Ageing and Stem cell therapy: AMPK as an applicable pharmacological target for Rejuvenation of Aged Stem Cells and achieving higher efficacy in stem cell therapy

Publication date: Available online 19 October 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Mohammadhossein Khorraminejad-Shirazi, Mohammad Farahmandnia, Bahareh Kardeh, Alireza Estedlal, Sina Kardeh, Ahmad Monabati
In recent years, tissue regeneration has become a promising field for developing stem cell-based transplantation therapies for human patients. Adult stem cells are affected by the same aging mechanisms that involve somatic cells. One of the mechanisms involved in cellular aging is hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and disruption of 5' adenosine monophosphate-activated protein kinase (AMPK). Aging of stem cells results in their impaired regenerative capacity and depletion of stem cell pools in adult tissue, which results in lower efficacy of stem cell therapy. By utilizing an effective therapeutic intervention for aged stem cells, stem cell therapy can become more promising for future application. mTORC1 inhibition is a practical approach to preserve the stem cell pool. In this article, we review the dynamic interaction between sirtuin 1, AMPK, and mTORC1. We propose that using AMPK activators such as 5-aminoimidazole-4-carboxamide ribonucleotide, A769662, metformin, and NAD⁺ are practical ways to be employed for achieving more optimal results in stem cell-based transplantation therapies.



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Evaluation of the head and neck cancer patient population and the incidence of hospitalization at an academic medical center

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Clinicopathologic implications of CD8 + /Foxp3 + ratio and miR-574-3p/PD-L1 axis in spinal chordoma patients

Abstract

Currently, little is known about the interactions between microRNAs (miRNAs) and the PD-1/PD-L1 signaling pathway in chordoma, and data discussing the role of the immune milieu in chordoma prognosis are limited. We aimed to analyze the relationship between PD-L1, miR-574-3p, microenvironmental tumor-infiltrating lymphocytes (TILs) and clinicopathological features of spinal chordoma patients. PD-L1 expression and TILs (including Foxp3⁺, CD8⁺, PD-1⁺ and PD-L1⁺) were assessed by immunohistochemistry in tumor specimens of 54 spinal chordoma patients. MiRNAs microarray and bioinformatical analysis were used to identify miRNAs potentially regulating PD-L1 expression, which were further validated by quantitative RT-PCR. miR-574-3p was identified to potentially regulate PD-L1 expression in chordoma, which inversely correlated with PD-L1. Positive PD-L1 expression on tumor cells was associated with advanced stages (P = 0.041) and TILs infiltration (P = 0.005), whereas decreased miR-574-3p level correlated with higher muscle invasion (P = 0.012), more severe tumor necrosis (P = 0.022) and poor patient survival. Importantly, a patient subgroup with PD-L1⁺/miR-574-3p^low chordoma phenotype was significantly associated with worse local recurrence-free survival (LRFS) (P = 0.026). PD-1⁺ TILs density was associated with surrounding muscle invasion (P = 0.014), and independently portended poor LRFS (P = 0.040), while PD-L1⁺ TILs showed tendencies of less aggressive clinical outcomes. Multivariate analysis of OS only found CD8⁺/Foxp3⁺ ratio to be independent prognostic factor (P = 0.022). These findings may be useful to stratify patients into prognostic groups and provide a rationale for the use of checkpoint blockade therapy, possibly by administering miR-574-3p mimics, in spinal chordoma.

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Metachronous solitary plasmacytoma

Solitary plasmacytoma is a rare disorder comprising 5%–10% of all plasma cell neoplasms. Progression to multiple myeloma is the most common pattern of relapse. Appearance of new lesions without any systemic disease is the most unusual pattern of relapse seen in <2% cases. We present a case of a 46-year-old female who presented with features of third and seventh cranial nerve palsy, diagnosed with solitary plasmacytoma, with no evidence of any systemic disease. As per standard recommendations, the patient received radiotherapy to the local site. The patient developed relapse twice, at three sites, during the follow-up period. Investigations revealed no evidence of any systemic disease. In view of repeat relapses, the patient was started on immune modulatory agent. Two and half years after the last radiotherapy, the patient is symptom free with no evidence of any new lesion.

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Acute-onset diplopia in a case of nephrotic syndrome

Description

A 12-year-old boy was evaluated in our emergency services for complaints of diplopia and mild generalised headache since past 4 days. The patient was a known case of frequently relapsing idiopathic nephrotic syndrome and was currently in remission since 5 days. He was normal and oriented on general physical and systemic examination. Urine microscopy had revealed only traces of protein on repeated evaluation, and serum albumin was 2.2 g/dL on presentation. Visual acuity was 6/6 in both eyes, and the pupillary reflexes were brisk. The ocular motility examination revealed an esotropia of 20 prism dioptres (figure 1A) along with limitation of the abduction movements in both eyes (figure 1B,C). However, right eye showed a greater limitation compared with left eye. Anterior segment of both the eyes were normal, but the fundus examination revealed bilateral severe established optic disc oedema (figure 2A,B). The...

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A case of autosplenectomy associated with T-cell checkpoint inhibitor treatment

Description

A 77-year-old Caucasian man presented to the oncology service with de novo v-raf murine sarcoma viral oncogene homolog B (BRAF), wild-type metastatic melanoma and widespread disease involving; subcutaneous fat, lymph nodes, bone and spleen with no history of autoimmunity. At diagnosis, the spleen was measured within normal limits on CT. In November 2013, he commenced treatment on a phase-III randomised double-blinded clinical trial (CA209-067) and received combination checkpoint inhibitor therapy with ipilimumab and nivolumab.

Radiological mixed response was observed after three months, with a partial response in all target lesions (RECIST V.1.1 criteria) but an increase in the size of the non-target splenic metastasis consistent with pseudoprogression. In conjunction, splenic enlargement was demonstrated (figure 1).

Figure 1

Subsequent restaging coronal abdominopelvic CT demonstrating an increased splenic length of 11.8 cm.

After seven months of immunotherapy, he achieved a complete radiological response to treatment with an...

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Non-infectious aortitis in an immunosuppressed renal transplant recipient with IgA nephropathy

A 54-year-old woman presented with atypical chest pain, fever and malaise. She was immunosuppressed with three agents following a living-donor kidney transplant 1 year previously. Her native kidney failure was secondary to biopsy-demonstrated crescentic IgA nephropathy, with systemic involvement. A CT pulmonary angiogram revealed an inflammatory cuff of soft tissue around the descending thoracic aorta suggesting aortitis. Inflammatory markers were elevated. Given her immunosuppression, the patient was screened extensively for infective causes and was empirically commenced on intravenous meropenem. After 72 hours of no clinical or serological response to antibiotic therapy, negative microbiological investigations and worsening inflammation on serial imaging, she was commenced on high-dose methylprednisolone for presumed inflammatory aortitis. Symptoms and inflammatory markers rapidly normalisedand the patient was discharged home on oral prednisolone. A clinical diagnosis of IgA-related aortitis was made. Imaging 3 months later showed complete resolution of the aortitis.

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Learning from errors: unnecessary intensive care unit admissions

An elderly man was transferred to our emergency department with reported ventricular tachycardia requiring intravenous amiodarone and intensive care unit admission. Device interrogation, the following day, revealed only frequent premature ventricular contractions and non-sustained ventricular tachycardia in a patient with a known history of these conditions. The patient underwent unnecessary invasive monitoring after being emergently transferred to our facility and admitted to the intensive care unit. Fortunately, our patient did not suffer any unwarranted side effects from intravenous amiodarone. This case reports on some negative consequences of inappropriate intensive care unit admissions and how they could have been avoided.

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A case of tuberculous gumma: there is more to it than meets the eye

We present a case of a young girl who presented with multiple cutaneous abscesses over 2 years at different sites. She had no constitutional symptoms or history of tuberculosis. On investigation, she was found to have rifampicin-sensitive tuberculosis presenting as tubercular gumma, a rare form of cutaneous tuberculosis which occurs due to haematogenous spread of the bacilli. She had disseminated disease involving the spinal column with associated psoas abscess. A thorough evaluation was done for immune-deficiency workup but was all negative. She was given antitubercular therapy and showed a good response to therapy at a follow-up of 1 month.

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Giant meningioma in skull radiograph

Description

A 35-year-old woman presented to peripheral hospital with loss of consciousness, urine incontinence and behavioural changes. The family noticed her impulsiveness and irritability 2 months prior to her presentation to the emergency department. No history of fever, vomiting, trauma or seizures. She was transferred to our hospital and on arrival, she was confused, with normal cranial nerve examination and equally reactive pupils. She had marked weakness in right upper and lower limbs. Because intracranial lesion was suspected, a lateral skull X-ray and a CT scan were done which revealed a large left frontal extra-axial calcified lesion with enlarged meningeal artery grooves (see figure 1 for the X-ray and figure 2 for the sagittal MRI). The patient underwent craniotomy and total removal of the meningioma with total weight of 347 g with pathological feature of psammomatous meningioma, WHO grade 1 (figure 3).1 She tolerated...

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Community-acquired Pseudomonas aeruginosa meningitis

Gram-negative bacilli such as Pseudomonas aeruginosa are a rare cause of meningitis. Patients developing P. aeruginosa meningitis most commonly have a history of neurosurgical procedures. We report a patient who presented with community-acquired chronic meningitis secondary to P. aeruginosa, related to surgery for otosclerosis 5 years previously.

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Result of Health Illiteracy and Cultural Stigma: Fourniers Gangrene, a Urological Emergency

A 63-year-old Caucasian man presents to his regional hospital 8 days postinsertion of beads in his urethra, causing Fournier's gangrene of the penis and delayed surgical management of his gangrene. The reasons for his delay are cultural stigma associated with sexual practices and health illiteracy.

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Anaesthesia and orphan disease: airway and anaesthetic management in Huntingtons disease

We present a case that highlights the issues surrounding the delivery of a safe general anaesthetic to a patient with Huntington's disease (HD) and bulbar dysfunction. In the case of a 46-year-old patient undergoing laparoscopic percutaneous endoscopic gastrostomy tube insertion, we discuss the rationale behind our chosen method and anaesthetic agents as well as airway issues specific to HD. In a patient whose condition would not allow for an awake fibreoptic intubation, we opted for a modified rapid sequence induction. Special considerations were made with regard to muscle relaxation given the complications associated with inadequate paralysis and reversal in patients with HD. The technique we describe may also apply to other patient categories, such as patients with movement disorders, bulbar dysfunction and dementia.

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Rare presentation of an old bug

We highlight a rare presentation of Legionella infection in a 77-year-old woman with a clinical diagnosis of giant cell arteritis 2 months prior to presentation. She was started on 60 mg prednisone that was tapered to 10 mg after 4 weeks following her diagnosis. She presented with a 1-month progressive dyspnoea in the absence of any other symptoms. Her exposure history was significant only for a recent trip to Florida where she stayed at a hotel. Initial laboratory workup was significant for hyponatraemia (127 mmol/L). Workup including bronchoalveolar lavage (BAL) and induced sputum for gram stain, acid fast stain and bacterial culture were negative for Pneumocystis jirovecii pneumonia and other opportunistic infectious agents. However, BAL was positive for Legionella pneumophila via PCR that was confirmed by a positive urinary Legionella antigen. The patient received treatment with levofloxacin that led to full resolution of her symptoms.

