Real-world experience of everolimus as second-line treatment in metastatic renal cell cancer after failure of pazopanib

http://ift.tt/2wOUB47

Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.

Abstract

Background

Combined CTLA-4 and PD-1 blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known.

Patients and Methods

We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs.

Results

Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids, and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (6 grade 1-2, 7 grade 3-4, 1 grade 5 Stevens-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% vs. 28%, p=0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2, 6 grade 3-4). Duration of steroid taper, severity of initial irAEs, and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% vs. 31%, p=0.03).

Conclusions

Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in select patients.

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The predictive value of interim FDG-PET in early-stage Hodgkin lymphoma is not well established

http://ift.tt/2i6OlCi

Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.

Abstract

Background

Combined CTLA-4 and PD-1 blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known.

Patients and Methods

We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs.

Results

Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids, and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (6 grade 1-2, 7 grade 3-4, 1 grade 5 Stevens-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% vs. 28%, p=0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2, 6 grade 3-4). Duration of steroid taper, severity of initial irAEs, and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% vs. 31%, p=0.03).

Conclusions

Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in select patients.

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The predictive value of interim FDG-PET in early-stage Hodgkin lymphoma is not well established

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Scorpion bite-induced ischaemic stroke

We report a 54-year-old woman with scorpion bite. After 3 hours of admission, the patient developed sudden onset tachycardia with hypotension. Cardiac evaluation showed raised creatine kinase MB isoenzyme was elevated; ECG and two-dimensional echocardiography findings were suggestive of myocarditis. Subsequently, she developed transient ventricular tachycardia before developing abrupt onset, right hemiplegia, global aphasia and progressive worsening of sensorium 12 hours after the bite. MRI of brain revealed massive left middle cerebral artery (MCA) territory infarct. The magnetic resonance angiography showed non-visualisation of left internal carotid artery (ICA) and MCA. Coagulation parameters were normal. Sudden complete occlusion of left ICA was probably secondary to cardioembolic phenomenon leading to massive infarct. Despite aggressive medical and supportive measures, she clinically worsened rapidly to Glasgow Coma Scale of 3/15 over next 6 hours and succumbed to her illness the next day.

http://ift.tt/2ydAluh

Oesophageal ischaemia: an uncommon cause of chest pain

A 79-year-old woman with a history of ischaemic heart disease and atrial fibrillation presented to hospital with severe chest pain. Blood tests showed an elevated D-dimer and a rise in troponin I. ECG showed right bundle branch block pattern and T wave inversion in leads V1 to V3, although these changes were present in old ECGs. A chest X-ray was done which was normal. Due to the nature and severity of her pain a CT aortic angiogram was done. This did not show any evidence of aortic dissection or a pulmonary embolism. The patient then had several episodes of haematemesis. An urgent oesophagogastroduodenoscopy was done which showed a circumferential, well demarcated area of blackened oesophageal mucosa. The patient was diagnosed with ischaemic damage to her oesophagus.

http://ift.tt/2wONpVD

Posterior fossa progressive multifocal leukoencephalopathy: first presentation of an unknown autoimmune disease

We present a case of a 57-year-old man who presented with progressive cerebellar dysarthria and cerebellar ataxia. Additional investigations confirmed the diagnosis of progressive multifocal leukoencephalopathy (PML) in the posterior fossa. This is a demyelinating disease of the central nervous system, caused by an opportunistic infection with John Cunningham virus. PML has previously been considered a lethal condition, but because of careful monitoring of patients with HIV and of patients using immunosuppressive drugs it is discovered in earlier stages and prognosis can be improved. Our patient had no known immune-compromising state, but further work-up revealed that the PML was most likely the first presentation of a previous untreated autoimmune disorder: sarcoidosis.

http://ift.tt/2yfh1wK

Subclinical meningoventriculitis as a cause of obstructive hydrocephalus

Communicating hydrocephalus may complicate infantile bacterial meningitis, typically presenting with systemic features of infection. We report a rare case of 'subclinical meningoventriculitis' causing obstructive hydrocephalus and its challenging management. A healthy 10-week-old immunocompetent male patient presented with failure to thrive and vomiting, secondary to presumed gastro-oesophageal reflux. The child was neurologically alert, afebrile with normal inflammatory markers. Progressive macrocephaly prompted an MRI confirming triventricular hydrocephalus secondary to aqueductal stenosis. An endoscopic third ventriculostomy was performed however abandoned intraoperatively due to the unexpected finding of intraventricular purulent cerebrospinal fluid. A 6-week course of intravenous ceftriaxone was commenced for Escherichia coli meningoventriculitis. However, the child was readmitted 18 days postoperatively with acute hydrocephalus requiring a ventricular washout and staged ventriculoperitoneal shunt insertion at 4 weeks. Serial head circumference measurements are paramount in the assessment of a paediatric patient. In an immunocompetent child, a subclinical fibropurulent meningoventriculitis can result in several management challenges.

http://ift.tt/2wONkBj

A unique case of nephrogenic systemic fibrosis from gadolinium exposure in a patient with normal eGFR

A 57-year-old woman presented with swelling and thickening of the skin of the lower extremities. Three months prior to presentation, patient had MRI with gadolinium as part of an evaluation for suspected pancreatic malignancy. Creatinine levels at the time of gadolinium exposure were 0.9–1.2 mg/dL, with a corresponding estimated glomerular filtration rate of 64 mL/min/1.73m² by modification of diet in renal disease equation. Twenty-four-hour urine creatinine clearance was performed as an outpatient following development of symptoms. This revealed a creatinine clearance of 23 mL/min, suggestive of advanced chronic kidney disease despite an estimated glomerular filtration rate of 64 mL/min/1.73m². Skin biopsy was positive for sclerosing dermopathy. These findings, in addition to the temporal association with gadolinium exposure, led to the diagnosis of nephrogenic systemic fibrosis.

http://ift.tt/2ydIOOb

Allergic bronchopulmonary mycosis presenting as a new lung mass

Description

A 69-year-old man with invasive pancreatic ductal adenocarcinoma underwent pancreaticoduodenectomy and adjuvant chemotherapy. Three years later, a right upper lobe (RUL) lung mass was noted on surveillance imaging, suspicious for disease recurrence. He was treated for bronchitis and remained asymptomatic 4 months later with an unremarkable physical exam. Chest imaging (figure 1A,B) showed an RUL central mass with an infiltrative pattern of growth and right paratracheal adenopathy that is negative for malignancy on endobronchial ultrasound-guided needle aspiration. Bronchoalveolar lavage and brushing grew branching septate hyphae identified as Bipolaris species. The presence of cylindrical bronchiectasis with bronchial wall thickening, mucus plugging, peripheral eosinophilia (810 cells/µL), elevated total serum immunoglobulin E (422.6 IU/mL) and negative aspergillus antibodies suggested allergic bronchopulmonary mycosis (ABPM) caused by Bipolaris species. After 3 months of therapy with prednisone and posaconazole, the mass-like consolidation was completely resolved (figure 1C,D).

