast brachytherapy: Implications of surgical volume.

Little is known about long-term radiographic findings after treatment with accelerated partial breast irradiation (APBI). Univariate and multivariate analysis of factors leading to formation and resolution of seroma were performed in patients treated with lumpectomy and APBI. Post-treatment images of 129 patients were reviewed by one radiologist. Median surgical excision volume was 108.9 cc (range 20.5-681.9). Primary mode of imaging was mammogram. Median time from end of RT to first and last surveillance image was 6 and 54 months, respectively. Median number of images was 7 (range 3-12). Seroma was identified in 98 (76%) patients, with median maximum diameter of 3.9 cm. Forty (41%) patients experienced resolution of seroma, at a median time of 29 months (range 6-74). On univariate analysis, surgical excision volume was associated with seroma formation, and tumor stage and margin re-excision were significant on univariate and multivariate analysis. No factors were associated with seroma resolution. Seroma formation after APBI resolves around 2.5 years for many patients, but persists for others possibly due to primary tumor and surgical excision volumes. With revised criteria on the definition of positive margins, smaller volumes may lead to decreased risk of seroma formation for future patients.

Confocal laser endomicroscopy in head and neck malignancies using FITC-labelled EpCAM- and EGF-R-antibodies in cell lines and tumor biopsies.

Intraoperative detection of residual malignant cells at tumor margins following excision of primary tumors could help improving surgery and thus patients' outcome. The feasibility of the tumor antigens epidermal growth factor receptor (EGF-R) and epithelial cell adhesion molecule (EpCAM) for antibody-dependent confocal laser scanning endomicroscopy (CLE)-mediated visualization of malignant cells was addressed. Both tumor antigens are highly and frequently expressed in the majority of carcinomas, including head and neck squamous cell carcinomas (HNSCC), and represent prognostic and therapeutic tumor target molecules. FITC-conjugated EGF-R- and EpCAM-specific antibodies served as molecular tools for the detection of antigen-positive cells using the CLE technology. Specificity of both antibodies and their ability to discriminate tumor from non-tumor cells were assessed in vitro with human fibroblasts and PCI-1 HNSCC cell lines, and ex vivo on primary HNSCC samples (n = 11) and healthy mucosa (n = 5). Antigen specificity of the used EpCAM-specific antibody was superior to that of the EGF-R-specific antibody both in vitro and ex vivo (100% vs. 31.25%), and allowed visualization of cellular structures in CLE measurements. These results hold promise for possible future applications in humans.

Primary and metastatic tumor dormancy as a result of population heterogeneity.

Existence of tumor dormancy, or cancer without disease, is supported both by autopsy studies that indicate presence of microscopic tumors in men and women who die of trauma (primary dormancy), and by long periods of latency between excision of primary tumors and disease recurrence (metastatic dormancy). Within dormant tumors, two general mechanisms underlying the dynamics are recognized, namely, the population existing at limited carrying capacity (tumor mass dormancy), and solitary cell dormancy, characterized by long periods of quiescence marked by cell cycle arrest. Here we focus on mechanisms that precede the avascular tumor reaching its carrying capacity, and propose that dynamics consistent with tumor dormancy and subsequent escape from it can be accounted for with simple models that take into account population heterogeneity. We evaluate parametrically heterogeneous Malthusian, logistic and Allee growth models and show that 1) time to escape from tumor dormancy is driven by the initial distribution of cell clones in the population and 2) escape from dormancy is accompanied by a large increase in variance, as well as the expected value of fitness-determining parameters. Based on our results, we propose that parametrically heterogeneous logistic model would be most likely to account for primary tumor dormancy, while distributed Allee model would be most appropriate for metastatic dormancy. We conclude with a discussion of dormancy as a stage within a larger context of cancer as a systemic disease.Reviewers: This article was reviewed by Heiko Enderling and Marek Kimmel.

Primary cardiac angiosarcoma: a prolonged response to surgical resection followed by concurrent chemoradiotherapy with docetaxel.