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Unusual cause of saddle nose

Description

A 53-year-old female presented with a 2-week history of shortness of breath, cough and fever. Over the past 6 months, she reported painful tongue ulcers and pain in her nose, accompanied with nasal crusting and yellowish discharge. She had a history of pulmonary coccidioidomycosis, diagnosed 10 years ago, and she was treated with antifungal regimen. Physical examination revealed rhonchi bilaterally, multiple shallow ulcerative lesions on her tongue and a saddle nose deformity (figure 1A). CT of the chest demonstrated extensive ground-glass opacities with areas of nodular consolidation. Given her symptoms and history of coccidioidomycosis, nasal cavity biopsy was performed that revealed focal ulceration, non-specific inflammation with many cocci spherules, confirmed by Grocott's methenamine silver stain (figure 1B). Cultures from the lesions and the sputum grew Coccidioides immitis. Treatment with fluconazole 400 mg daily was initiated, and after several days her symptoms improved. 

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Gentamicin-vancomycin-colistin local antibiotherapy in a cement spacer in a 54-year-old haemophilic patient with relapsing plurimicrobial severe prosthetic joint infection

Description

A 54-year-old patient with haemophilia and hepatitis C virus infection experienced acute left prosthetic joint infection due to Klebsiella pneumoniae and Staphylococcus aureus following unipolar exchange in September 2015. As the outcome was not favourable with bloody discharge despite haemophilic factor substitution, a new local debridement was performed in May 2016 and multidrug-resistant Enterobacter asburiae (only susceptible to imipenem, colistin, amikacin and fosfomycin) and Corynebacterium striatum (only susceptible to vancomycin, rifampin and linezolid) grew in cultures. As explantation was considered too risky due to the potential bleeding, systemic intravenous treatment was proposed with imipenem (3 g/day), vancomycin (2.5 g/day) and fosfomycin (12 g/day). After 3 months of therapy, the bloody discharge persisted. One month after discontinuation of antibiotics, the patient presented a large 'bourgeon charnu' with impressive bloody discharge (figure 1A). X-ray revealed trochanter osteolysis, without prosthesis loosening (figure 1B). Prosthesis explantation was performed, and a...

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Primary hepatic hemangioendothelioma in a patient with Budd-Chiari syndrome

A 36-year-old woman was diagnosed with compensated cirrhosis of liver secondary to Budd-Chiari syndrome (BCS) and had undergone stenting of a thrombosed left hepatic vein. Eight months later, she presented with jaundice and right upper quadrant pain. CT revealed multiple focal lesions in the liver, which on biopsy proved to be hepatic hemangioendothelioma (HHE). Her liver disease and ascites progressively increased. Four months later, magnetic resonance cholangiopancreatography showed an advanced stage of HHE with infiltration of the common bile duct and vascular invasion with a blocked stent, with metastasis to the spleen and dorsolumbar vertebrae. We believe this is the first reported case of an HHE developing in the background of BCS.

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Amyands hernia detected incidentally in two patients

The appendix is rarely present inside the inguinal hernia sac. The risk of appendicitis increases in these patients since the blood supply to the appendix can be impaired. The condition is frequently asymptomatic, and even if symptomatic it gives rise to non-specific symptoms. There is no specific laboratory finding. Diagnosis is frequently made with radiological imaging. We report two cases diagnosed as Amyand's hernia with CT.

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Re-correction osteotomy with osteophyte graft for correction loss with non-union after high tibial osteotomy

A 68-year-old man with right knee varus osteoarthritis was treated by lateral closed-wedge high tibial osteotomy. A correction loss with non-union occurred 6 months after surgery and a re-correction osteotomy was performed. Removing the proximal screws of the lateral plate, a medial opening-wedge re-osteotomy was performed. Arthroscopically harvested osteophytes were used to fill the gap after opening. An additional medial locking plate was installed on the medial side. Finally, the proximal lateral screws were reinserted and locked again. Mature trabecular continuity was obtained in the gap by 6 months, and there was no varus deformity 4 years after re-correction. Re-correction osteotomy could be a viable treatment when lateral compartment osteoarthritis has not progressed and good range of motion still exists. Osteophyte grafting may be an effective option not only to avoid iliac bone grafting but also to promote bone healing in re-osteotomy.

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Honeycomb and necklace signs in liver abscesses secondary to melioidosis

Melioidosis is endemic in Southeast Asia and tropical Australia with varying clinical features from benign skin lesions to fatal septicaemia. Imaging plays an important role in evaluation of the melioid liver abscesses. A 45-year-old man with underlying diabetes presented with fever and lethargy for 2 weeks and abdominal pain for 2 days. His liver was enlarged on examination. Blood investigations revealed mild leucocytosis and raised liver enzymes. Ultrasound showed multiple multiloculated hypoechoic lesions throughout the liver and spleen. CT of abdomen confirmed that some liver lesions were made up of asymmetric locules of varying sizes (honeycomb sign), while others had hypodense centre with small symmetric peripheral locules in radial fashion (necklace sign). Blood culture was positive for Burkholderia pseudomallei. He was subsequently treated with ceftazidime for a month followed by oral trimethoprim–sulfamethoxazole for 3 months. Follow-up CT of abdomen a month after diagnosis and treatment showed resolving hepatic and splenic lesions.

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Memory of World War II with loud atypical friction rub due to pulmonary asbestosis

Description

An 87-year-old healthy woman was admitted to our hospital with progressive dyspnoea on effort since the preceding 6 months. She had a history of total gastrectomy, performed 5 years earlier. She was a non-smoker and worked as a business manager.

She did not abuse drugs. During World War II, when she was 15 years old, she worked for a year in a factory manufacturing the brake pads of fighter planes using copious amounts of asbestos. Physical examination revealed the presence of a 'hard and high-pitched knocking sound during the early inspiratory phase', in the right middle to lower lung fields, anteriorly (online ).

A chest radiograph showed massive calcifications in both lungs, including at the level of the diaphragm (figure 1A). Thoracic CT confirmed that these calcifications corresponded to the deposition of massive pleural plaques (figure 1B, C), especially in the visceral pleura (figure...

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Clinicopathologic implications of CD8 + /Foxp3 + ratio and miR-574-3p/PD-L1 axis in spinal chordoma patients

Abstract

Currently, little is known about the interactions between microRNAs (miRNAs) and the PD-1/PD-L1 signaling pathway in chordoma, and data discussing the role of the immune milieu in chordoma prognosis are limited. We aimed to analyze the relationship between PD-L1, miR-574-3p, microenvironmental tumor-infiltrating lymphocytes (TILs) and clinicopathological features of spinal chordoma patients. PD-L1 expression and TILs (including Foxp3⁺, CD8⁺, PD-1⁺ and PD-L1⁺) were assessed by immunohistochemistry in tumor specimens of 54 spinal chordoma patients. MiRNAs microarray and bioinformatical analysis were used to identify miRNAs potentially regulating PD-L1 expression, which were further validated by quantitative RT-PCR. miR-574-3p was identified to potentially regulate PD-L1 expression in chordoma, which inversely correlated with PD-L1. Positive PD-L1 expression on tumor cells was associated with advanced stages (P = 0.041) and TILs infiltration (P = 0.005), whereas decreased miR-574-3p level correlated with higher muscle invasion (P = 0.012), more severe tumor necrosis (P = 0.022) and poor patient survival. Importantly, a patient subgroup with PD-L1⁺/miR-574-3p^low chordoma phenotype was significantly associated with worse local recurrence-free survival (LRFS) (P = 0.026). PD-1⁺ TILs density was associated with surrounding muscle invasion (P = 0.014), and independently portended poor LRFS (P = 0.040), while PD-L1⁺ TILs showed tendencies of less aggressive clinical outcomes. Multivariate analysis of OS only found CD8⁺/Foxp3⁺ ratio to be independent prognostic factor (P = 0.022). These findings may be useful to stratify patients into prognostic groups and provide a rationale for the use of checkpoint blockade therapy, possibly by administering miR-574-3p mimics, in spinal chordoma.

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Clinicopathologic implications of CD8 + /Foxp3 + ratio and miR-574-3p/PD-L1 axis in spinal chordoma patients

Abstract

Currently, little is known about the interactions between microRNAs (miRNAs) and the PD-1/PD-L1 signaling pathway in chordoma, and data discussing the role of the immune milieu in chordoma prognosis are limited. We aimed to analyze the relationship between PD-L1, miR-574-3p, microenvironmental tumor-infiltrating lymphocytes (TILs) and clinicopathological features of spinal chordoma patients. PD-L1 expression and TILs (including Foxp3⁺, CD8⁺, PD-1⁺ and PD-L1⁺) were assessed by immunohistochemistry in tumor specimens of 54 spinal chordoma patients. MiRNAs microarray and bioinformatical analysis were used to identify miRNAs potentially regulating PD-L1 expression, which were further validated by quantitative RT-PCR. miR-574-3p was identified to potentially regulate PD-L1 expression in chordoma, which inversely correlated with PD-L1. Positive PD-L1 expression on tumor cells was associated with advanced stages (P = 0.041) and TILs infiltration (P = 0.005), whereas decreased miR-574-3p level correlated with higher muscle invasion (P = 0.012), more severe tumor necrosis (P = 0.022) and poor patient survival. Importantly, a patient subgroup with PD-L1⁺/miR-574-3p^low chordoma phenotype was significantly associated with worse local recurrence-free survival (LRFS) (P = 0.026). PD-1⁺ TILs density was associated with surrounding muscle invasion (P = 0.014), and independently portended poor LRFS (P = 0.040), while PD-L1⁺ TILs showed tendencies of less aggressive clinical outcomes. Multivariate analysis of OS only found CD8⁺/Foxp3⁺ ratio to be independent prognostic factor (P = 0.022). These findings may be useful to stratify patients into prognostic groups and provide a rationale for the use of checkpoint blockade therapy, possibly by administering miR-574-3p mimics, in spinal chordoma.

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Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4

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Clinicopathologic implications of CD8 + /Foxp3 + ratio and miR-574-3p/PD-L1 axis in spinal chordoma patients

Abstract

Currently, little is known about the interactions between microRNAs (miRNAs) and the PD-1/PD-L1 signaling pathway in chordoma, and data discussing the role of the immune milieu in chordoma prognosis are limited. We aimed to analyze the relationship between PD-L1, miR-574-3p, microenvironmental tumor-infiltrating lymphocytes (TILs) and clinicopathological features of spinal chordoma patients. PD-L1 expression and TILs (including Foxp3⁺, CD8⁺, PD-1⁺ and PD-L1⁺) were assessed by immunohistochemistry in tumor specimens of 54 spinal chordoma patients. MiRNAs microarray and bioinformatical analysis were used to identify miRNAs potentially regulating PD-L1 expression, which were further validated by quantitative RT-PCR. miR-574-3p was identified to potentially regulate PD-L1 expression in chordoma, which inversely correlated with PD-L1. Positive PD-L1 expression on tumor cells was associated with advanced stages (P = 0.041) and TILs infiltration (P = 0.005), whereas decreased miR-574-3p level correlated with higher muscle invasion (P = 0.012), more severe tumor necrosis (P = 0.022) and poor patient survival. Importantly, a patient subgroup with PD-L1⁺/miR-574-3p^low chordoma phenotype was significantly associated with worse local recurrence-free survival (LRFS) (P = 0.026). PD-1⁺ TILs density was associated with surrounding muscle invasion (P = 0.014), and independently portended poor LRFS (P = 0.040), while PD-L1⁺ TILs showed tendencies of less aggressive clinical outcomes. Multivariate analysis of OS only found CD8⁺/Foxp3⁺ ratio to be independent prognostic factor (P = 0.022). These findings may be useful to stratify patients into prognostic groups and provide a rationale for the use of checkpoint blockade therapy, possibly by administering miR-574-3p mimics, in spinal chordoma.