Figure 1

Chest CT...

http://ift.tt/2wQ7dIi

Unusual case of prosthetic joint infection caused by Francisella Tularensis

Tularaemia is a zoonotic infection caused by Francisella tularensis.Ulceroglandular, glandular, oculoglandular, pharyngeal, typhoidal and pneumonic types are the different types of the disease. Infection of prosthetic joints occurs at an exceedingly uncommon rate. We report a case of prosthetic joint infection involving the hip with F. tularensis, which to the best of our knowledge after a thorough literature review is the second of its kind.

http://ift.tt/2yeeenH

Cryptococcus neoformans osteomyelitis and intramuscular abscess in a liver transplant patient

Cryptococcus neoformans is an important pathogen that can cause severe illness and mortality in immunocompromised patients. We highlight here the case of a 53-year-old man presenting to hospital 4 years postliver transplant with fever, acute renal failure and a medial thigh lesion. Initially treated as bacterial sepsis, the patient failed to improve on broad-spectrum antibiotics. Further investigations revealed disseminated cryptococcemia complicated by patellar osteomyelitis and an intramuscular abscess. Unfortunately, although the patient initially showed signs of clinical improvement after starting standard antifungal agents, he deteriorated and died secondary to acute renal failure. Osteomyelitis is a rare manifestation of cryptococcal infection for which there is often a significant delay to diagnosis and treatment. This is the fourth reported case of cryptococcal osteomyelitis in a liver transplant patient and underlines the importance of considering fungal infections in the differential diagnosis of osseous lesions in solid organ transplant and other immunocompromised patients.

http://ift.tt/2wQErHD

Olfactory bulb agenesis with normal sexual hormones

An 18-year-old Caucasian man presented with a lack of sense of surrounding smell. The problem was first noticed when a family member discussed the smell of the food, which he had no idea what it was. The patient had normal development and sexual function, no history of trauma, surgery, chemical exposure or infection. Physical examination revealed no significant abnormalities. Smell threshold test using phenyl-ethyl-alcohol revealed bilateral anosmia. MRI showed bilateral aplastic olfactory bulbs and tracts associated with absent cortical growth of the olfactory sulci and asymmetrical gyrus rectus. Circulating hormones including cortisol, growth hormone, insulin-like growth factor 1, adrenocorticotropic hormone, thyroid hormones, follicle-stimulating hormone, luteinizing hormone, prolactin and testosterone were within normal ranges. Doppler ultrasound showed normal testis with bilateral supratesticular varicoceles. Given the loss of warning smell sensation, counselling for daily living precautions especially those related to gas, fire and rotten food was given.

http://ift.tt/2yfgQl4

Hydatid cyst of the thigh: a challenging diagnosis

Description

Hydatid disease is a common infection in Mediterranean countries. It is caused by a parasite 'Echinococcus granulosus', which may affect several organs. Liver and lungs are frequent locations. Primary hydatid cyst located in the musculoskeletal system is uncommon.1

These images illustrate the case of a 27-year-old man without past medical history who presented with a swelling of the right thigh that appeared 6 months ago. Physical examination showed a tender mass of the upper third of the right thigh. There was no history of trauma or fever. Inflammatory blood markers were normal. Ultrasonography was first performed revealing a huge multilocular intramuscular cystic mass of the thigh without tissue components or calcifications. The aspect was suspicious of a cystic lymphangioma. An MRI of the thigh was performed to evaluate accurately the size of the mass and its location. It revealed a voluminous mass of 10x6 cm developed in the...

http://ift.tt/2wPfYCu

Syncope from radiation-induced baroreceptor failure

Orthostatic hypotension has a vast differential that has been previously described throughout the literature. However, baroreceptor failure as a sequela of head and neck radiation is not often recognised as an important cause of dramatic haemodynamic variability. As a result, individuals suffering from baroreceptor failure likely have been undertreated. Herein, we report a case of a patient with a history of radiation to the neck for squamous cell carcinoma of the tongue and resultant baroreceptor failure resulting in syncope.

http://ift.tt/2ye6VfG

Live 'Baby dance among the red blood cells

Description

A 35-year-old woman presented to outpatients with a 1-week history of high-grade fever and generalised malaise. General and systemic examination was unremarkable. On evaluation, her complete haemogram was within normal limits; however peripheral smear revealed the presence of thread-like larval forms of filaria, belonging to the species Wuchereria bancrofti. A wet mount preparation of the centrifuged whole blood sample was done, which demonstrated 'dancing' microfilaria, recorded in real time (see online ).

Dancing adult worms can be visualised within the dilated lymphatic channels on high-resolution ultrasound by their characteristic wriggling type movements, known as the 'filarial dance sign'.1 A wet mount of blood from a patient with microfilaraemia can demonstrate 'dance sign' of the baby worms under a microscope, identical to the parental wriggling movements. Microfilariae are larval forms, released into the blood from adult female worms inhabiting the regional lymphatic vessels. Circulating microfilariae are...

http://ift.tt/2wPSIEk

Erdheim-Chester disease: atypical presentation of a rare disease

We report the clinical case of an adult patient referred to our hospital because of trismus due to a tumour in the right infratemporal and pterygomaxillary fossa. He referred hyporexia, weight loss and right trigeminal neuralgia. On physical examination, he had trismus and diplopia. On neuroimaging, the tumour invaded the central nervous system affecting the right temporal lobe and orbit, and the sellar region. Tumour biopsy revealed foamy histiocytes and isolated giant multinuclear cells immunoreactive to CD68 and negative to CD1a and S100. A diagnosis of Erdheim-Chester disease was made. Non-evidence of large bone involvement was found in neither plain radiographs nor Technetium 99 m bone scintigraphy. BRAFV600E mutation analysis was negative. Because of raised intracranial pressure, a debulking surgery of the intracranial histiocytic process was performed. The patient improved his symptoms and remains clinically stable after 12 months of treatment with pegylated interferon-α–2a 180 µg/weekly.

http://ift.tt/2yfgJ98

Improved knowledge of and difficulties in palliative care among physicians during 2008 and 2015 in Japan: Association with a nationwide palliative care education program

BACKGROUND

Palliative care education for health care professionals is a key element in improving access to quality palliative care. The Palliative Care Emphasis Program on Symptom Management and Assessment for Continuous Medical Education (PEACE) was designed to provide educational opportunities for all physicians in Japan. As of 2015, 57,764 physicians had completed it. The objective of this study was to estimate the effects of the program.

METHODS

This study was an analysis of 2 nationwide observational studies from 2008 and 2015. We conducted 2 questionnaire surveys for representative samples of physicians. The measurements used were the Palliative Care Knowledge Test (range, 0-100) and the Palliative Care Difficulties Scale (range, 1-4). Comparisons were made with the unpaired Student t test and with a multivariate linear regression model using 2 cohorts and a propensity score–matched sample.

RESULTS

This study analyzed a total of 48,487 physicians in 2008 and a total of 2720 physicians in 2015. Between 2008 and 2015, physicians' knowledge and difficulties significantly improved on the Palliative Care Knowledge Test with total scores of 68 and 78, respectively (P < .001; effect size, 0.40) and on the Palliative Care Difficulties Scale with total scores of 2.65 and 2.49, respectively (P < .001; effect size, 0.29). Propensity-score matching resulted in 619 untrained physicians matched to 619 trained physicians, and physicians who trained with the PEACE program had a higher knowledge score (74 vs 86; P < .001; effect size, 0.64) and a lower difficulties score (2.6 vs 2.3; P < .001; effect size, 0.42).

CONCLUSIONS

Physicians' knowledge of and difficulties with palliative care improved on a national level. The PEACE program may have contributed to these improvements. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2z2k8Yd

Improved knowledge of and difficulties in palliative care among physicians during 2008 and 2015 in Japan: Association with a nationwide palliative care education program

BACKGROUND

Palliative care education for health care professionals is a key element in improving access to quality palliative care. The Palliative Care Emphasis Program on Symptom Management and Assessment for Continuous Medical Education (PEACE) was designed to provide educational opportunities for all physicians in Japan. As of 2015, 57,764 physicians had completed it. The objective of this study was to estimate the effects of the program.