IntroductionPrimary cardiac cancer is a very rare disease, among which primary cardiac angiosarcoma is one of the most frequent type and is characterized by extremely poor prognosis without established optimal treatment.Case descriptionHere we report a case of primary cardiac angiosarcoma with hemorrhagic pericardial effusion who achieved a durable response with tumor excision followed by concurrent chemoradiotherapy with docetaxel. A sixty year old man was presented with dyspnea and was diagnosed with primary cardiac angiosarcoma with hemorrhagic pericardial effusion. After surgical excision of primary tumor with microscopic residual disease followed by concurrent chemoradiotherapy with docetaxel, the patient showed durable response of progression free survival of 12 months.Discussion and evaluationThis case shows benefit of concurrent chemoradiotherapy with taxane. Further investigation of aggressive multimodal treatment strategy is warranted for primary cardiac angiosarcoma with pauci-metastasis even when achievement of complete resection seems unlikely.

Primary Intracranial Ewing's Sarcoma (Peripheral Primitive Neuroectodermal Tumour of Parietal Bone) with Spinal and Pelvic Metastasis in a Young Female Child: Rare Case Report and Review

Introduction The Peripheral Primitive Neuroectodermal Tumour (pPNET)/Ewing's sarcoma family tumor (ESFT) group is a recently redefined term which includes all small round cell tumors of bone, soft tissue, and nerve with a common neuroectodermal origin. These highly aggressive pediatric soft tissue tumors occur less frequently in the craniospinal axis. Primary cranial lesion associated with spinal and pelvic metastasis is a rare presentation. Clinical Presentation A 9-year old girl was hospitalized with features of progressive increase in intracranial pressure with quadriparesis. The patient had ⅘ quadriparesis with bilateral papilledema. Brain MRI showed a large, hetero intense, contrast enhancing right parietal bony lesion infiltrating the dura with mass effect over the brain. Brain CT showed bony expansion and multiple calvarial lytic lesions. MRI cervical spine revealed collapsed fourth cervical vertebral body with extensive paravertebral and paraspinal soft tissue components with cord compression. Metastatic workup revealed a lytic lesion in the left iliac bone and left lung. The patient underwent a surgically challenging C4 corpectomy with cage fixation followed by craniotomy and excision of parietal bony lesion with titanium mesh cranioplasty in the same sitting. Histopathology revealed pPNET and was confirmed by CD99 positivity. Conclusion This rare multiple site tumor presentation was carefully planned and effectively managed by a combined single-stage surgical approach involving total excision of primary parietal bone and metastatic cervical spine tumors with primary titanium mesh cranioplasty and cervical spine stabilization, followed with radiotherapy and chemotherapy, which resulted in good recovery and improved the overall prognosis for the patient.

Occult level IV metastases in clinically node-negative patients with oral tongue squamous cell carcinoma.

The present study was conducted to determine the rate of level IV lymph node involvement among node-negative (N0) necks in patients with squamous cell carcinoma of the tongue. The study comprised 32 patients with squamous cell carcinoma of the tongue, with tumour-node-metastasis staging of T1-3N0M0, who were admitted to the Otolaryngology Department at Tehran University of Medical Sciences from March 2012 to March 2014. After a complete diagnostic evaluation, wide primary tumour excision (with 1.5-2cm margins) and extended supraomohyoid neck dissection (levels I-IV) were accomplished. Occult metastasis was found in 28 per cent of the patients. Level I, II and III metastases were the most common (18.75, 18.75 and 15.62 per cent, respectively). Level IV metastasis was found in 6.25 per cent of patients. Supraomohyoid neck dissection appears to be an appropriate treatment for N0 tongue squamous cell carcinoma and there is no need for level IV lymph node dissection in a N0 patient.

An Oral Salmonella-Based Vaccine Inhibits Liver Metastases by Promoting Tumor-Specific T-Cell-Mediated Immunity in Celiac and Portal Lymph Nodes: A Preclinical Study.