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Clinicopathologic implications of CD8 + /Foxp3 + ratio and miR-574-3p/PD-L1 axis in spinal chordoma patients

Abstract

Currently, little is known about the interactions between microRNAs (miRNAs) and the PD-1/PD-L1 signaling pathway in chordoma, and data discussing the role of the immune milieu in chordoma prognosis are limited. We aimed to analyze the relationship between PD-L1, miR-574-3p, microenvironmental tumor-infiltrating lymphocytes (TILs) and clinicopathological features of spinal chordoma patients. PD-L1 expression and TILs (including Foxp3⁺, CD8⁺, PD-1⁺ and PD-L1⁺) were assessed by immunohistochemistry in tumor specimens of 54 spinal chordoma patients. MiRNAs microarray and bioinformatical analysis were used to identify miRNAs potentially regulating PD-L1 expression, which were further validated by quantitative RT-PCR. miR-574-3p was identified to potentially regulate PD-L1 expression in chordoma, which inversely correlated with PD-L1. Positive PD-L1 expression on tumor cells was associated with advanced stages (P = 0.041) and TILs infiltration (P = 0.005), whereas decreased miR-574-3p level correlated with higher muscle invasion (P = 0.012), more severe tumor necrosis (P = 0.022) and poor patient survival. Importantly, a patient subgroup with PD-L1⁺/miR-574-3p^low chordoma phenotype was significantly associated with worse local recurrence-free survival (LRFS) (P = 0.026). PD-1⁺ TILs density was associated with surrounding muscle invasion (P = 0.014), and independently portended poor LRFS (P = 0.040), while PD-L1⁺ TILs showed tendencies of less aggressive clinical outcomes. Multivariate analysis of OS only found CD8⁺/Foxp3⁺ ratio to be independent prognostic factor (P = 0.022). These findings may be useful to stratify patients into prognostic groups and provide a rationale for the use of checkpoint blockade therapy, possibly by administering miR-574-3p mimics, in spinal chordoma.

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Clinicopathologic implications of CD8 + /Foxp3 + ratio and miR-574-3p/PD-L1 axis in spinal chordoma patients

Abstract

Currently, little is known about the interactions between microRNAs (miRNAs) and the PD-1/PD-L1 signaling pathway in chordoma, and data discussing the role of the immune milieu in chordoma prognosis are limited. We aimed to analyze the relationship between PD-L1, miR-574-3p, microenvironmental tumor-infiltrating lymphocytes (TILs) and clinicopathological features of spinal chordoma patients. PD-L1 expression and TILs (including Foxp3⁺, CD8⁺, PD-1⁺ and PD-L1⁺) were assessed by immunohistochemistry in tumor specimens of 54 spinal chordoma patients. MiRNAs microarray and bioinformatical analysis were used to identify miRNAs potentially regulating PD-L1 expression, which were further validated by quantitative RT-PCR. miR-574-3p was identified to potentially regulate PD-L1 expression in chordoma, which inversely correlated with PD-L1. Positive PD-L1 expression on tumor cells was associated with advanced stages (P = 0.041) and TILs infiltration (P = 0.005), whereas decreased miR-574-3p level correlated with higher muscle invasion (P = 0.012), more severe tumor necrosis (P = 0.022) and poor patient survival. Importantly, a patient subgroup with PD-L1⁺/miR-574-3p^low chordoma phenotype was significantly associated with worse local recurrence-free survival (LRFS) (P = 0.026). PD-1⁺ TILs density was associated with surrounding muscle invasion (P = 0.014), and independently portended poor LRFS (P = 0.040), while PD-L1⁺ TILs showed tendencies of less aggressive clinical outcomes. Multivariate analysis of OS only found CD8⁺/Foxp3⁺ ratio to be independent prognostic factor (P = 0.022). These findings may be useful to stratify patients into prognostic groups and provide a rationale for the use of checkpoint blockade therapy, possibly by administering miR-574-3p mimics, in spinal chordoma.

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CCL26 participates in the PRL-3-induced promotion of colorectal cancer invasion by stimulating tumor-associated macrophage infiltration

Both phosphatase of regenerating liver-3 (PRL-3) and tumor-associated macrophages (TAMs) influence cancer progression. Whether PRL-3 plays a critical role in colorectal cancer (CRC) invasion and metastasis by inducing TAM infiltration remains unclear. In the present study, we investigated the effects of chemokine ligand 26 (CCL26) on TAM infiltration and CRC invasion and the underlying mechanism in CRC cells by overexpressing or silencing PRL-3. We found that PRL-3 up-regulated CCL26 expression correlatively and participated in cell migration, according to the results of gene ontology analysis. Additionally, immunohistochemistry (IHC) analysis results indicated that the PRL-3 and CCL26 levels were positively correlated and elevated in stage III and IV CRC tissues and were associated with a worse prognosis in CRC patients. Furthermore, we demonstrated that CCL26 induced TAM infiltration by CCL26 binding to the CCR3 receptor. When LoVo-P and HT29-C cells were co-cultured with TAMs, CCL26 binding to the CCR3 receptor enhanced the invasiveness of LoVo-P and HT29-C cells by mobilizing intracellular Ca2+of TAMs to increase the expression of IL-6 and IL-8. Additionally, IHC results indicated that protein levels of CCR3 and TAMs counts were higher in stage III and IV CRC tissues and correlated with CCL26. Moreover, similar results were observed in vivo using mice injected with LoVo-P and HT29-C cells. These data indicate that PRL-3 may represent a potential prognostic marker that promotes CRC invasion and metastasis by up-regulating CCL26 to induce TAM infiltration.

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Combinatorial treatment with mTOR inhibitors and streptozotocin leads to synergistic in vitro and in vivo antitumor effects in insulinoma cells

Streptozotocin (STZ)-based chemotherapy is the first-line chemotherapy recommended for advanced pancreatic neuroendocrine tumors (pNETs), while targeted therapies, including mTOR inhibitors, are available in second-line treatment. Unfortunately objective response rates to both treatments are limited. Since mTOR pathway activation, commonly observed in pNETs, has been reported as one of the major mechanisms accounting for chemoresistance, we investigated the potential benefit of mTOR inhibition combined with STZ treatment in a subset of pNETs, namely insulinomas. To evaluate the potential of mTOR inhibition in combination with STZ, we selected four different inhibitors acting at various levels of the pathway (everolimus: inhibition of mTORC1, MK-2206: inhibition of AKT, BKM120: inhibition of PI3K, mTORC1 and mTORC2, and BEZ235: inhibition of mTORC1 and mTORC2). Effects on cell viability and apoptosis were assessed in insulinoma cell lines INS-1E (rat) and MIN6 (mouse) in vitro and were confirmed in vivo by using a mouse model of hepatic tumor dissemination after intrasplenic xenograft. In vitro, all four combinations display synergistic effects. These combinations lead to heterogeneous mTOR pathway inhibition, in agreement with their respective target, and increased apoptosis. In vivo, tumor growth in the liver was significantly inhibited by combining STZ with everolimus (P=0.0014), BKM120 (P=0.0092) or BEZ235 (P=0.008) as compared to each agent alone. These results suggest that targeting the mTOR pathway in combination with STZ could be of potential benefit for insulinomas and pNET patients and thus support further clinical investigations.

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CCL26 participates in the PRL-3-induced promotion of colorectal cancer invasion by stimulating tumor-associated macrophage infiltration

Both phosphatase of regenerating liver-3 (PRL-3) and tumor-associated macrophages (TAMs) influence cancer progression. Whether PRL-3 plays a critical role in colorectal cancer (CRC) invasion and metastasis by inducing TAM infiltration remains unclear. In the present study, we investigated the effects of chemokine ligand 26 (CCL26) on TAM infiltration and CRC invasion and the underlying mechanism in CRC cells by overexpressing or silencing PRL-3. We found that PRL-3 up-regulated CCL26 expression correlatively and participated in cell migration, according to the results of gene ontology analysis. Additionally, immunohistochemistry (IHC) analysis results indicated that the PRL-3 and CCL26 levels were positively correlated and elevated in stage III and IV CRC tissues and were associated with a worse prognosis in CRC patients. Furthermore, we demonstrated that CCL26 induced TAM infiltration by CCL26 binding to the CCR3 receptor. When LoVo-P and HT29-C cells were co-cultured with TAMs, CCL26 binding to the CCR3 receptor enhanced the invasiveness of LoVo-P and HT29-C cells by mobilizing intracellular Ca2+of TAMs to increase the expression of IL-6 and IL-8. Additionally, IHC results indicated that protein levels of CCR3 and TAMs counts were higher in stage III and IV CRC tissues and correlated with CCL26. Moreover, similar results were observed in vivo using mice injected with LoVo-P and HT29-C cells. These data indicate that PRL-3 may represent a potential prognostic marker that promotes CRC invasion and metastasis by up-regulating CCL26 to induce TAM infiltration.

http://ift.tt/2gSJm4u

Combinatorial treatment with mTOR inhibitors and streptozotocin leads to synergistic in vitro and in vivo antitumor effects in insulinoma cells

Streptozotocin (STZ)-based chemotherapy is the first-line chemotherapy recommended for advanced pancreatic neuroendocrine tumors (pNETs), while targeted therapies, including mTOR inhibitors, are available in second-line treatment. Unfortunately objective response rates to both treatments are limited. Since mTOR pathway activation, commonly observed in pNETs, has been reported as one of the major mechanisms accounting for chemoresistance, we investigated the potential benefit of mTOR inhibition combined with STZ treatment in a subset of pNETs, namely insulinomas. To evaluate the potential of mTOR inhibition in combination with STZ, we selected four different inhibitors acting at various levels of the pathway (everolimus: inhibition of mTORC1, MK-2206: inhibition of AKT, BKM120: inhibition of PI3K, mTORC1 and mTORC2, and BEZ235: inhibition of mTORC1 and mTORC2). Effects on cell viability and apoptosis were assessed in insulinoma cell lines INS-1E (rat) and MIN6 (mouse) in vitro and were confirmed in vivo by using a mouse model of hepatic tumor dissemination after intrasplenic xenograft. In vitro, all four combinations display synergistic effects. These combinations lead to heterogeneous mTOR pathway inhibition, in agreement with their respective target, and increased apoptosis. In vivo, tumor growth in the liver was significantly inhibited by combining STZ with everolimus (P=0.0014), BKM120 (P=0.0092) or BEZ235 (P=0.008) as compared to each agent alone. These results suggest that targeting the mTOR pathway in combination with STZ could be of potential benefit for insulinomas and pNET patients and thus support further clinical investigations.

http://ift.tt/2imeMnx

Statin Use and Breast Cancer Prognosis in Black and White Women

Abstract

Studies show decreased risk of breast cancer recurrence and improved survival with statin use, but data on racial disparities regarding breast cancer prognosis and statin use are lacking. Our objective was to investigate if racial disparities in breast cancer prognosis can be partially explained by differences in pre-diagnosis statin use. Patients were identified from a prospective, multicenter study examining the effects of metabolic factors on breast cancer prognosis in Black and White women. Statin use, prognosis (as measured by Nottingham Prognostic Index), anthropometric, tumor, and socio-demographic characteristics were examined. Five hundred eighty-seven women (487 White, 100 Black) with newly diagnosed primary invasive breast cancer were recruited. Obesity was more prevalent in Black women than White women (47 vs 19%, p < 0.01); both groups had similar low-density lipoprotein (LDL) cholesterol levels (113 ± 41 vs 113 ± 36 mg/dl, p = 0.90). More Black women used statins than White women (18 vs 11%, p = 0.06). Black women had a worse prognosis in an adjusted model than White women (OR 2.13 95% CI 1.23–3.67). Statin use was not associated with prognosis in unadjusted (OR 1.03, 95% CI 0.53–2.0) and adjusted models (OR 1.14, 95% CI 0.56–2.31). In women with newly diagnosed breast cancer, Black women were more likely to be treated with statins than White women, contrary to previous studies. Black women had worse prognosis than White women, but this difference was not explained by differences in pre-diagnosis statin use. Our study suggests that differences in pre-diagnosis statin use do not contribute to racial disparities in breast cancer prognosis.