METHODS

This study was an analysis of 2 nationwide observational studies from 2008 and 2015. We conducted 2 questionnaire surveys for representative samples of physicians. The measurements used were the Palliative Care Knowledge Test (range, 0-100) and the Palliative Care Difficulties Scale (range, 1-4). Comparisons were made with the unpaired Student t test and with a multivariate linear regression model using 2 cohorts and a propensity score–matched sample.

RESULTS

This study analyzed a total of 48,487 physicians in 2008 and a total of 2720 physicians in 2015. Between 2008 and 2015, physicians' knowledge and difficulties significantly improved on the Palliative Care Knowledge Test with total scores of 68 and 78, respectively (P < .001; effect size, 0.40) and on the Palliative Care Difficulties Scale with total scores of 2.65 and 2.49, respectively (P < .001; effect size, 0.29). Propensity-score matching resulted in 619 untrained physicians matched to 619 trained physicians, and physicians who trained with the PEACE program had a higher knowledge score (74 vs 86; P < .001; effect size, 0.64) and a lower difficulties score (2.6 vs 2.3; P < .001; effect size, 0.42).

CONCLUSIONS

Physicians' knowledge of and difficulties with palliative care improved on a national level. The PEACE program may have contributed to these improvements. Cancer 2017. © 2017 American Cancer Society.

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The TERT hypermethylated oncologic region predicts recurrence and survival in pancreatic cancer

Future Oncology, Ahead of Print.


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What role does stereotactic ablative radiotherapy have in advanced castrate-resistant prostate cancer?

Future Oncology, Ahead of Print.


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The TERT hypermethylated oncologic region predicts recurrence and survival in pancreatic cancer

Future Oncology, Ahead of Print.


http://ift.tt/2gd88zy

What role does stereotactic ablative radiotherapy have in advanced castrate-resistant prostate cancer?

Future Oncology, Ahead of Print.


http://ift.tt/2ygyTtq

NIH Funds Pediatric Data Resource Center [News in Brief]

New portal to help identify genetic pathways underlying childhood cancer and birth defects.

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Paxillin binding to the cytoplasmic domain of CD103 promotes cell adhesion and effector functions for CD8+ resident memory T cells in tumors

CD8+/CD103+ tissue resident memory T cells (TRM cells) accumulate in several human solid tumors where they have been associated with a favorable prognosis. However, the role of CD103 - the α subunit of the integrin αEβ7 (also known as CD103) - in the retention and functions of these TRM is undefined. In this report, we investigated the role of CD103 cytoplasmic domain and the focal adhesion-associated protein paxillin (Pxn) in downstream signaling and functional activities triggered through αE/CD103 chain. Binding to immobilized recombinant (r)E-cadherin-Fc of CD103 integrin expressed on tumor-specific CTL clones promotes phosphorylation of Pxn and Pyk2 and binding of Pxn to the αE/CD103 subunit tail. Inhibition of Pxn phosphorylation by the Src inhibitor saracatinib or its knockdown via shRNA dramatically altered adhesion and spreading of freshly isolated CD8+/CD103+ lung-tumor-infiltrating lymphocytes (TIL) and CD103+ tumor-specific CTL clones. Inhibition of Pxn phosphorylation with saracatinib in these CTL clones also severely compromised their functional activities toward autologous tumor cells. Using Jurkat T cells as a model to study CD103 integrin activation, we demonstrated a key role of serine residue S1163 of the αE chain intracellular domain in polarization of CD103 and recruitment of lysosomes and Pxn at the contact zone of T lymphocytes with rE-cadherin-Fc-coated beads. Overall, our results show how Pxn binding to the CD103 cytoplasmic tail triggers αEβ7 integrin outside-in signaling that promotes CD8+ T-cell migratory behavior and effector functions. These results also explain the more favorable prognosis associated with retention of TRM cells in the tumor microenvironment.

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Glutamine addiction in kidney cancer suppresses oxidative stress and can be exploited for real-time imaging

Many cancers appear to activate intrinsic antioxidant systems as a means to counteract oxidative stress. Some cancers, such as clear cell renal cell carcinoma (ccRCC), require exogenous glutamine for growth and exhibit reprogrammed glutamine metabolism, at least in part due to the glutathione pathway, an efficient cellular buffering system that counteracts reactive oxygen species (ROS) and other oxidants. We show here that ccRCC xenograft tumors under the renal capsule exhibit enhanced oxidative stress compared to adjacent normal tissue and the contralateral kidney. Upon glutaminase inhibition with CB-839 or BPTES, the RCC cell lines SN12PM-6-1 (SN12) and 786-O exhibited decreased survival and pronounced apoptosis associated with a decreased GSH/GSSG ratio, augmented nuclear factor erythroid related factor 2 (NRF2), and increased 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a marker of DNA damage. SN12 tumor xenografts showed decreased growth when treated with CB-839. Furthermore, PET imaging confirmed that ccRCC tumors exhibited increased tumoral uptake of 18F-(2S,4R)4- fluoroglutamine (18F-FGln) compared to the kidney in the orthotopic mouse model. This technique can be utilized to follow changes in ccRCC metabolism in vivo. Further development of these paradigms will lead to new treatment options with glutaminase inhibitors and the utility of PET to identify and manage ccRCC patients who are likely to respond to glutaminase inhibitors in the clinic.-

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DDB2 is a Novel Regulator of Wnt-Signaling in Colon Cancer

Deregulation of the Wnt/β-catenin signaling pathway drives the development of colorectal cancer (CRC) but understanding of this pathway remains incomplete. Here we report that the damage-specific DNA-binding protein DDB2 is critical for β-catenin-mediated activation of RNF43, which restricts Wnt signaling by removing Wnt receptors from the cell surface. Reduced expression of DDB2 and RNF43 was observed in human hyperplastic colonic foci. DDB2 recruited EZH2 and β-catenin at an upstream site in the RNF43 gene, enabling functional interaction with distant TCF4/β-catenin binding sites in the intron of RNF43. This novel activity of DDB2 was required for RNF43 function as a negative feedback regulator of Wnt signaling. Mice genetically deficient in DDB2 exhibited increased susceptibility to colon tumor development in a manner associated with higher abundance of Wnt receptor-expressing cells and greater activation of the downstream Wnt-pathway. Our results identify DDB2 as both a partner and regulator of Wnt signaling with an important role in suppressing colon cancer development.

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Distinct angiogenic changes during carcinogenesis defined by novel label-free dark field imaging in a hamster cheek pouch model

There remain gaps in knowledge concerning how vascular morphology evolves during carcinogenesis. In this study, we imaged neovascularization by label-free dark field microscopy of a DMBA-induced hamster cheek pouch model of oral squamous cell carcinoma (SCC). Wavelength-dependent imaging revealed distinct vascular features at different imaging depths and vessel sizes. Vascular tortuosity increased significantly in high-risk lesions, while diameter decreased significantly in hyperplastic and SCC lesions. Large vessels preserved the same trends seen in the original images, whereas small vessels displayed different trends, with length and diameter increasing during carcinogenesis. Based on these data we developed and validated a classification algorithm incorporating vascular features from different vessel masks. Receiver operator curves generated from the classification results demonstrated high accuracies in discriminating normal and hyperplasia from high-grade lesions (area under the curve>0.95). Overall, these results provided automated imaging of vasculature in the earliest stages of carcinogenesis from which one can extract robust endpoints. The optical toolbox described here is simple, low-cost and portable and can be used in a variety of health care and research settings for cancer prevention and pharmacology research.

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Histone acetyltransferase KAT6A upregulates PI3K/Akt signaling through TRIM24 binding

Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM) where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity- deficient mutants or TRIM24 mutants lacking H3K23ac binding sites promoted PIK3CA expression, AKT phosphorylation and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment.