Primary tumor excision is one of the most widely used therapies of cancer. However, the risk of metastases development still exists following tumor resection. The liver is a common site of metastatic disease for numerous cancers. Breast cancer is one of the most frequent sources of metastases to the liver. The aim of this work was to evaluate the efficacy of the orally administered Salmonella Typhi vaccine strain CVD 915 on the development of liver metastases in a mouse model of breast cancer. To this end, one group of BALB/c mice was orogastrically immunized with CVD 915, while another received PBS as a control. After 24 h, mice were injected with LM3 mammary adenocarcinoma cells into the spleen and subjected to splenectomy. This oral Salmonella-based vaccine produced an antitumor effect, leading to a decrease in the number and volume of liver metastases. Immunization with Salmonella induced an early cellular immune response in mice. This innate stimulation rendered a large production of IFN-γ by intrahepatic immune cells (IHIC) detected within 24 h. An antitumor adaptive immunity was found in the liver and celiac and portal lymph nodes (LDLN) 21 days after oral bacterial inoculation. The antitumor immune response inside the liver was associated with increased CD4+ and dendritic cell populations as well as with an inflammatory infiltrate located around liver metastatic nodules. Enlarged levels of inflammatory cytokines (IFN-γ and TNF) were also detected in IHIC. Furthermore, a tumor-specific production of IFN-γ and TNF as well as tumor-specific IFN-γ-producing CD8 T cells (CD8+IFN-γ+) were found in the celiac and portal lymph nodes of Salmonella-treated mice. This study provides first evidence for the involvement of LDLN in the development of an efficient cellular immune response against hepatic tumors, which resulted in the elimination of liver metastases after oral Salmonella-based vaccination.

Erectile Function Recovery after Radical Prostatectomy in Men with High Risk Features

We describe the efficacy of radical prostatectomy to achieve complete primary tumor excision while preserving erectile function in a cohort of patients with high risk features in whom surgical resection was tailored according to clinical staging, biopsy data, preoperative imaging and intraoperative findings. In a retrospective review we identified 584 patients with high risk features (prostate specific antigen 20 ng/ml or greater, clinical stage T3 or greater, preoperative Gleason grade 8-10) who underwent radical prostatectomy between 2006 and 2012. The probability of neurovascular bundle preservation was estimated based on preoperative characteristics. Positive surgical margin rates and erectile function recovery were determined in patients who had some degree of neurovascular bundle preservation. The neurovascular bundles were resected bilaterally in 69 (12%) and unilaterally in 91 (16%) patients. The remaining patients had some degree of bilateral neurovascular bundle preservation. Preoperative features associated with a lower probability of neurovascular bundle preservation were primary biopsy Gleason grade 5 and clinical stage T3 disease. Among the patients with some degree of neurovascular bundle preservation 125 of 515 (24%) had a positive surgical margin, and 75 of 160 (47%) men with preoperatively functional erections and available erectile function followup had recovered erectile function within 2 years. High risk features should not be considered an indication for complete bilateral neurovascular bundle resection. Some degree of neurovascular bundle preservation can be done safely by high volume surgeons in the majority of these patients with an acceptable rate of positive surgical margins. Nearly half of high risk patients with functional erections preoperatively recover erectile function after radical prostatectomy.

Vulvar cancer: initial management and systematic review of literature on currently applied treatment approaches.

This review provides guidelines and aims to estimate utilisation rates of treatment modalities applied in vulvar cancer. Current standards of treatment are as follows: wide local excision instead of radical vulvectomy in the case of small tumour (T<2cm), no lymph node dissection in the case of a micro-invasive tumour (invasion <1mm), unilateral lymph node dissection in the case of a lateral tumour and inguinal-femoral lymphadenectomy by separate incisions instead of en bloc inguinal-femoral lymph node excision. Implementation of sentinel lymph node biopsy in patients with tumours not exceeding 4cm is safe and efficiently eliminates redundant groin dissections. Pre-operative treatment with chemoradiotherapy reduces tumour size and improves surgical excision of inoperable primary tumours or fixed lymph nodes, but side effects are considerable. Literature search performed using PubMed database (from: 1 June 2005 to 1 June 2015) with the terms 'consecutive', 'vulvar cancer', 'treatment' identified seven full-text manuscripts, including data on 1114 patients. Utilisation rates of neoadjuvant radiochemotherapy, chemotherapy alone, surgery, adjuvant radiotherapy and adjuvant radiochemotherapy were 5.9%, 0.3%, 89.3%, 22.6% and 0.2% respectively. An evidence-based estimation of appropriate rates of surgery, radiotherapy and chemotherapy for vulvar cancer is needed to compare management reflecting guidelines with presented here real frequency of applied modalities.

Acral lentiginous melanoma with multiple brain metastases in an Indian male.

Acral lentiginous melanoma with multiple brain metastases in an Indian male.

An Ectopic ACTH Secreting Metastatic Parotid Tumour.