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Liquid Biopsies Using Plasma Exosomal Nucleic Acids and Plasma Cell-Free DNA compared with Clinical Outcomes of Patients with Advanced Cancers

Purpose: Blood-based liquid biopsies offer easy access to genomic material for molecular diagnostics in cancer. Commonly used cell-free DNA (cfDNA) originates from dying cells. Exosomal nucleic acids (exoNA) originate from living cells, which can better reflect underlying cancer biology. Experimental Design: Next-generation sequencing (NGS) was used to test exosomal nucleic acids (exoNA), and droplet digital PCR (ddPCR) and BEAMing PCR were used to test cfDNA for BRAF V600, KRAS G12/G13, and EGFR exon19del/L858R mutations in 43 patients with progressing advanced cancers. Results were compared with clinical testing of archival tumor tissue and clinical outcomes. Results: Forty-one patients had BRAF, KRAS, or EGFR mutations in tumor tissue. These mutations were detected by NGS in 95% of plasma exoNA samples, by ddPCR in 92% of cfDNA samples, and by BEAMing in 97% cfDNA samples. NGS of exoNA did not detect any mutations not present in tumor, whereas ddPCR and BEAMing detected 1 and 2 such mutations, respectively. Compared with patients with high exoNA mutation allelic frequency (MAF), patients with low MAF had longer median survival (11.8 vs. 5.9 months; P=0.006) and time to treatment failure (7.4 vs. 2.2 months; P=0.009). A low amount of exoNA was associated with partial response and stable disease ≥6 months P=0.006). Conclusions: NGS of plasma exoNA for common BRAF, KRAS, and EGFR mutations has high sensitivity compared with clinical testing of archival tumor and testing of plasma cfDNA. Low exoNA MAF is an independent prognostic factor for longer survival.

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A multicenter phase I study evaluating dual PI3K and BRAF inhibition with PX-866 and vemurafenib in patients with advanced BRAF V600 mutant solid tumors

Purpose: The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination. Experimental Design: We conducted a phase I, open-label, dose escalation study in patients with advanced BRAF V600 mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment. Results: 24 patients were enrolled. The most common treatment-related adverse events were gastrointestinal side effects. One dose limiting toxicity (DLT) of grade 3 rash and one DLT of grade 3 pancreatitis were observed in cohort 2 (PX-866 6mg daily; vemurafenib 960mg twice daily) and cohort 3 (PX-866 8mg daily; vemurafenib 960mg twice daily), respectively. Of 23 response evaluable patients, 7 had confirmed partial responses (PRs), 10 had stable disease and 6 had disease progression. Decreases in intra-tumoral pAKT expression were observed following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss by immunohistochemistry (80% vs 58%) and pathogenic PTEN mutations and/or deletions (57% vs 25%). Two patients with durable PRs had an increase in intra-tumoral CD8 T-cell infiltration following treatment with PX-866. Conclusions: PX-866 was well tolerated at its maximal tolerated single-agent dose when given in combination with a modified dose of vemurafenib (720mg twice daily). Response to treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to increase CD8 T-cell infiltration in some patients.

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Statin Use and Breast Cancer Prognosis in Black and White Women

Abstract

Studies show decreased risk of breast cancer recurrence and improved survival with statin use, but data on racial disparities regarding breast cancer prognosis and statin use are lacking. Our objective was to investigate if racial disparities in breast cancer prognosis can be partially explained by differences in pre-diagnosis statin use. Patients were identified from a prospective, multicenter study examining the effects of metabolic factors on breast cancer prognosis in Black and White women. Statin use, prognosis (as measured by Nottingham Prognostic Index), anthropometric, tumor, and socio-demographic characteristics were examined. Five hundred eighty-seven women (487 White, 100 Black) with newly diagnosed primary invasive breast cancer were recruited. Obesity was more prevalent in Black women than White women (47 vs 19%, p < 0.01); both groups had similar low-density lipoprotein (LDL) cholesterol levels (113 ± 41 vs 113 ± 36 mg/dl, p = 0.90). More Black women used statins than White women (18 vs 11%, p = 0.06). Black women had a worse prognosis in an adjusted model than White women (OR 2.13 95% CI 1.23–3.67). Statin use was not associated with prognosis in unadjusted (OR 1.03, 95% CI 0.53–2.0) and adjusted models (OR 1.14, 95% CI 0.56–2.31). In women with newly diagnosed breast cancer, Black women were more likely to be treated with statins than White women, contrary to previous studies. Black women had worse prognosis than White women, but this difference was not explained by differences in pre-diagnosis statin use. Our study suggests that differences in pre-diagnosis statin use do not contribute to racial disparities in breast cancer prognosis.

http://ift.tt/2yCadf4

High-sensitive troponin T assay can predict anthracycline- and trastuzumab-induced cardiotoxicity in breast cancer patients

Abstract

Background

Trastuzumab following anthracycline causes cardiotoxicity in up to 28% of patients. Although the cardiotoxicity is often irreversible once cardiac dysfunction is detected, the early predictor has not been established yet.

Methods

We prospectively observed breast cancer patients treated with anthracycline or trastuzumab at Tonan Hospital. All patients underwent echocardiography and blood sampling at baseline, and every three months during chemotherapy. Cardiotoxicity was defined as a decline in left ventricular ejection fraction >10% points.

Results

Of 40 patients, 34 patients (85%) were treated with anthracycline (epirubicin), 18 (45%) with trastuzumab, and 12 (30%) with both agents. Cardiotoxicity was observed in four patients (10%), who were all treated with both agents. The absolute levels of high-sensitive troponin T (hs-TnT) were increased in all four patients with cardiotoxicity, and all the highest points were observed before or at the time of detection of cardiotoxicity. The highest level of hs-TnT was not significantly different in patients with and without cardiotoxicity. "Hs-TnT increment from baseline to the highest value" and "hs-TnT integration value above baseline" were significantly greater in patients with cardiotoxicity (0.039 vs. 0.007 ng/mL, P = 0.046, 0.113 vs. 0.022 ng months/mL, P = 0.013, respectively). The integration value had 100% sensitivity and specificity with a cutoff level at 0.070 ng months/mL.

Conclusions

Hs-TnT assay may be able to predict anthracycline- and trastuzumab-induced cardiotoxicity in breast cancer patients, and the hs-TnT increment or hs-TnT integration value above baseline was more reliable than the absolute value.

http://ift.tt/2gwYGqT

A phase II, multicenter, single-arm study of tri-weekly low-dose nanoparticle albumin-bound paclitaxel chemotherapy for patients with metastatic or recurrent breast cancer

Abstract

Background

Nanoparticle albumin-bound (nab)-paclitaxel is a solvent-free formulation of paclitaxel that is bound to albumin and has demonstrated improved progression free survival in previous studies of breast cancer. However, it is difficult to treat Japanese patients with metastatic or recurrent breast cancer with the recommended dose of 260 mg/m² of (nab)-paclitaxel for more than six cycles due to the occurrence of adverse events. To evaluate the treatment continuity and safety of low-dose nab-paclitaxel, we conducted a phase II study of nab-paclitaxel in patients with metastatic or recurrent breast cancer who had received up to one prior chemotherapy.

Patients and methods

Treatment included low doses of 180 mg/m² nab-paclitaxel that were administered on day 1 of each 3-week cycle to 35 patients. The primary endpoint was the completion rate of six cycles of treatment.

Results

A total of 35 eligible patients were enrolled and received a median of eight (range 2–24) cycles of low-dose nab-paclitaxel therapy. The completion rate of six cycles of treatment was 66%. ORR and clinical benefit rate was 23 and 71%, respectively. Median PFS was 6.5 months and median OS was 44 months. Adverse events were relatively mild. Commonly observed grade 3/4 adverse events were neutropenia (46%), leukopenia (9%), and hypertension (3%). No grade 3-4 peripheral sensory neuropathy occurred.

Conclusion

Treatment with a low dose of nab-paclitaxel once every 3 weeks was tolerable and of acceptable safety and might be beneficial for patients with metastatic or recurrent breast cancer.

http://ift.tt/2yCR8Jz

Therapeutic alliance and treatment outcome in psychodynamic psychotherapy of depressed breast cancer patients: the same old story or different from other populations?

Abstract

Background

A good therapeutic alliance is associated with better treatment outcomes in diverse types of psychotherapy and patient populations, but little is known about therapeutic alliance in psychotherapies with cancer patients. This study examines the association of therapeutic alliance and treatment outcome in short term psychodynamic psychotherapy (STPP) for breast cancer patients.

Methods

Within a randomized controlled trial, 47 completers of STPP could be included in the analyses. The therapeutic alliance was assessed by patients and therapists at treatment termination with the Helping Alliance Questionnaire. Outcome was defined as no diagnosis of depression assessed with Structured Clinical Interview for DSM-IV (SCID-I) and a reduction of the HADS-depression score by at least two points at treatment termination.

Results

Patients' alliance ratings were significantly associated with outcome (r = 0.46, p = 0.015), while, in contrast to findings in non-cancer populations, therapists' ratings were unrelated. There was no association between patients' and therapists' ratings of therapeutic alliance. Especially success and working related aspects of patients' alliance scores were associated with outcome. Patients' and therapists' alliance scores were unrelated to any of their baseline characteristics, therapist characteristic or treatment variables.

Conclusion

We conclude that therapists should regularly assess the quality of patients' perceived therapeutic alliance in the course of psychotherapy with breast cancer patients to improve psychotherapy outcome. The breast cancer patients' perspective should be actively inquired and considered throughout treatment by therapists. Possible discrepancies between both judgements can be addressed in treatment.

http://ift.tt/2yCz829

Acknowledgement to reviewers 2017

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Clinicopathological and prognostic significance of Ki-67 immunohistochemical expression of distant metastatic lesions in patients with metastatic breast cancer

Abstract

Background

Surgical biopsy of metastatic lesions followed by pathological confirmation for the investigation of biomarkers is occasionally proposed as an effective strategy in the treatment of metastatic breast cancer. However, few reports have examined Ki-67 immunohistochemical expression in distant metastatic lesions of breast cancer patients. This study aimed to investigate the clinicopathological significance of subtypes and Ki-67 immunohistochemical expression in metastatic breast cancer lesions.