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Paxillin binding to the cytoplasmic domain of CD103 promotes cell adhesion and effector functions for CD8+ resident memory T cells in tumors

CD8+/CD103+ tissue resident memory T cells (TRM cells) accumulate in several human solid tumors where they have been associated with a favorable prognosis. However, the role of CD103 - the α subunit of the integrin αEβ7 (also known as CD103) - in the retention and functions of these TRM is undefined. In this report, we investigated the role of CD103 cytoplasmic domain and the focal adhesion-associated protein paxillin (Pxn) in downstream signaling and functional activities triggered through αE/CD103 chain. Binding to immobilized recombinant (r)E-cadherin-Fc of CD103 integrin expressed on tumor-specific CTL clones promotes phosphorylation of Pxn and Pyk2 and binding of Pxn to the αE/CD103 subunit tail. Inhibition of Pxn phosphorylation by the Src inhibitor saracatinib or its knockdown via shRNA dramatically altered adhesion and spreading of freshly isolated CD8+/CD103+ lung-tumor-infiltrating lymphocytes (TIL) and CD103+ tumor-specific CTL clones. Inhibition of Pxn phosphorylation with saracatinib in these CTL clones also severely compromised their functional activities toward autologous tumor cells. Using Jurkat T cells as a model to study CD103 integrin activation, we demonstrated a key role of serine residue S1163 of the αE chain intracellular domain in polarization of CD103 and recruitment of lysosomes and Pxn at the contact zone of T lymphocytes with rE-cadherin-Fc-coated beads. Overall, our results show how Pxn binding to the CD103 cytoplasmic tail triggers αEβ7 integrin outside-in signaling that promotes CD8+ T-cell migratory behavior and effector functions. These results also explain the more favorable prognosis associated with retention of TRM cells in the tumor microenvironment.

http://ift.tt/2yFxM7A

Glutamine addiction in kidney cancer suppresses oxidative stress and can be exploited for real-time imaging

Many cancers appear to activate intrinsic antioxidant systems as a means to counteract oxidative stress. Some cancers, such as clear cell renal cell carcinoma (ccRCC), require exogenous glutamine for growth and exhibit reprogrammed glutamine metabolism, at least in part due to the glutathione pathway, an efficient cellular buffering system that counteracts reactive oxygen species (ROS) and other oxidants. We show here that ccRCC xenograft tumors under the renal capsule exhibit enhanced oxidative stress compared to adjacent normal tissue and the contralateral kidney. Upon glutaminase inhibition with CB-839 or BPTES, the RCC cell lines SN12PM-6-1 (SN12) and 786-O exhibited decreased survival and pronounced apoptosis associated with a decreased GSH/GSSG ratio, augmented nuclear factor erythroid related factor 2 (NRF2), and increased 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a marker of DNA damage. SN12 tumor xenografts showed decreased growth when treated with CB-839. Furthermore, PET imaging confirmed that ccRCC tumors exhibited increased tumoral uptake of 18F-(2S,4R)4- fluoroglutamine (18F-FGln) compared to the kidney in the orthotopic mouse model. This technique can be utilized to follow changes in ccRCC metabolism in vivo. Further development of these paradigms will lead to new treatment options with glutaminase inhibitors and the utility of PET to identify and manage ccRCC patients who are likely to respond to glutaminase inhibitors in the clinic.-

http://ift.tt/2hCutTP

DDB2 is a Novel Regulator of Wnt-Signaling in Colon Cancer

Deregulation of the Wnt/β-catenin signaling pathway drives the development of colorectal cancer (CRC) but understanding of this pathway remains incomplete. Here we report that the damage-specific DNA-binding protein DDB2 is critical for β-catenin-mediated activation of RNF43, which restricts Wnt signaling by removing Wnt receptors from the cell surface. Reduced expression of DDB2 and RNF43 was observed in human hyperplastic colonic foci. DDB2 recruited EZH2 and β-catenin at an upstream site in the RNF43 gene, enabling functional interaction with distant TCF4/β-catenin binding sites in the intron of RNF43. This novel activity of DDB2 was required for RNF43 function as a negative feedback regulator of Wnt signaling. Mice genetically deficient in DDB2 exhibited increased susceptibility to colon tumor development in a manner associated with higher abundance of Wnt receptor-expressing cells and greater activation of the downstream Wnt-pathway. Our results identify DDB2 as both a partner and regulator of Wnt signaling with an important role in suppressing colon cancer development.

http://ift.tt/2yFxLR4

Distinct angiogenic changes during carcinogenesis defined by novel label-free dark field imaging in a hamster cheek pouch model

There remain gaps in knowledge concerning how vascular morphology evolves during carcinogenesis. In this study, we imaged neovascularization by label-free dark field microscopy of a DMBA-induced hamster cheek pouch model of oral squamous cell carcinoma (SCC). Wavelength-dependent imaging revealed distinct vascular features at different imaging depths and vessel sizes. Vascular tortuosity increased significantly in high-risk lesions, while diameter decreased significantly in hyperplastic and SCC lesions. Large vessels preserved the same trends seen in the original images, whereas small vessels displayed different trends, with length and diameter increasing during carcinogenesis. Based on these data we developed and validated a classification algorithm incorporating vascular features from different vessel masks. Receiver operator curves generated from the classification results demonstrated high accuracies in discriminating normal and hyperplasia from high-grade lesions (area under the curve>0.95). Overall, these results provided automated imaging of vasculature in the earliest stages of carcinogenesis from which one can extract robust endpoints. The optical toolbox described here is simple, low-cost and portable and can be used in a variety of health care and research settings for cancer prevention and pharmacology research.

http://ift.tt/2hCkpKu

Histone acetyltransferase KAT6A upregulates PI3K/Akt signaling through TRIM24 binding

Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM) where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity- deficient mutants or TRIM24 mutants lacking H3K23ac binding sites promoted PIK3CA expression, AKT phosphorylation and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment.

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Metabolite profiling reveals the glutathione biosynthetic pathway as a therapeutic target in triple negative breast cancer

Cancer cells can exhibit altered dependency on specific metabolic pathways and targeting these dependencies is a promising therapeutic strategy. Triple negative breast cancer (TNBC) is an aggressive and genomically heterogeneous subset of breast cancer that is resistant to existing targeted therapies. To identify metabolic pathway dependencies in TNBC, we first conducted mass spectrometry-based metabolomics of TNBC and control cells. Relative levels of intracellular metabolites distinguished TNBC from non-transformed breast epithelia and revealed two metabolic subtypes within TNBC that correlate with markers of basal-like versus non-basal-like status. Among the distinguishing metabolites, levels of the cellular redox buffer glutathione were lower in TNBC cell lines compared to controls and markedly lower in non-basal-like TNBC. Significantly, these cell lines showed enhanced sensitivity to pharmacological inhibition of glutathione biosynthesis that was rescued by N-acetylcysteine, demonstrating a dependence on glutathione production to suppress ROS and support tumor cell survival. Consistent with this, patients whose tumors express elevated levels of –glutamylcysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, had significantly poorer survival. We find, further, that agents that limit the availability of glutathione precursors enhance both glutathione depletion and TNBC cell killing by –glutamylcysteine ligase inhibitors in vitro. Importantly, we demonstrate the ability to this approach to suppress glutathione levels and TNBC xenograft growth in vivo. Overall, these findings support the potential of targeting the glutathione biosynthetic pathway as a therapeutic strategy in TNBC and identify the non-basal-like subset as most likely to respond.

http://ift.tt/2gwKvia

Metabolite profiling reveals the glutathione biosynthetic pathway as a therapeutic target in triple negative breast cancer