A 60-year old woman presented with features of Cushing's syndrome (CS) secondary to an ectopic adrenocorticotropic hormone (ACTH) secreting metastatic parotid tumour 3 years after excision of the original tumour. She subsequently developed fatal intestinal perforation and unfortunately died despite best possible medical measures. Ectopic ACTH secretion accounts for 5–10% of all patients presenting with ACTH dependent hypercortisolism; small cell carcinoma of lung (SCLC) and neuroendocrine tumours (NET) account for the majority of such cases. Although there are 4 previous case reports of ectopic ACTH secreting salivary tumours in literature, to our knowledge this is the first published case report in which the CS developed after 3 years of what was deemed as a successful surgical excision of primary salivary tumour. Our patient initially had nonspecific symptoms which may have contributed to a delay in diagnosis. Perforation of sigmoid colon is a recognised though underdiagnosed complication associated with steroid therapy and hypercortisolism. This case demonstrates the challenges faced in diagnosis as well as management of patients with CS apart from the practical difficulties faced while trying to identify source of ectopic ACTH.

Histopathological Parameters predicting Occult Nodal Metastases in Tongue Carcinoma Cases: An Indian Perspective.

It is a well-established fact that in squamous cell carcinoma cases, the presence of lymph node metastases decreased the 5-year survival rate by 50% and also caused the recurrence of the primary tumor with development of distant metastases. Till date, the predictive factors for occult cervical lymph nodes metastases in cases of tongue squamous cell carcinoma remain inconclusive. Therefore, it is imperative to identify patients who are at the greatest risk for occult cervical metastases. This study was thus performed with the aim to identify various histopathologic parameters of the primary tumor that predict occult nodal metastases. The clinicopathologic features of 56 cases of lateral tongue squamous cell carcinoma with cT1NoMo/cT2NoMo as the stage and without prior radiotherapy or chemotherapy were considered. The surgical excision of primary tumor was followed by elective neck dissection. The glossectomy specimen along with the neck nodes were fixed in formalin and 5 urn thick sections were obtained. The hematoxylin & eosin stained sections were then subjected to microscopic examination. The primary tumor characteristics that were analyzed include tumor grade, invading front, depth of tumor, lymphovascular invasion, perineural invasion and inflammatory response. The nodes were examined for possible metastases using hematoxylin & eosin followed by cytokeratin immunohistochemistry. A total of 12 cases were found with positive occult nodal metastases. On performing univariate analysis, the histopathologic parameters that were found to be statistically significant were lymphovascular invasion (p = 0.004) and perineural invasion (p = 0.003) along with a cut-off depth of infiltration more than 5 mm (p = 0.01). Histopathologic assessment of the primary tumor specimen therefore continues to provide information that is central to guide clinical management, particularly in cases of occult nodal metastases. Clinical significance The study highlights the importance of extensive histopathological screening, which holds the key for establishing occult metastases. Pathological upgrading of tumors is possible following histopathological studies similar to the present one. Presence of occult metastases justify neck dissection in these clinically N0 cases. In an Indian setting, histopathological evaluation assumes a bigger role than other expensive and advanced techniques.

Abstract B138: Single low-dose administration of anti-CTLA-4/tremelimumab at the tumor excision site boosts systemic antitumor immunity in early-stage melanoma patients: Results from a Phase-1 study