Methods

We retrospectively studied surgical specimens of primary breast cancer tumors and their corresponding metastatic lesions from patients (n = 68) who underwent surgery for primary breast cancer tumors between December 1977 and March 2013. Tissue microarrays were constructed using primary and metastatic lesions, and were stained with antibodies against estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67. We also examined the clinicopathological characteristics and outcome measures of patients with metastatic breast cancer using primary and paired metastatic lesions.

Results

Compared with the primary lesions, there was no significant difference in subtypes in the metastatic lesions according to metastatic sites. Metastatic lesions of the brain, viscera, and bone exhibited slightly higher levels of Ki-67 immunohistochemical expression compared with primary lesions. A Cox proportional hazards model using multivariate analysis demonstrated that high Ki-67 immunohistochemical expression in distant metastatic lesions was associated with poorer overall survival outcomes after biopsy of recurrence lesion (hazard ratio 2.307; 95% confidence interval 1.207–4.407, P = 0.011).

Conclusions

High Ki-67 immunohistochemical expression levels in distant metastatic lesions were independently associated with poorer overall survival outcomes after biopsy of recurrence lesion in breast cancer patients.

http://ift.tt/2yDtixt

Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM

Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. Results: We observed that mesenchymal EGFR mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. De-repression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance "free" cellular BIM levels both led to re-sensitization of mesenchymal EGFR mutant cancers to EGFR inhibitors. This relationship between EMT and loss of BIM is not restricted to EGFR mutant cancers as it was also observed in KRAS mutant lung cancers and large datasets including different cancer subtypes. Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies.

http://ift.tt/2yvkrhO

Liquid Biopsies Using Plasma Exosomal Nucleic Acids and Plasma Cell-Free DNA compared with Clinical Outcomes of Patients with Advanced Cancers

Purpose: Blood-based liquid biopsies offer easy access to genomic material for molecular diagnostics in cancer. Commonly used cell-free DNA (cfDNA) originates from dying cells. Exosomal nucleic acids (exoNA) originate from living cells, which can better reflect underlying cancer biology. Experimental Design: Next-generation sequencing (NGS) was used to test exosomal nucleic acids (exoNA), and droplet digital PCR (ddPCR) and BEAMing PCR were used to test cfDNA for BRAF V600, KRAS G12/G13, and EGFR exon19del/L858R mutations in 43 patients with progressing advanced cancers. Results were compared with clinical testing of archival tumor tissue and clinical outcomes. Results: Forty-one patients had BRAF, KRAS, or EGFR mutations in tumor tissue. These mutations were detected by NGS in 95% of plasma exoNA samples, by ddPCR in 92% of cfDNA samples, and by BEAMing in 97% cfDNA samples. NGS of exoNA did not detect any mutations not present in tumor, whereas ddPCR and BEAMing detected 1 and 2 such mutations, respectively. Compared with patients with high exoNA mutation allelic frequency (MAF), patients with low MAF had longer median survival (11.8 vs. 5.9 months; P=0.006) and time to treatment failure (7.4 vs. 2.2 months; P=0.009). A low amount of exoNA was associated with partial response and stable disease ≥6 months P=0.006). Conclusions: NGS of plasma exoNA for common BRAF, KRAS, and EGFR mutations has high sensitivity compared with clinical testing of archival tumor and testing of plasma cfDNA. Low exoNA MAF is an independent prognostic factor for longer survival.

http://ift.tt/2gmUGFz

A multicenter phase I study evaluating dual PI3K and BRAF inhibition with PX-866 and vemurafenib in patients with advanced BRAF V600 mutant solid tumors

Purpose: The objectives of the study were to evaluate the safety of daily oral PX-866 in combination with twice daily vemurafenib and to identify potential predictive biomarkers for this novel combination. Experimental Design: We conducted a phase I, open-label, dose escalation study in patients with advanced BRAF V600 mutant solid tumors. PX-866 was administered on a continuous schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment biopsy after 1-week of PX-866 monotherapy for biomarker assessment. Results: 24 patients were enrolled. The most common treatment-related adverse events were gastrointestinal side effects. One dose limiting toxicity (DLT) of grade 3 rash and one DLT of grade 3 pancreatitis were observed in cohort 2 (PX-866 6mg daily; vemurafenib 960mg twice daily) and cohort 3 (PX-866 8mg daily; vemurafenib 960mg twice daily), respectively. Of 23 response evaluable patients, 7 had confirmed partial responses (PRs), 10 had stable disease and 6 had disease progression. Decreases in intra-tumoral pAKT expression were observed following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss by immunohistochemistry (80% vs 58%) and pathogenic PTEN mutations and/or deletions (57% vs 25%). Two patients with durable PRs had an increase in intra-tumoral CD8 T-cell infiltration following treatment with PX-866. Conclusions: PX-866 was well tolerated at its maximal tolerated single-agent dose when given in combination with a modified dose of vemurafenib (720mg twice daily). Response to treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to increase CD8 T-cell infiltration in some patients.

http://ift.tt/2yvkoTa

TLR4-mediated inflammation promotes KSHV-induced cellular transformation and tumorigenesis by activating the STAT3 pathway

Toll-like receptors (TLR) are conserved immune sensors mediating antimicrobial and antitumoral responses, but recent evidence implicates them in promoting carcinogenesis in certain cancers. Kaposi's sarcoma (KS) is caused by infection of Kaposi's sarcoma-associated herpesvirus (KSHV) and is characterized by uncontrolled neoangiogenesis and inflammation. Here we show that TLR4 is upregulated in KSHV-infected spindle tumor cells in human KS lesions. In a model of KSHV-induced cellular transformation, KSHV upregulated expression of TLR4, its adaptor MyD88, and coreceptors CD14 and MD2. KSHV induction of TLR4 was mediated by multiple viral microRNAs. Importantly, the TLR4 pathway was activated constitutively in KSHV-transformed cells resulting in chronic induction of IL-6, IL-1β and IL-18. Accordingly, IL-6 mediated constitutive activation of the STAT3 pathway, an essential event for uncontrolled cellular proliferation and transformation. TLR4 stimulation with lipopolysaccharides or live bacteria enhanced tumorigenesis while TLR4 antagonist CLI095 inhibited it. These results highlight an essential role of the TLR4 pathway and chronic inflammation in KSHV-induced tumorigenesis, which helps explain why HIV-infected patients, who frequently suffer from opportunistic bacterial infections and metabolic complications, frequently develop KS.

http://ift.tt/2gmT66B

TLR4-mediated inflammation promotes KSHV-induced cellular transformation and tumorigenesis by activating the STAT3 pathway

Toll-like receptors (TLR) are conserved immune sensors mediating antimicrobial and antitumoral responses, but recent evidence implicates them in promoting carcinogenesis in certain cancers. Kaposi's sarcoma (KS) is caused by infection of Kaposi's sarcoma-associated herpesvirus (KSHV) and is characterized by uncontrolled neoangiogenesis and inflammation. Here we show that TLR4 is upregulated in KSHV-infected spindle tumor cells in human KS lesions. In a model of KSHV-induced cellular transformation, KSHV upregulated expression of TLR4, its adaptor MyD88, and coreceptors CD14 and MD2. KSHV induction of TLR4 was mediated by multiple viral microRNAs. Importantly, the TLR4 pathway was activated constitutively in KSHV-transformed cells resulting in chronic induction of IL-6, IL-1β and IL-18. Accordingly, IL-6 mediated constitutive activation of the STAT3 pathway, an essential event for uncontrolled cellular proliferation and transformation. TLR4 stimulation with lipopolysaccharides or live bacteria enhanced tumorigenesis while TLR4 antagonist CLI095 inhibited it. These results highlight an essential role of the TLR4 pathway and chronic inflammation in KSHV-induced tumorigenesis, which helps explain why HIV-infected patients, who frequently suffer from opportunistic bacterial infections and metabolic complications, frequently develop KS.

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Understanding personal risk of oropharyngeal cancer: risk-groups for oncogenic oral HPV infection and oropharyngeal cancer

Abstract

Background

Incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing. There is interest in identifying healthy individuals most at risk for development of oropharyngeal cancer to inform screening strategies.

Patients and methods

All data are from 2009 to 2014, including 13 089 people ages 20–69 in the National Health and Nutrition Examination Survey (NHANES), oropharyngeal cancer cases from the Surveillance, Epidemiology, and End Results (SEER 18) registries (representing ∼28% of the US population), and oropharyngeal cancer mortality from National Center for Health Statistics (NCHS). Primary study outcomes are (i) prevalence of oncogenic HPV DNA in an oral rinse and gargle sample, and (ii) incident oropharyngeal squamous cell cancer.

Results

Oncogenic oral HPV DNA is detected in 3.5% of all adults age 20–69 years; however, the lifetime risk of oropharyngeal cancer is low (37 per 10 000). Among men 50–59 years old, 8.1% have an oncogenic oral HPV infection, 2.1% have an oral HPV16 infection, yet only 0.7% will 'ever' develop oropharyngeal cancer in their lifetime. Oncogenic oral HPV prevalence was higher in men than women, and increased with number of lifetime oral sexual partners and tobacco use. Men who currently smoked and had ≥5 lifetime oral sexual partners had 'elevated risk' (prevalence = 14.9%). Men with only one of these risk factors (i.e. either smoked and had 2–4 partners or did not smoke and had ≥5 partners) had 'medium risk' (7.3%). Regardless of what other risk factors participants had, oncogenic oral HPV prevalence was 'low' among those with only ≤1 lifetime oral sexual partner (women = 0.7% and men = 1.7%).

Conclusions

Screening based upon oncogenic oral HPV detection would be challenging. Most groups have low oncogenic oral HPV prevalence. In addition to the large numbers of individuals who would need to be screened to identify prevalent oncogenic oral HPV, the lifetime risk of developing oropharyngeal caner among those with infection remains low.

http://ift.tt/2iqvn9J

Comparison of Young Patients with Gastric Cancer in the United States and China

Abstract

Background

This study aimed to compare the clinicopathologic characteristics and stage-specific prognosis of young patients with gastric cancer (GC) after curative resection (R0) in the United States and China.

Methods

Data were collected on young patients (age ≤40 years) undergoing R0 resection at one U.S. (n = 79) and one Chinese (n = 257) institution. Patient, surgical, and pathologic variables and stage-specific survival rates were compared. Factors associated with 5-year disease-specific survival (DSS) were determined via multivariate analysis.

Results

Tumor location was most often proximal in U.S. patients and distal in Chinese patients. The Chinese patients had more advanced-stage tumors, with a greater number of positive lymph nodes identified. Preoperative chemotherapy was administered more often in the United States. The 5-year overall survival (p = 0.07) and DSS (p = 0.07) did not differ statistically between the U.S. and Chinese cohorts. Among the patients with early GC receiving surgery alone, DSS did not differ significantly between the two cohorts (p = 0.44). Among the patients with advanced GC, DSS was comparable between the U.S. patients receiving preoperative chemotherapy plus surgery and the Chinese patients receiving surgery plus postoperative chemotherapy (p = 0.85). Lauren classification, depth of invasion, number of metastatic lymph nodes, and type of gastrectomy, but not country, were independent predictors of DSS.