Cancer cells can exhibit altered dependency on specific metabolic pathways and targeting these dependencies is a promising therapeutic strategy. Triple negative breast cancer (TNBC) is an aggressive and genomically heterogeneous subset of breast cancer that is resistant to existing targeted therapies. To identify metabolic pathway dependencies in TNBC, we first conducted mass spectrometry-based metabolomics of TNBC and control cells. Relative levels of intracellular metabolites distinguished TNBC from non-transformed breast epithelia and revealed two metabolic subtypes within TNBC that correlate with markers of basal-like versus non-basal-like status. Among the distinguishing metabolites, levels of the cellular redox buffer glutathione were lower in TNBC cell lines compared to controls and markedly lower in non-basal-like TNBC. Significantly, these cell lines showed enhanced sensitivity to pharmacological inhibition of glutathione biosynthesis that was rescued by N-acetylcysteine, demonstrating a dependence on glutathione production to suppress ROS and support tumor cell survival. Consistent with this, patients whose tumors express elevated levels of –glutamylcysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, had significantly poorer survival. We find, further, that agents that limit the availability of glutathione precursors enhance both glutathione depletion and TNBC cell killing by –glutamylcysteine ligase inhibitors in vitro. Importantly, we demonstrate the ability to this approach to suppress glutathione levels and TNBC xenograft growth in vivo. Overall, these findings support the potential of targeting the glutathione biosynthetic pathway as a therapeutic strategy in TNBC and identify the non-basal-like subset as most likely to respond.

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Down-regulation of KLF5 in cancer-associated fibroblasts inhibit gastric cancer cells progression by CCL5/CCR5 axis

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Down-regulation of KLF5 in cancer-associated fibroblasts inhibit gastric cancer cells progression by CCL5/CCR5 axis

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Comparative Safety of Targeted Therapies for Metastatic Colorectal Cancer between Elderly and Younger Patients: a Study Using the International Pharmacovigilance Database

Abstract

Background

Metastatic colorectal cancer (mCRC) is increasingly treated using targeted therapies. Post-marketing safety of these agents is understudied, especially in the elderly.

Objective

This study aimed to compare, according to age, the adverse drug reactions (ADRs) of targeted therapies used for mCRC in real life.

Patients and Methods

An extraction of VigiBase, which contains World Health Organization individual case safety reports (ICSRs), was performed. All ADR reports with aflibercept, bevacizumab, cetuximab, panitumumab, or regorafenib used in CRC were considered. For all drugs, chi-square tests were used to compare frequencies of serious ADRs between patients aged ≥75 and <75 years. For selected ADRs and each drug, the drug-ADR association compared to other anticancer drugs was estimated through the proportional reporting ratio (PRR) in both age groups.

Results

There were 21,565 ICSRs included, among which 74% were serious and 11% were fatal. Median age was 64 years (Inter Quartile Range = 56–71) and 15% of patients were aged ≥75; 57% were male. Serious ICSRs accounted for 47,292 ADRs. Neutropenia was not more reported in elderly for all drugs while diarrhea was more reported in elderly for panitumumab. Cardiac disorders were more reported in elderly patients, in particular heart failure, especially for bevacizumab, cetuximab, and regorafenib, as were respiratory, thoracic, and mediastinal disorders. Most of PRR were not different between the two groups, except encephalopathies, which were significantly associated with bevacizumab in the elderly only.

Conclusions

ADRs related to targeted therapies used for mCRC treatment were different across age groups; yet, not systematically more reported or worse in elderly patients. Selected elderly patients could, therefore, be treated with these targeted therapies.

http://ift.tt/2zhzqcz

Enhancement of multiple cranial and spinal nerves in vanishing white matter: expanding the differential diagnosis

Abstract

Abnormal cranial or spinal nerve contrast enhancement on MRI in cases of suspected pediatric leukodystrophy is recognized as an important clue to the diagnosis of either metachromatic leukodystrophy or globoid cell leukodystrophy (Krabbe disease). We report a case of genetically confirmed childhood vanishing white matter with enhancement of multiple cranial and spinal nerves in addition to the more typical intracranial findings. This case expands the limited differential diagnosis of cranial nerve or spinal nerve enhancement in cases of suspected leukodystrophy and may aid in more efficient work-up and earlier diagnosis of vanishing white matter.

http://ift.tt/2xArBBs

Enhancement of multiple cranial and spinal nerves in vanishing white matter: expanding the differential diagnosis

Abstract

Abnormal cranial or spinal nerve contrast enhancement on MRI in cases of suspected pediatric leukodystrophy is recognized as an important clue to the diagnosis of either metachromatic leukodystrophy or globoid cell leukodystrophy (Krabbe disease). We report a case of genetically confirmed childhood vanishing white matter with enhancement of multiple cranial and spinal nerves in addition to the more typical intracranial findings. This case expands the limited differential diagnosis of cranial nerve or spinal nerve enhancement in cases of suspected leukodystrophy and may aid in more efficient work-up and earlier diagnosis of vanishing white matter.

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High LC3/Beclin Expression Correlates with Poor Survival in Glioma: a Definitive Role for Autophagy as Evidenced by In Vitro Autophagic Flux

Abstract

Recent studies suggest the role of autophagy, an evolutionarily conserved catabolic process, in determining the response of gliomas to treatment either positively or negatively. The study attempts to characterize autophagy in low and high-grade glioma by investigating the autophagic flux and clinical significance of autophagy proteins (LC3 and beclin 1) in a group of glioma patients. We evaluated the expression of autophagic markers in resected specimens of low-grade glioma (LGG) and high-grade glioma (HGG) tissues, by immunohistochemistry and Western blotting. Our results show that expression of autophagy proteins were more prominent in HGG than in LGG. Increased level of autophagic proteins in HGG can be due to an increased rate of autophagy or can be because of blockage in the final degradation step of autophagy (defective autophagy). To distinguish these possibilities, the autophagic flux assay which helps to determine the rate of degradation/synthesis of autophagic proteins (LC3-II and p62) over a period of time by blocking the final degradation step of autophagy using bafilomycin A1 was used . The assessment of autophagic flux in ex vivo culture of primary glioma cells revealed for the first time increased turnover of autophagy in high grade compared to low grade-glioma. Though autophagic markers were reduced in LGG, functionally autophagy was non defective in both grades of glioma. We then investigated whether autophagy in gliomas is regulated by nutrient sensing pathways including mTOR and promote cell survival by providing an alternate energy source in response to metabolic stress. The results depicted that the role of autophagy during stress varies with tissue and has a negative correlation with mTOR substrate phosphorylation. We also evaluated the expression of LC3 and beclin 1 with progression free survival (PFS) using Kaplan-Meier survival analysis and have found that patients with low LC3/beclin 1 expression had better PFS than those with high expression of LC3/beclin 1 in their tumors. Together, we provide evidence that autophagy is non-defective in glioma and also show that high LC3/beclin 1 expression correlates with poor PFS in both LGG and HGG.

http://ift.tt/2xApkpV

High LC3/Beclin Expression Correlates with Poor Survival in Glioma: a Definitive Role for Autophagy as Evidenced by In Vitro Autophagic Flux