Abstract While systemic immune checkpoint blockade is unsurpassed in the induction of clinically effective T cell immunity in advanced-stage melanoma patients, the risk of autoimmune-related side effects precludes its application in earlier stages. In a Phase-1 dose escalation study we have studied the safety, feasibility and immunological effects of intradermal delivery of a single low dose of anti-CTLA-4/tremelimumab at the primary tumor excision site of patients with clinically Stage I-II melanoma. Dose escalation (4x3 cohorts of 2, 5, 10 and 20 mg) has been concluded with one additional patient enrolled in a 20 mg expansion cohort. Breslow thickness ranged from 0.9 to 6 mm (mean 1.98 mm). Examination of the sentinel lymph node (SLN) revealed (micro-)metastases in five of the patients. The tremelimub administration was found to be safe without apparent side effects except for one case of localized vitiligo at the highest (20 mg) dose level. Of note, potent immunological effects were observed in equal measure at all dose levels. In all patients a decrease in systemic rates of activated Tregs (aTregs, defined as CD4+CD25hiFoxP3hi T cells) was observed after 7 days of treatment (p&amp;lt;0.001). In 8/13 patients aTreg rates remained low at 12 weeks whereas in five patients aTreg rates had rebounced to pre-treatment levels by that time. In 11/13 patients the percentage of ICOS expressing CD4+ T cells (a recognized biodynamic marker of CTLA-4 blockade) transiently increased with in 1-3 weeks post-treatment. Specific T cell reactivity against long peptides derived from the melanoma antigens NY-ESO-1 and MART-1 was tested after in vitro re-stimulation in an IFNγ Elispot assay. In 7/13 patients evidence was found of tremelimumab-induced increases in systemic T cell rates, which remained elevated up to 12 weeks post-treatment. Remarkably, 5/13 patients showed pre-existent NY-ESO-1 reactivity, which in all cases had decreased by day 7, and in 3/5 patients had increased over baseline levels by day 21. T cell reactivity to either NY-ESO-1 or MART-1 was observed in 4/4 tested SLN. Of note, both NY-ESO-1 and MART-1 reactive T cells were detected in the SLN of the patient experiencing an isolated incidence of vitiligo after receiving 20 mg tremelimumab. In conclusion, local administration of a single low dose of anti-CTLA-4/tremelimumab has proven safe and effective in terms of attenuating aTreg levels in peripheral blood and boosting systemic antitumor immunity. As such it may offer an attractive, and up to now sorely lacking, adjuvant treatment option for early-stage melanoma patients at risk for tumor recurrence. Citation Format: Anita G.M. Stam, Kim M. van Pul, Bas D. Koster, Dafni Chondronasiou, Sinéad M. Lougheed, M. Petrousjka van den Tol, Karin Jooss, Ronald J.C.L.M. Vuylsteke, Alfons J.M. van den Eertwegh, Tanja D. de Gruijl. Single low-dose administration of anti-CTLA-4/tremelimumab at the tumor excision site boosts systemic antitumor immunity in early-stage melanoma patients: Results from a Phase-1 study. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B138.

Monitoring therapeutic efficacy of sunitinib using [(18)F]FDG and [(18)F]FMISO PET in an immunocompetent model of luminal B (HER2-positive)-type mammary carcinoma.

BackgroundClinical studies implying the sunitinib multi-kinase inhibitor have led to disappointing results for breast cancer care but mostly focused on HER2-negative subtypes. Preclinical researches involving this drug mostly concern Triple Negative Breast Cancer (TNBC) murine models. Here, we explored the therapeutic efficacy of sunitinib on a PyMT-derived transplanted model classified as luminal B (HER2-positive) and monitored the response to treatment using both in vivo and ex vivo approaches.MethodsTumour-induced animals were treated for 9 (n = 7) or 14 (n = 8) days with sunitinib at 40 mg/kg or with vehicle only. Response to therapy was assessed in vivo by monitoring glucose tumour metabolism and hypoxia using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and [18F]fluoromisonidazole ([18F]FMISO) Positron Emission Tomography (PET). After primary tumour excision, ex vivo digital microscopy was performed on treated and control samples to estimate vascular density (CD31), apoptosis (Tunel), proliferation (Ki-67), Tumour-Associated Macrophage (TAM) infiltration (F4/80), metabolism (GLUT1) and cellular response to hypoxia (HIF1 alpha). The drug impact on the metastasis rate was evaluated by monitoring the PyMT gene expression in the lungs of the treated and control groups.ResultsConcomitant with sunitinib-induced tumour size regression, [18F]FDG PET imaging showed a stable glycolysis-related metabolism inside tumours undergoing treatment compared to an increased metabolism in untreated tumours, resulting at treatment end in 1.5 less [18F]FDG uptake in treated (n = 4) vs control (n = 3) tumours (p < 0.05). With this small sample, [18F]FMISO PET showed a non-significant decrease of hypoxia in treated vs control tumours. The drug triggered a 4.9 fold vascular volume regression (p < 0.05), as well as a 17.7 fold induction of tumour cell apoptosis (p < 0.001). The hypoxia induced factor 1 alpha (HIF1 alpha) expression was twice lower in the treated group than in the control group (p < 0.05). Moreover, the occurrence of lung metastases was not reduced by the drug.Conclusions[18F]FDG and [18F]FMISO PET were relevant approaches to study the response to sunitinib in this luminal B (HER2-positive) model. The sunitinib-induced vascular network shrinkage did not significantly increase tumour hypoxia, suggesting that tumour regression was mainly due to the pro-apoptotic properties of the drug. Sunitinib did not inhibit the metastatic process in this PyMT transplanted model.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1540-2) contains supplementary material, which is available to authorized users.