Conclusions

Tumor features and therapeutic strategies among young patients with GC differ between the United States and China. Survival is comparable between young patients with advanced GC receiving preoperative chemotherapy plus surgery in the United States and those receiving surgery plus postoperative chemotherapy in China, suggesting that the outcomes for young patients with GC are stage dependent but not country specific.

http://ift.tt/2yDC8eH

Comparison of Young Patients with Gastric Cancer in the United States and China

Abstract

Background

This study aimed to compare the clinicopathologic characteristics and stage-specific prognosis of young patients with gastric cancer (GC) after curative resection (R0) in the United States and China.

Methods

Data were collected on young patients (age ≤40 years) undergoing R0 resection at one U.S. (n = 79) and one Chinese (n = 257) institution. Patient, surgical, and pathologic variables and stage-specific survival rates were compared. Factors associated with 5-year disease-specific survival (DSS) were determined via multivariate analysis.

Results

Tumor location was most often proximal in U.S. patients and distal in Chinese patients. The Chinese patients had more advanced-stage tumors, with a greater number of positive lymph nodes identified. Preoperative chemotherapy was administered more often in the United States. The 5-year overall survival (p = 0.07) and DSS (p = 0.07) did not differ statistically between the U.S. and Chinese cohorts. Among the patients with early GC receiving surgery alone, DSS did not differ significantly between the two cohorts (p = 0.44). Among the patients with advanced GC, DSS was comparable between the U.S. patients receiving preoperative chemotherapy plus surgery and the Chinese patients receiving surgery plus postoperative chemotherapy (p = 0.85). Lauren classification, depth of invasion, number of metastatic lymph nodes, and type of gastrectomy, but not country, were independent predictors of DSS.

Conclusions

Tumor features and therapeutic strategies among young patients with GC differ between the United States and China. Survival is comparable between young patients with advanced GC receiving preoperative chemotherapy plus surgery in the United States and those receiving surgery plus postoperative chemotherapy in China, suggesting that the outcomes for young patients with GC are stage dependent but not country specific.

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Eligibility of Metastatic Pancreatic Cancer Patients for First-Line Palliative Intent nab-Paclitaxel Plus Gemcitabine Versus FOLFIRINOX

Objectives: The PRODIGE and MPACT trials showed superiority of FOLFIRINOX and nab-paclitaxel plus gemcitabine (NG) over gemcitabine alone, respectively. However, both had strict inclusion criteria. We sought to determine the characteristics of patients with metastatic pancreatic cancer (MPC) which inform the appropriateness of first-line chemotherapy FOLFIRINOX and NG in routine practice. Materials and Methods: Patients with MPC who initiated palliative chemotherapy with gemcitabine from 2000 to 2011 at the British Columbia Cancer Agency were identified. Clinicopathologic variables and outcomes were retrospectively collected and compared among groups. Eligibility criteria for each regimen were in accordance with the respective pivotal phase III trials. Results: A total of 473 patients were included: 25% of the patients were eligible for FOLFIRINOX versus 45% for NG. Main reasons for FOLFIRINOX ineligibility were Eastern Cooperative Oncology Group (ECOG) performance status (PS)≥2 (56.5%), age older than 75 years (19.0%), and bilirubin>1.5× upper limit of normal (18.6%), whereas those for NG ineligibility were bilirubin > upper limit of normal (24.5%), ECOG PS≥3 (14.6%), and cardiac dysfunction (13.8%). Univariate analyses revealed that FOLFIRINOX and NG-eligible patients had longer median overall survival than their respective ineligible group (8.6 vs. 4.7 mo, P

http://ift.tt/2x8HH0Z

Alcohol Abuse Decreases Pelvic Control and Survival in Cervical Cancer: An Opportunity of Lifestyle Intervention for Outcome Improvement

Purpose: We examined the incidence and the effect of alcohol abuse on pelvic control (PC), disease-free survival (DFS), and overall survival (OS) in locally advanced cervical cancer patients undergoing definitive radiation therapy (RT). Methods: Between 2007 and 2013, 95 patients treated with RT were reviewed, and the tumor characteristics, the RT dose, the treatment time, chemotherapy, and the number of cycles were recorded. The association between alcohol abuse and DFS, OS, and the duration of PC was analyzed using multivariable Cox proportional hazards models. Results: Of the 95 patients with an average age of 54.8 years (range, 27 to 91 y), 30% were FIGO stage 1B1, 1B2, 2A, 52% stage 2B, 3A; and 18% stage 3B; 86% of the patients were treated with weekly cisplatin chemotherapy. Alcohol history showed that 10 (10.5%) patients met the CDC criteria for heavy alcohol use. With a mean follow-up time of 2 years, 85 patients (88.5%) achieved PC and 86 patients (90.5%) were free of distant metastasis. A total of 82 patients (86.3%) were alive at the last follow-up. When controlling for the total treatment time, excessive alcohol abuse was significantly associated with a decrease in DFS (P=0.005; hazard ratio [HR], 6.19; 95% confidence interval [CI]: 1.73, 22.18), OS (P=0.001; HR, 6.68; 95% CI: 2.10, 21.26), and PC (P=0.029; HR, 3.10; 95% CI: 1.13, 8.56) on univariable analysis. On multivariable analysis, excessive alcohol abuse was significantly associated with a decrease in DFS (P=0.005; HR, 10.57; 95% CI: 2.07, 53.93) and OS (P=0.001; HR, 10.80; 95% CI: 2.57, 45.40). Conclusions: In this small hypothesis-generating series of patients with heavy alcohol use, the data support the association that heavy alcohol use increases the risk of cancer recurrence and mortality. Additional research is required to better define the patient- and treatment-related factors that may be targeted for intervention.

http://ift.tt/2xaDvO7

Stage IIIC Endometrial Cancer: Relapse and Survival Outcomes in Women Treated With Pelvic or Extended Field Para-Aortic Nodal Radiation Therapy

Purpose: The optimal radiation (RT) volume for node-positive endometrial cancer is controversial. This study evaluates clinical outcomes in patients with stage IIIC, N1 endometrial cancer who received RT to the pelvis (PV RT) or pelvis plus para-aortic nodes (PV-PAN RT). Methods: Overall, there were 89 women with stage IIIC endometrial cancer. Of these, 57 women had N1-only disease, forming the study cohort. Clinicopathologic characteristics, recurrence rates, endometrial cancer–specific survival (ECSS), and overall survival (OS) were examined among patients treated with pelvic RT (n=23) compared with pelvic plus para-aortic RT (n=34). Multivariable analysis of ECSS and OS was performed using Cox regression modeling. Results: Median follow-up was 5.1 years. Adjuvant chemotherapy was used in 51/57 (89%) of N1 cases. Women with N1 disease who received PV-PAN RT compared with PV RT experienced lower recurrence (26% vs. 52%, P=0.06) and higher survival rates (5 y ECSS 81.5% vs. 47.0%, P=0.04 and OS 79.1% vs. 47.0%, P=0.01). On multivariable analysis, RT volume was not significantly associated with OS, whereas chemotherapy was associated with improved ECSS and OS. Conclusions: RT conferred excellent local control, whereas chemotherapy was associated with improved survival in women with N1 endometrial cancer. Distant relapse remains the most common site of recurrence despite chemotherapy.

http://ift.tt/2xaDrhl

Improving Survival in Patients Treated for a Lung Cancer Using Self-Evaluated Symptoms Reported Through a Web Application

Objectives: We retrospectively compared survivals in patients with a lung cancer history and followed by the so-called sentinel Web-application that allows early detection of relapse and early palliative care initiation versus a conventional follow-up in our center. Methods: The survival in 98 consecutive patients with lung cancer was assessed. The first part of them (the control arm) was retrospectively recruited between March 2011 and August 2012. The second half of them (the experimental arm) was prospectively recruited between August 2012 and December 2013 to weekly fill a form of 11 self-assessed symptoms, then processed by the "sentinel" Web-application. Data were sent to this sentinel application in real-time between planned visits. An email alert was sent to the oncologist when self-scored symptoms matched some predefined criteria. Follow-up visit and imaging were then organized after a phone call for confirming the suspect symptoms. In the control arm (49 patients), a common follow-up was applied (visit and imaging every 2 to 6 mo according to stage of tumor and kind of treatment). Results: Median follow-up duration was 12.3 months in the experimental arm and 16.7 months in the control arm (P=0.27). Survival was significantly better in the sentinel arm than in the control arm (P=0.0014). Median survival was 16.7 months in the control arm and 22.4 months in the experimental arm. One-year survival was 86.6% in the experimental arm and 59.1% in the control arm. Conclusions: Survival may be improved by early detection of relapse and early palliative care initiation by using sentinel-like Web-application.

http://ift.tt/2xaDn15

Factors Associated With Guideline-recommended KRAS Testing in Colorectal Cancer Patients: A Population-based Study

Objectives: Response to epidermal growth factor receptor inhibitors is poorer among stage IV colorectal cancer (CRC) patients with KRAS mutations; thus KRAS testing is recommended before treatment. KRAS testing was collected by Surveillance, Epidemiology, and End Results (SEER) registries for 2010 CRC cases, and our goal was to provide the first population-based estimates of testing in the United States. Methods: SEER CRC cases diagnosed in 2010 were evaluated (n=30,351). χ2 tests and logistic regression were conducted to determine patient characteristics associated with KRAS testing, stratified by stages I-III versus stage IV. Log-rank tests were used to examine survival by testing status. Results: KRAS testing among stage IV cases ranged from 39% in New Mexico to 15% in Louisiana. In the model, younger age, being married, living in a metropolitan area, and having primary site surgery were associated with greater odds of receiving KRAS testing. Those who received testing had significantly better survival than those who did not (P

http://ift.tt/2xaDjOT

Treatment Toxicity in Elderly Patients With Advanced Non–Small Cell Lung Cancer

Objectives: Toxicity is a main concern limiting the use of chemotherapy and radiotherapy (RT) for elderly patients with non–small cell lung cancer (NSCLC). The objective of this study was to assess the rates of treatment-related toxicity among elderly stage IIIB and IV NSCLC patients. Materials and Methods: We used the Surveillance, Epidemiology, and End Results registry linked to Medicare records to identify 2596 stage IIIB and 14,803 stage IV NSCLC patients aged 70 years and above, diagnosed in 2000 or later. We compared rates of toxicity requiring hospitalization according to treatment (chemotherapy, RT, or chemoradiation [CRT]) in unadjusted and adjusted models controlling for selection bias using propensity scores. Results: Among stage IIIB patients, rates of any severe toxicity were 10.1%, 23.8%, 30.4%, and 39.2% for patients who received no treatment, RT, chemotherapy alone, and CRT, respectively. In stage IV patients, rates of any severe toxicity were 31.5% versus 13.5% among those treated with and without chemotherapy, respectively. In stage IIIB patients treated with CRT, the most common toxicities was esophagitis (odds ratio, 48.5; 95% confidence interval, 6.7-350.5). Among stage IV patients treated with chemotherapy, the risk of toxicity was highest for neutropenia (odds ratio, 8.4; 95% confidence interval, 6.1-11.5). Conclusions: Toxicity was relatively common among stage IIIB patients with up to a 6-fold increase in elderly individuals treated with CRT and a 4-fold increase in toxicities among stage IV patients. This information should be helpful to guide discussions about the risk-benefit ratio of chemotherapy and RT in elderly patients with advanced NSCLC.

http://ift.tt/2xa0ngY

Oncologic Outcome of ypT1-2N0 Rectal Cancer After Neoadjuvant Chemoradiotherapy Compared With pT1-2N0 Rectal Cancer