Abstract

Recent studies suggest the role of autophagy, an evolutionarily conserved catabolic process, in determining the response of gliomas to treatment either positively or negatively. The study attempts to characterize autophagy in low and high-grade glioma by investigating the autophagic flux and clinical significance of autophagy proteins (LC3 and beclin 1) in a group of glioma patients. We evaluated the expression of autophagic markers in resected specimens of low-grade glioma (LGG) and high-grade glioma (HGG) tissues, by immunohistochemistry and Western blotting. Our results show that expression of autophagy proteins were more prominent in HGG than in LGG. Increased level of autophagic proteins in HGG can be due to an increased rate of autophagy or can be because of blockage in the final degradation step of autophagy (defective autophagy). To distinguish these possibilities, the autophagic flux assay which helps to determine the rate of degradation/synthesis of autophagic proteins (LC3-II and p62) over a period of time by blocking the final degradation step of autophagy using bafilomycin A1 was used . The assessment of autophagic flux in ex vivo culture of primary glioma cells revealed for the first time increased turnover of autophagy in high grade compared to low grade-glioma. Though autophagic markers were reduced in LGG, functionally autophagy was non defective in both grades of glioma. We then investigated whether autophagy in gliomas is regulated by nutrient sensing pathways including mTOR and promote cell survival by providing an alternate energy source in response to metabolic stress. The results depicted that the role of autophagy during stress varies with tissue and has a negative correlation with mTOR substrate phosphorylation. We also evaluated the expression of LC3 and beclin 1 with progression free survival (PFS) using Kaplan-Meier survival analysis and have found that patients with low LC3/beclin 1 expression had better PFS than those with high expression of LC3/beclin 1 in their tumors. Together, we provide evidence that autophagy is non-defective in glioma and also show that high LC3/beclin 1 expression correlates with poor PFS in both LGG and HGG.

http://ift.tt/2xApkpV

Ex Situ Hepatectomy and Liver Autotransplantation for Cholangiocarcinoma

Abstract

Background

Hepatic resection of tumors invading the retrohepatic vena cava and hepatic veins are a challenge for surgeons, who consider them unresectable most of the time.1 ^,2 Ex situ hepatectomy and liver autotransplantation has developed to improve resectability of these malignancies.3,4

Methods

The patient was a 51-year-old man who had jaundice secondary to a intrahepatic cholangiocarcinoma 7 cm in diameter in the right lobe of the liver and the caudate lobe. A volumetric scan showed a future liver remnant (segments 2 and 3) not sufficient according to the body weight. The patient was considered to be unresectable by conventional resection due to the critical invasion to the retrohepatic vena cava together with the three hepatic veins. Therefore, an ex vivo extended right hepatectomy and autotransplantation were indicated.

Results

The patient underwent biliary decompression through a percutaneous transhepatic catheter and right portal vein embolization for left lobe hypertrophy. During the surgery, the liver was removed with the retrohepatic vena cava, which was replaced by a prosthetic graft without a veno-venous bypass. Ex vivo extended right hepatectomy was performed, and a prosthetic graft was used to replace the vena cava where the remaining left hepatic vein was anastomosed. The surgery duration was 9 h, and the anhepatic time was 4.5 h. The postoperative hospital stay was 19 days, and at this writing, 3 years later, the patient is disease-free.

Conclusion

Ex vivo hepatectomy without veno-venous bypass should be considered a valid therapeutic option for selected patients with cholangiocarcinoma invading the retrohepatic vena cava.

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Ex Situ Hepatectomy and Liver Autotransplantation for Cholangiocarcinoma

Abstract

Background

Hepatic resection of tumors invading the retrohepatic vena cava and hepatic veins are a challenge for surgeons, who consider them unresectable most of the time.1 ^,2 Ex situ hepatectomy and liver autotransplantation has developed to improve resectability of these malignancies.3,4

Methods

The patient was a 51-year-old man who had jaundice secondary to a intrahepatic cholangiocarcinoma 7 cm in diameter in the right lobe of the liver and the caudate lobe. A volumetric scan showed a future liver remnant (segments 2 and 3) not sufficient according to the body weight. The patient was considered to be unresectable by conventional resection due to the critical invasion to the retrohepatic vena cava together with the three hepatic veins. Therefore, an ex vivo extended right hepatectomy and autotransplantation were indicated.

Results

The patient underwent biliary decompression through a percutaneous transhepatic catheter and right portal vein embolization for left lobe hypertrophy. During the surgery, the liver was removed with the retrohepatic vena cava, which was replaced by a prosthetic graft without a veno-venous bypass. Ex vivo extended right hepatectomy was performed, and a prosthetic graft was used to replace the vena cava where the remaining left hepatic vein was anastomosed. The surgery duration was 9 h, and the anhepatic time was 4.5 h. The postoperative hospital stay was 19 days, and at this writing, 3 years later, the patient is disease-free.

Conclusion

Ex vivo hepatectomy without veno-venous bypass should be considered a valid therapeutic option for selected patients with cholangiocarcinoma invading the retrohepatic vena cava.

http://ift.tt/2g2YsUx

Initial evaluation of the Celesteion large-bore PET/CT scanner in accordance with the NEMA NU2-2012 standard and the Japanese guideline for oncology FDG PET/CT data acquisition protocol version 2.0

Abstract

Background

The goal of this study was to evaluate the performance of the Celesteion positron emission tomography/computed tomography (PET/CT) scanner, which is characterized by a large-bore and time-of-flight (TOF) function, in accordance with the NEMA NU-2 2012 standard and version 2.0 of the Japanese guideline for oncology fluorodeoxyglucose PET/CT data acquisition protocol. Spatial resolution, sensitivity, count rate characteristic, scatter fraction, energy resolution, TOF timing resolution, and image quality were evaluated according to the NEMA NU-2 2012 standard. Phantom experiments were performed using ¹⁸F-solution and an IEC body phantom of the type described in the NEMA NU-2 2012 standard. The minimum scanning time required for the detection of a 10-mm hot sphere with a 4:1 target-to-background ratio, the phantom noise equivalent count (NEC_phantom), % background variability (N _10mm), % contrast (Q _H,10mm), and recovery coefficient (RC) were calculated according to the Japanese guideline.

Results

The measured spatial resolution ranged from 4.5- to 5-mm full width at half maximum (FWHM). The sensitivity and scatter fraction were 3.8 cps/kBq and 37.3%, respectively. The peak noise-equivalent count rate was 70 kcps in the presence of 29.6 kBq mL⁻¹ in the phantom. The system energy resolution was 12.4% and the TOF timing resolution was 411 ps at FWHM. Minimum scanning times of 2, 7, 6, and 2 min per bed position, respectively, are recommended for visual score, noise-equivalent count (NEC)_phantom, N _10mm, and the Q _H,10mm to N _10mm ratio (QNR) by the Japanese guideline. The RC of a 10-mm-diameter sphere was 0.49, which exceeded the minimum recommended value.

Conclusions

The Celesteion large-bore PET/CT system had low sensitivity and NEC, but good spatial and time resolution when compared to other PET/CT scanners. The QNR met the recommended values of the Japanese guideline even at 2 min. The Celesteion is therefore thought to provide acceptable image quality with 2 min/bed position acquisition, which is the most common scan protocol in Japan.

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Initial evaluation of the Celesteion large-bore PET/CT scanner in accordance with the NEMA NU2-2012 standard and the Japanese guideline for oncology FDG PET/CT data acquisition protocol version 2.0

Abstract

Background

The goal of this study was to evaluate the performance of the Celesteion positron emission tomography/computed tomography (PET/CT) scanner, which is characterized by a large-bore and time-of-flight (TOF) function, in accordance with the NEMA NU-2 2012 standard and version 2.0 of the Japanese guideline for oncology fluorodeoxyglucose PET/CT data acquisition protocol. Spatial resolution, sensitivity, count rate characteristic, scatter fraction, energy resolution, TOF timing resolution, and image quality were evaluated according to the NEMA NU-2 2012 standard. Phantom experiments were performed using ¹⁸F-solution and an IEC body phantom of the type described in the NEMA NU-2 2012 standard. The minimum scanning time required for the detection of a 10-mm hot sphere with a 4:1 target-to-background ratio, the phantom noise equivalent count (NEC_phantom), % background variability (N _10mm), % contrast (Q _H,10mm), and recovery coefficient (RC) were calculated according to the Japanese guideline.

Results

The measured spatial resolution ranged from 4.5- to 5-mm full width at half maximum (FWHM). The sensitivity and scatter fraction were 3.8 cps/kBq and 37.3%, respectively. The peak noise-equivalent count rate was 70 kcps in the presence of 29.6 kBq mL⁻¹ in the phantom. The system energy resolution was 12.4% and the TOF timing resolution was 411 ps at FWHM. Minimum scanning times of 2, 7, 6, and 2 min per bed position, respectively, are recommended for visual score, noise-equivalent count (NEC)_phantom, N _10mm, and the Q _H,10mm to N _10mm ratio (QNR) by the Japanese guideline. The RC of a 10-mm-diameter sphere was 0.49, which exceeded the minimum recommended value.

Conclusions

The Celesteion large-bore PET/CT system had low sensitivity and NEC, but good spatial and time resolution when compared to other PET/CT scanners. The QNR met the recommended values of the Japanese guideline even at 2 min. The Celesteion is therefore thought to provide acceptable image quality with 2 min/bed position acquisition, which is the most common scan protocol in Japan.

http://ift.tt/2g1deer

The prognostic value of C-X-C motif chemokine receptor 4 in patients with sporadic malignant peripheral nerve sheath tumors

Recent studies indicate that C-X-C motif chemokine receptor 4 (CXCR4) and its ligand, C-X-C motif chemokine ligand 12 (CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofibro...

http://ift.tt/2yhmOUv

The prognostic value of C-X-C motif chemokine receptor 4 in patients with sporadic malignant peripheral nerve sheath tumors

Recent studies indicate that C-X-C motif chemokine receptor 4 (CXCR4) and its ligand, C-X-C motif chemokine ligand 12 (CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofibro...

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Isolated Limb Perfusion and Infusion for Extremity Soft Tissue Sarcoma: A Contemporary Systematic Review and Meta-Analysis

Abstract

Background

Isolated limb perfusion (ILP) and isolated limb infusion (ILI) have been variably used in recent years for the treatment of locally advanced or marginally resectable extremity soft tissue sarcomas (STSs). We performed a systematic review and meta-analysis of contemporary studies to further characterize treatment patterns and outcomes.

Methods

PubMed was queried for articles published in or after the year 2000, in the English language, with > 10 patients, and with adequate outcome data following ILP/ILI. Descriptive aggregate statistics were performed.

Results

Nineteen studies that met the inclusion criteria were identified, with a total of 1288 patients. Weighted mean patient age was 55.9 years and 52% were male. The majority underwent ILP (88%) versus 12% for ILI, and chemotherapeutic regimens used were as follows: (1) melphalan with tumor necrosis factor (TNF)-α (78%), (2) melphalan ± actinomycin (10%), and (3) other regimens (12%). Most common histologies treated were malignant fibrous histiocytoma (21%), liposarcoma (16%), synovial (11%) and leiomyosarcoma (7%). Aggregate overall response rate (ORR) post-procedure was 73.3%, with 25.8% demonstrating a complete response (CR). Similar unadjusted ORRs were noted in the melphalan treatment groups with and without TNFα (72.0 and 67.0%, respectively; p = 0.27). Grade III toxicity was observed in 15.4% of patients, and grade IV/V toxicity was observed in 6.0% of patients. Overall limb salvage rate was 73.8% and median time to local (in-field) progression ranged from 4 to 28 months (weighted median 22.1 months).

Conclusion

ILP and ILI for extremity STS can be safely performed with appreciable response rates and significant limb salvage rates. Further study is needed to identify optimal treatment regimens by histology.

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High Expression of the Mitophagy-Related Protein Pink1 is Associated with a Poor Response to Chemotherapy and a Poor Prognosis for Patients Treated with Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma

Abstract

Background

Autophagy plays a major role in cellular homeostasis and is implicated in cancer progression. Damaged mitochondria are scavenged and eliminated by mitochondrial autophagy, referred to as mitophagy, which can promote cancer cell survival. This study investigated the expression and effects of the autophagy-related protein LC3 and the mitophagy-related protein Pink1 in human esophageal squamous cell carcinoma (ESCC).

Methods

Both LC3 and Pink1 were analyzed by immunohistochemistry in tissues from 217 ESCC patients, including 159 patients undergoing neoadjuvant chemotherapy. The relationships between LC3 and Pink1 expression and various clinicopathologic factors were determined. In vitro assays were performed to assess the role of LC3 and Pink1 in ESCC chemoresistance.

Results

High LC3 expression was observed in 47.9% and high Pink1 expression in 48.4% of the ESCC patients. Pink1 expression was significantly higher in patients who underwent chemotherapy than in patients who did not (p = 0.032). High LC3 and Pink1 expression was significantly correlated with poor response to chemotherapy (p = 0.004 and p < 0.001, respectively), and high expression of Pink1, but not LC3, was significantly correlated with a poor prognosis for patients treated with preoperative chemotherapy (p = 0.007). Multivariate analysis identified Pink1 expression as an independent prognostic factor (p = 0.042). In vitro assays demonstrated that LC3-II and Pink1 expression increased after chemotherapeutic treatment in the ESCC cell line, and inhibition of autophagy and mitophagy using chloroquine and siPink1, respectively, restored chemosensitivity.

Conclusions

High expression of Pink1 is associated with chemoresistance and a poor prognosis for ESCC patients undergoing neoadjuvant chemotherapy.

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Isolated Limb Perfusion and Infusion for Extremity Soft Tissue Sarcoma: A Contemporary Systematic Review and Meta-Analysis

Abstract

Background

Isolated limb perfusion (ILP) and isolated limb infusion (ILI) have been variably used in recent years for the treatment of locally advanced or marginally resectable extremity soft tissue sarcomas (STSs). We performed a systematic review and meta-analysis of contemporary studies to further characterize treatment patterns and outcomes.

Methods

PubMed was queried for articles published in or after the year 2000, in the English language, with > 10 patients, and with adequate outcome data following ILP/ILI. Descriptive aggregate statistics were performed.

Results

Nineteen studies that met the inclusion criteria were identified, with a total of 1288 patients. Weighted mean patient age was 55.9 years and 52% were male. The majority underwent ILP (88%) versus 12% for ILI, and chemotherapeutic regimens used were as follows: (1) melphalan with tumor necrosis factor (TNF)-α (78%), (2) melphalan ± actinomycin (10%), and (3) other regimens (12%). Most common histologies treated were malignant fibrous histiocytoma (21%), liposarcoma (16%), synovial (11%) and leiomyosarcoma (7%). Aggregate overall response rate (ORR) post-procedure was 73.3%, with 25.8% demonstrating a complete response (CR). Similar unadjusted ORRs were noted in the melphalan treatment groups with and without TNFα (72.0 and 67.0%, respectively; p = 0.27). Grade III toxicity was observed in 15.4% of patients, and grade IV/V toxicity was observed in 6.0% of patients. Overall limb salvage rate was 73.8% and median time to local (in-field) progression ranged from 4 to 28 months (weighted median 22.1 months).