Objective: To investigate the oncologic outcome of ypT1-2N0 mid and lower rectal cancer after chemoradiotherapy (CRT) compared with pT1-2N0 rectal cancer. Methods: We compared the oncologic outcome of patients with mid and lower rectal cancer who underwent preoperative CRT and who did not, between February 2005 and August 2012. Results: Compared with patients who did not receive preoperative CRT, patients who received preoperative CRT did not have significantly different clinicopathologic features except clinical stage and distal resection margin. The 5-year disease-free survival (DFS) rates were lower in patients who received preoperative CRT than those who did not (84.4% vs. 95.5%, P=0.029). Preoperative CRT was a prognostic factor affecting 5-year DFS in patients with pathologically proven stage T1N0 mid and lower rectal cancer (HR, 11.157; 95% CI, 1.735-71.762; P=0.011) Conclusions: ypT2N0 rectal cancer after neoadjuvant CRT showed shorter DFS compared with pT2N0 rectal cancer.

http://ift.tt/2xaD1HN

Dose-Volume Predictors of Esophagitis After Thoracic Stereotactic Body Radiation Therapy

Objectives: Esophageal toxicity has become a major concern as stereotactic hypofractionated radiation therapy is increasingly utilized for central pulmonary tumors. Our purpose was to define esophageal dosimetric parameters that predict potentially dose-limiting toxicities. Materials and Methods: In total, 157 patients with a planning target volume ≤5 cm from the esophagus were selected from an institutional database. Toxicity was scored with the CTCAE v4.0. Esophageal Dmax and Dv (dose D in Gy covering volume v in mL) in 0.5 mL increments were collected. Corresponding biologically effective dose (BED) was calculated for α/β=10,3 (BED10, BED3). Normal tissue complication probability was computed with conventionally fractionated radiotherapy parameters and equivalent dose in 2 Gy per fraction (EQD2). Dosimetric predictors were identified with multivariate logistic regression with a manual forward stepwise selection technique. Results: The grade≥2 esophagitis rate was 5.7%. BED10 to 1.5 mL was the best predictor of esophagitis. BED10 to 0.5, 1.0, 2.0, 3.0, and 3.5 mL were also predictive but less strong. Results were similar when BED3 and physical dose were examined. Tumor-esophageal distance correlated with esophagitis (10.5% risk of≥grade 2 events with distance≤3.9 cm vs. 1.3% when>3.9 cm, P=0.016). BED10 to 1.5 mL correlated well with EQD2 normal tissue complication probability estimates. Conclusions: BED to 1.5 mL was the strongest predictor of grade≥2 esophagitis (independent of α/β ratio) with a 10.6% toxicity risk when BED10>21.1 Gy (14.3 Gy in 3 fractions, 16.0 Gy in 5). The overall rate of severe toxicity is low, suggesting that higher doses may be tolerable.

http://ift.tt/2x9Xvkf

A Model to Predict the Feasibility of Concurrent Chemoradiotherapy With Temozolomide in Glioblastoma Multiforme Patients Over Age 65

Objectives: It is controversial whether concurrent chemoradiotherapy (CRT) with temozolomide is feasible and beneficial in elderly patients with glioblastoma. Materials and Methods: Retrospective analysis of 74 elderly glioblastoma patients (65 y and above) treated with concurrent CRT with temozolomide. Factors influencing prognosis and feasibility of CRT were investigated. Results: The median overall survival was 11.3 months. Univariate analysis showed a significant difference in median overall survival for cumulative dose of concurrent temozolomide (optimal cutoff, 2655 mg/m2; 13.9 mo for >2655 mg/m2 vs. 4.9 mo for ≤2655 mg/m2; P=0.0216, adjusted for multiple testing). Furthermore, cumulative dose of concurrent temozolomide >2655 mg/m2 was a significant independent prognostic parameter in multivariate analysis (hazard ratio, 0.33; P=0.002). Hematotoxicity was the most common cause of treatment interruption or discontinuation in patients with an insufficient cumulative temozolomide dose. Prognostic factors for successful performance of CRT with a cumulative dose of concurrent temozolomide >2655 mg/m2 were female sex (odds ratio [OR], 0.174; P=0.006), age (OR, 0.826 per year; P=0.017), and pretreatment platelet count (OR, 1.013 per 1000 platelets/µL; P=0.001). For easy clinical application of the model an online calculator was developed, which is available at http://www.OldTMZ.com . Conclusions: The probability of successful performance of concurrent CRT with temozolomide can be estimated based on the patient's age, sex, and pretreatment platelet count using the model developed in this study. Thus, a subgroup of elderly glioblastoma patients suitable for chemoradiation with temozolomide can be identified.

http://ift.tt/2x9mkg2

Eligibility of Metastatic Pancreatic Cancer Patients for First-Line Palliative Intent nab-Paclitaxel Plus Gemcitabine Versus FOLFIRINOX

Objectives: The PRODIGE and MPACT trials showed superiority of FOLFIRINOX and nab-paclitaxel plus gemcitabine (NG) over gemcitabine alone, respectively. However, both had strict inclusion criteria. We sought to determine the characteristics of patients with metastatic pancreatic cancer (MPC) which inform the appropriateness of first-line chemotherapy FOLFIRINOX and NG in routine practice. Materials and Methods: Patients with MPC who initiated palliative chemotherapy with gemcitabine from 2000 to 2011 at the British Columbia Cancer Agency were identified. Clinicopathologic variables and outcomes were retrospectively collected and compared among groups. Eligibility criteria for each regimen were in accordance with the respective pivotal phase III trials. Results: A total of 473 patients were included: 25% of the patients were eligible for FOLFIRINOX versus 45% for NG. Main reasons for FOLFIRINOX ineligibility were Eastern Cooperative Oncology Group (ECOG) performance status (PS)≥2 (56.5%), age older than 75 years (19.0%), and bilirubin>1.5× upper limit of normal (18.6%), whereas those for NG ineligibility were bilirubin > upper limit of normal (24.5%), ECOG PS≥3 (14.6%), and cardiac dysfunction (13.8%). Univariate analyses revealed that FOLFIRINOX and NG-eligible patients had longer median overall survival than their respective ineligible group (8.6 vs. 4.7 mo, P

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Locoregional and Overall Recurrence After Neaodjuvant Endocrine Therapy Versus Chemotherapy in Postmenopausal Women With Estrogen Receptor+ HER2− Breast Cancer

Purpose: We report clinical outcomes in patients treated with neoadjuvant endocrine therapy (NET) versus neoadjuvant cytotoxic chemotherapy (NCT) in a cohort of postmenopausal women with ER+, HER2− breast cancer. Materials and Methods: We retrospectively reviewed 140 patients treated between May 1998 and September 2010 and collected patient, disease, and treatment characteristics, response to neoadjuvant therapy, and clinical outcome. Results: The median age was 59.5 years. Stage group: stage I 2.2%, stage II 26.8%, stage III 71%, the median tumor size 6 cm (range, 1.5 to 19 cm). Fifty-seven (40.7%) received NET and 83 (59.3%) NCT. One patient (1.8%) in the NET group and 7 (8.4%) in the NCT group had a pathologic complete response (P=0.142). The median follow-up was 48.1 months. Five-year cumulative incidence of locoregional recurrence (LRR) among the entire cohort was 4.1% (95% confidence interval [CI]: 1.5, 8.9), and any recurrence 25.3% (95% CI: 17.6, 33.6). There was no difference in cumulative incidence of LRR or overall recurrence between NET and NCT. On multivariate analysis adjusting for receipt of chemotherapy, presenting stage, and positive lymph nodes, the use of adjuvant radiation therapy was associated with decreased risk of LRR (hazard ratio [HR]=0.24, P=0.035), and ypN2 status with higher risk of LRR (HR=4.91, P=0.032). When the same multivariate model was fitted for any recurrence outcome, only ypN2 status was a significant predictor of overall recurrence (HR=3.02, P=0.005). Conclusions: We have demonstrated equivalent locoregional and overall outcomes in patients receiving NET versus NCT in a cohort of postmenopausal women with locally advanced ER+HER2−tumors.

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Alcohol Abuse Decreases Pelvic Control and Survival in Cervical Cancer: An Opportunity of Lifestyle Intervention for Outcome Improvement

Purpose: We examined the incidence and the effect of alcohol abuse on pelvic control (PC), disease-free survival (DFS), and overall survival (OS) in locally advanced cervical cancer patients undergoing definitive radiation therapy (RT). Methods: Between 2007 and 2013, 95 patients treated with RT were reviewed, and the tumor characteristics, the RT dose, the treatment time, chemotherapy, and the number of cycles were recorded. The association between alcohol abuse and DFS, OS, and the duration of PC was analyzed using multivariable Cox proportional hazards models. Results: Of the 95 patients with an average age of 54.8 years (range, 27 to 91 y), 30% were FIGO stage 1B1, 1B2, 2A, 52% stage 2B, 3A; and 18% stage 3B; 86% of the patients were treated with weekly cisplatin chemotherapy. Alcohol history showed that 10 (10.5%) patients met the CDC criteria for heavy alcohol use. With a mean follow-up time of 2 years, 85 patients (88.5%) achieved PC and 86 patients (90.5%) were free of distant metastasis. A total of 82 patients (86.3%) were alive at the last follow-up. When controlling for the total treatment time, excessive alcohol abuse was significantly associated with a decrease in DFS (P=0.005; hazard ratio [HR], 6.19; 95% confidence interval [CI]: 1.73, 22.18), OS (P=0.001; HR, 6.68; 95% CI: 2.10, 21.26), and PC (P=0.029; HR, 3.10; 95% CI: 1.13, 8.56) on univariable analysis. On multivariable analysis, excessive alcohol abuse was significantly associated with a decrease in DFS (P=0.005; HR, 10.57; 95% CI: 2.07, 53.93) and OS (P=0.001; HR, 10.80; 95% CI: 2.57, 45.40). Conclusions: In this small hypothesis-generating series of patients with heavy alcohol use, the data support the association that heavy alcohol use increases the risk of cancer recurrence and mortality. Additional research is required to better define the patient- and treatment-related factors that may be targeted for intervention.

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Stage IIIC Endometrial Cancer: Relapse and Survival Outcomes in Women Treated With Pelvic or Extended Field Para-Aortic Nodal Radiation Therapy

Purpose: The optimal radiation (RT) volume for node-positive endometrial cancer is controversial. This study evaluates clinical outcomes in patients with stage IIIC, N1 endometrial cancer who received RT to the pelvis (PV RT) or pelvis plus para-aortic nodes (PV-PAN RT). Methods: Overall, there were 89 women with stage IIIC endometrial cancer. Of these, 57 women had N1-only disease, forming the study cohort. Clinicopathologic characteristics, recurrence rates, endometrial cancer–specific survival (ECSS), and overall survival (OS) were examined among patients treated with pelvic RT (n=23) compared with pelvic plus para-aortic RT (n=34). Multivariable analysis of ECSS and OS was performed using Cox regression modeling. Results: Median follow-up was 5.1 years. Adjuvant chemotherapy was used in 51/57 (89%) of N1 cases. Women with N1 disease who received PV-PAN RT compared with PV RT experienced lower recurrence (26% vs. 52%, P=0.06) and higher survival rates (5 y ECSS 81.5% vs. 47.0%, P=0.04 and OS 79.1% vs. 47.0%, P=0.01). On multivariable analysis, RT volume was not significantly associated with OS, whereas chemotherapy was associated with improved ECSS and OS. Conclusions: RT conferred excellent local control, whereas chemotherapy was associated with improved survival in women with N1 endometrial cancer. Distant relapse remains the most common site of recurrence despite chemotherapy.

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Seven-Year Outcomes Following Accelerated Partial Breast Irradiation Stratified by ASTRO Consensus Groupings

Objectives: Limited long-term data exist regarding outcomes for patients treated with accelerated partial breast irradiation (APBI), particularly, when stratified by American Society for Radiation Oncology (ASTRO) Consensus Statement (CS) risk groups. The purpose of this analysis is to present 5- and 7-year outcomes following APBI based on CS groupings. Materials and Methods: A total of 690 patients with early-stage breast cancer underwent APBI from 1993 to 2012, receiving interstitial brachytherapy (n=195), balloon-based brachytherapy (n=290), or 3-dimensional conformal radiotherapy (n=205) at a single institution. Patients were stratified into suitable, cautionary, and unsuitable groups with 5-year outcomes analyzed. Seven-year outcomes were analyzed for a subset with follow-up of ≥2 years (n=625). Results: Median follow-up was 6.7 years (range, 0.1 to 20.1 y). Patients assigned to cautionary and unsuitable categories were more likely to have high-grade tumors (21% to 25% vs. 9%, P=0.001), receive chemotherapy (15% to 38% vs. 6%, P

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Improving Survival in Patients Treated for a Lung Cancer Using Self-Evaluated Symptoms Reported Through a Web Application

Objectives: We retrospectively compared survivals in patients with a lung cancer history and followed by the so-called sentinel Web-application that allows early detection of relapse and early palliative care initiation versus a conventional follow-up in our center. Methods: The survival in 98 consecutive patients with lung cancer was assessed. The first part of them (the control arm) was retrospectively recruited between March 2011 and August 2012. The second half of them (the experimental arm) was prospectively recruited between August 2012 and December 2013 to weekly fill a form of 11 self-assessed symptoms, then processed by the "sentinel" Web-application. Data were sent to this sentinel application in real-time between planned visits. An email alert was sent to the oncologist when self-scored symptoms matched some predefined criteria. Follow-up visit and imaging were then organized after a phone call for confirming the suspect symptoms. In the control arm (49 patients), a common follow-up was applied (visit and imaging every 2 to 6 mo according to stage of tumor and kind of treatment). Results: Median follow-up duration was 12.3 months in the experimental arm and 16.7 months in the control arm (P=0.27). Survival was significantly better in the sentinel arm than in the control arm (P=0.0014). Median survival was 16.7 months in the control arm and 22.4 months in the experimental arm. One-year survival was 86.6% in the experimental arm and 59.1% in the control arm. Conclusions: Survival may be improved by early detection of relapse and early palliative care initiation by using sentinel-like Web-application.

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Factors Associated With Guideline-recommended KRAS Testing in Colorectal Cancer Patients: A Population-based Study

Objectives: Response to epidermal growth factor receptor inhibitors is poorer among stage IV colorectal cancer (CRC) patients with KRAS mutations; thus KRAS testing is recommended before treatment. KRAS testing was collected by Surveillance, Epidemiology, and End Results (SEER) registries for 2010 CRC cases, and our goal was to provide the first population-based estimates of testing in the United States. Methods: SEER CRC cases diagnosed in 2010 were evaluated (n=30,351). χ2 tests and logistic regression were conducted to determine patient characteristics associated with KRAS testing, stratified by stages I-III versus stage IV. Log-rank tests were used to examine survival by testing status. Results: KRAS testing among stage IV cases ranged from 39% in New Mexico to 15% in Louisiana. In the model, younger age, being married, living in a metropolitan area, and having primary site surgery were associated with greater odds of receiving KRAS testing. Those who received testing had significantly better survival than those who did not (P

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Treatment Toxicity in Elderly Patients With Advanced Non–Small Cell Lung Cancer

Objectives: Toxicity is a main concern limiting the use of chemotherapy and radiotherapy (RT) for elderly patients with non–small cell lung cancer (NSCLC). The objective of this study was to assess the rates of treatment-related toxicity among elderly stage IIIB and IV NSCLC patients. Materials and Methods: We used the Surveillance, Epidemiology, and End Results registry linked to Medicare records to identify 2596 stage IIIB and 14,803 stage IV NSCLC patients aged 70 years and above, diagnosed in 2000 or later. We compared rates of toxicity requiring hospitalization according to treatment (chemotherapy, RT, or chemoradiation [CRT]) in unadjusted and adjusted models controlling for selection bias using propensity scores. Results: Among stage IIIB patients, rates of any severe toxicity were 10.1%, 23.8%, 30.4%, and 39.2% for patients who received no treatment, RT, chemotherapy alone, and CRT, respectively. In stage IV patients, rates of any severe toxicity were 31.5% versus 13.5% among those treated with and without chemotherapy, respectively. In stage IIIB patients treated with CRT, the most common toxicities was esophagitis (odds ratio, 48.5; 95% confidence interval, 6.7-350.5). Among stage IV patients treated with chemotherapy, the risk of toxicity was highest for neutropenia (odds ratio, 8.4; 95% confidence interval, 6.1-11.5). Conclusions: Toxicity was relatively common among stage IIIB patients with up to a 6-fold increase in elderly individuals treated with CRT and a 4-fold increase in toxicities among stage IV patients. This information should be helpful to guide discussions about the risk-benefit ratio of chemotherapy and RT in elderly patients with advanced NSCLC.

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Oncologic Outcome of ypT1-2N0 Rectal Cancer After Neoadjuvant Chemoradiotherapy Compared With pT1-2N0 Rectal Cancer

Objective: To investigate the oncologic outcome of ypT1-2N0 mid and lower rectal cancer after chemoradiotherapy (CRT) compared with pT1-2N0 rectal cancer. Methods: We compared the oncologic outcome of patients with mid and lower rectal cancer who underwent preoperative CRT and who did not, between February 2005 and August 2012. Results: Compared with patients who did not receive preoperative CRT, patients who received preoperative CRT did not have significantly different clinicopathologic features except clinical stage and distal resection margin. The 5-year disease-free survival (DFS) rates were lower in patients who received preoperative CRT than those who did not (84.4% vs. 95.5%, P=0.029). Preoperative CRT was a prognostic factor affecting 5-year DFS in patients with pathologically proven stage T1N0 mid and lower rectal cancer (HR, 11.157; 95% CI, 1.735-71.762; P=0.011) Conclusions: ypT2N0 rectal cancer after neoadjuvant CRT showed shorter DFS compared with pT2N0 rectal cancer.

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Dose-Volume Predictors of Esophagitis After Thoracic Stereotactic Body Radiation Therapy

Objectives: Esophageal toxicity has become a major concern as stereotactic hypofractionated radiation therapy is increasingly utilized for central pulmonary tumors. Our purpose was to define esophageal dosimetric parameters that predict potentially dose-limiting toxicities. Materials and Methods: In total, 157 patients with a planning target volume ≤5 cm from the esophagus were selected from an institutional database. Toxicity was scored with the CTCAE v4.0. Esophageal Dmax and Dv (dose D in Gy covering volume v in mL) in 0.5 mL increments were collected. Corresponding biologically effective dose (BED) was calculated for α/β=10,3 (BED10, BED3). Normal tissue complication probability was computed with conventionally fractionated radiotherapy parameters and equivalent dose in 2 Gy per fraction (EQD2). Dosimetric predictors were identified with multivariate logistic regression with a manual forward stepwise selection technique. Results: The grade≥2 esophagitis rate was 5.7%. BED10 to 1.5 mL was the best predictor of esophagitis. BED10 to 0.5, 1.0, 2.0, 3.0, and 3.5 mL were also predictive but less strong. Results were similar when BED3 and physical dose were examined. Tumor-esophageal distance correlated with esophagitis (10.5% risk of≥grade 2 events with distance≤3.9 cm vs. 1.3% when>3.9 cm, P=0.016). BED10 to 1.5 mL correlated well with EQD2 normal tissue complication probability estimates. Conclusions: BED to 1.5 mL was the strongest predictor of grade≥2 esophagitis (independent of α/β ratio) with a 10.6% toxicity risk when BED10>21.1 Gy (14.3 Gy in 3 fractions, 16.0 Gy in 5). The overall rate of severe toxicity is low, suggesting that higher doses may be tolerable.

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A Model to Predict the Feasibility of Concurrent Chemoradiotherapy With Temozolomide in Glioblastoma Multiforme Patients Over Age 65

Objectives: It is controversial whether concurrent chemoradiotherapy (CRT) with temozolomide is feasible and beneficial in elderly patients with glioblastoma. Materials and Methods: Retrospective analysis of 74 elderly glioblastoma patients (65 y and above) treated with concurrent CRT with temozolomide. Factors influencing prognosis and feasibility of CRT were investigated. Results: The median overall survival was 11.3 months. Univariate analysis showed a significant difference in median overall survival for cumulative dose of concurrent temozolomide (optimal cutoff, 2655 mg/m2; 13.9 mo for >2655 mg/m2 vs. 4.9 mo for ≤2655 mg/m2; P=0.0216, adjusted for multiple testing). Furthermore, cumulative dose of concurrent temozolomide >2655 mg/m2 was a significant independent prognostic parameter in multivariate analysis (hazard ratio, 0.33; P=0.002). Hematotoxicity was the most common cause of treatment interruption or discontinuation in patients with an insufficient cumulative temozolomide dose. Prognostic factors for successful performance of CRT with a cumulative dose of concurrent temozolomide >2655 mg/m2 were female sex (odds ratio [OR], 0.174; P=0.006), age (OR, 0.826 per year; P=0.017), and pretreatment platelet count (OR, 1.013 per 1000 platelets/µL; P=0.001). For easy clinical application of the model an online calculator was developed, which is available at http://www.OldTMZ.com . Conclusions: The probability of successful performance of concurrent CRT with temozolomide can be estimated based on the patient's age, sex, and pretreatment platelet count using the model developed in this study. Thus, a subgroup of elderly glioblastoma patients suitable for chemoradiation with temozolomide can be identified.

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Developing a Novel Model to Improve Research and care for Cancer Survivors: a Feasibility Study

Abstract

Despite a growing number of clinical trials and supportive care programs for cancer survivors, recruitment of patients for these opportunities during the survivorship phase of care is challenging. We piloted a novel process to systematically educate patients about available research studies and supportive care programs as part of a survivorship care visit. Between 3/2015 and 8/2015, patients seen in the Adult Survivorship Program who had not previously received a treatment summary and survivorship care plan (TS/SCP) were provided with one accompanied by a list of survivorship research studies and care programs tailored to their diagnosis. Survivorship providers discussed the opportunities and recorded whether the patient was interested in relevant studies and placed referrals to study staff. Following the visit, we tracked study enrollment and surveyed patients about their experience. Fifty of 56 (89%) pilot participants completed the survey. Almost all (98%) reported that the TS/SCP visit and document helped with knowledge of research opportunities and supportive care interventions. Following receipt of the TS/SCP, 44% were interested in at least one study and in further follow-up with research staff. Of the 30 survivors eligible for at least one study, 6 (20%) have enrolled in at least one study to date. This pilot program demonstrates that the systematic sharing of available clinical studies and supportive care programming as part of a survivorship care plan visit is feasible and well received by cancer survivors and may facilitate and enhance accrual to clinical trials in the survivorship phase of care.

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