Conclusion

ILP and ILI for extremity STS can be safely performed with appreciable response rates and significant limb salvage rates. Further study is needed to identify optimal treatment regimens by histology.

http://ift.tt/2yF4aao

High Expression of the Mitophagy-Related Protein Pink1 is Associated with a Poor Response to Chemotherapy and a Poor Prognosis for Patients Treated with Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma

Abstract

Background

Autophagy plays a major role in cellular homeostasis and is implicated in cancer progression. Damaged mitochondria are scavenged and eliminated by mitochondrial autophagy, referred to as mitophagy, which can promote cancer cell survival. This study investigated the expression and effects of the autophagy-related protein LC3 and the mitophagy-related protein Pink1 in human esophageal squamous cell carcinoma (ESCC).

Methods

Both LC3 and Pink1 were analyzed by immunohistochemistry in tissues from 217 ESCC patients, including 159 patients undergoing neoadjuvant chemotherapy. The relationships between LC3 and Pink1 expression and various clinicopathologic factors were determined. In vitro assays were performed to assess the role of LC3 and Pink1 in ESCC chemoresistance.

Results

High LC3 expression was observed in 47.9% and high Pink1 expression in 48.4% of the ESCC patients. Pink1 expression was significantly higher in patients who underwent chemotherapy than in patients who did not (p = 0.032). High LC3 and Pink1 expression was significantly correlated with poor response to chemotherapy (p = 0.004 and p < 0.001, respectively), and high expression of Pink1, but not LC3, was significantly correlated with a poor prognosis for patients treated with preoperative chemotherapy (p = 0.007). Multivariate analysis identified Pink1 expression as an independent prognostic factor (p = 0.042). In vitro assays demonstrated that LC3-II and Pink1 expression increased after chemotherapeutic treatment in the ESCC cell line, and inhibition of autophagy and mitophagy using chloroquine and siPink1, respectively, restored chemosensitivity.

Conclusions

High expression of Pink1 is associated with chemoresistance and a poor prognosis for ESCC patients undergoing neoadjuvant chemotherapy.

http://ift.tt/2ygxvqc

Application of EGFR inhibitor reduces circulating tumor cells during transcatheter arterial embolization

Abstract

Purpose

Transcatheter arterial embolization (TAE) has been widely used in treating non-curative hepatocellular carcinoma (HCC). However, it is noticed that TAE may cause invasion of some cancer cells into circulation, resulting in distal metastasis and poor therapeutic outcome. Here, we aimed to reduce the side effects of TAE using the inhibitors for epidermal growth factor receptor (EGFR).

Methods

Transient hepatic artery ligation (HAL) was used as a mouse model for TAE. EGFR inhibitors were applied. Tumor size, presence of tumor cells in circulation, distal tumor formation, and activation of genes associated with tumor cell invasion and metastasis were analyzed.

Results

Inhibitors for EGFR significantly reduced the size of primary tumor, presence of tumor cells in circulation, and distal tumor formation after HAL. Further studies showed that EGFR inhibition suppressed several genes associated with tumor cell invasion and metastasis, such as vascular endothelial growth factor-A, stromal cell-derived factor 1, and Slug.

Conclusion

EGFR inhibitor application may reduce circulating cancer cells during TAE and thus improve the therapy for advanced HCC.

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Application of EGFR inhibitor reduces circulating tumor cells during transcatheter arterial embolization

Abstract

Purpose

Transcatheter arterial embolization (TAE) has been widely used in treating non-curative hepatocellular carcinoma (HCC). However, it is noticed that TAE may cause invasion of some cancer cells into circulation, resulting in distal metastasis and poor therapeutic outcome. Here, we aimed to reduce the side effects of TAE using the inhibitors for epidermal growth factor receptor (EGFR).

Methods

Transient hepatic artery ligation (HAL) was used as a mouse model for TAE. EGFR inhibitors were applied. Tumor size, presence of tumor cells in circulation, distal tumor formation, and activation of genes associated with tumor cell invasion and metastasis were analyzed.

Results

Inhibitors for EGFR significantly reduced the size of primary tumor, presence of tumor cells in circulation, and distal tumor formation after HAL. Further studies showed that EGFR inhibition suppressed several genes associated with tumor cell invasion and metastasis, such as vascular endothelial growth factor-A, stromal cell-derived factor 1, and Slug.

Conclusion

EGFR inhibitor application may reduce circulating cancer cells during TAE and thus improve the therapy for advanced HCC.

http://ift.tt/2i2VWSp

Concurrent radiotherapy with temozolomide vs. concurrent radiotherapy with a cisplatinum-based polychemotherapy regimen

Abstract

Purpose

As the efficacy of all pediatric high-grade glioma (HGG) treatments is similar and still disappointing, it is essential to also investigate the toxicity of available treatments.

Methods

Prospectively recorded hematologic and nonhematologic toxicities of children treated with radiochemotherapy in the HIT GBM-C/D and HIT-HGG-2007 trials were compared. Children aged 3–18 years with histologically proven HGG (WHO grade III and IV tumors) or unequivocal radiologic diagnosis of diffuse intrinsic pontine glioma (DIPG) were included in these trials. The HIT-HGG-2007 protocol comprised concomitant radiochemotherapy with temozolomide, while cisplatinum/etoposide (PE) and PE plus ifosfamide (PEI) in combination with weekly vincristine injections were applied during radiochemotherapy in the HIT GBM-C/D protocol.

Results

Regular blood counts and information about cellular nadirs were available from 304 patients (leukocytes) and 306 patients (thrombocytes), respectively. Grade 3–4 leukopenia was much more frequent in the HIT GBM-C/D cohort (n = 88, 52%) vs. HIT-HGG-2007 (n = 13, 10%; P <0.001). Grade 3–4 thrombopenia was also more likely in the HIT GBM-C/D cohort (n = 21, 12% vs. n = 3,2%; P <0.001). Grade 3–4 leukopenia appeared more often in children aged 3–7 years (n = 38/85, 45%) than in children aged 8–12 years (n = 39/120, 33%) and 13–18 years (24/100, 24%; P =0.034). In addition, sickness was more frequent in the HIT GBM-C/D cohort (grade 1–2: 44%, grade 3–4: 6% vs. grade 1–2: 28%, grade 3–4: 1%; P <0.001).

Conclusion

Radiochemotherapy involving cisplatinum-based polychemotherapy is more toxic than radiotherapy in combination with temozolomide. Without evidence of differences in therapeutic efficacy, the treatment with lower toxicity, i. e., radiotherapy with temozolomide should be used.

http://ift.tt/2hAuabQ

Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer

Abstract

Background

Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)–positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer.

Methods

Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided.

Results

RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm³, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm³, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance–associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor–1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity–independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen resistance (RBP2-overexpressing cells: % cell viability [SD], tamoxifen = 89.0 [3.8]%, vs tamoxifen with BKM120 = 41.3 [5.6]%, P < .001).

Conclusions

RBP2 activates ER-IGF1R-ErbB signaling cascade in multiple ways to induce tamoxifen resistance, suggesting that RBP2 is a potential therapeutic target for ER-driven cancer.

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Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer

Abstract

Background

Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)–positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer.

Methods

Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided.

Results

RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm³, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm³, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance–associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor–1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity–independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen resistance (RBP2-overexpressing cells: % cell viability [SD], tamoxifen = 89.0 [3.8]%, vs tamoxifen with BKM120 = 41.3 [5.6]%, P < .001).

Conclusions

RBP2 activates ER-IGF1R-ErbB signaling cascade in multiple ways to induce tamoxifen resistance, suggesting that RBP2 is a potential therapeutic target for ER-driven cancer.

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Prevalence of fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell carcinomas of the head and neck

Abstract

Background

FGFR1 is a receptor tyrosine kinases involved in tumor growth signaling, survival, and differentiation in many solid cancer types. There is growing evidence that FGFR1 amplification might predict therapy response to FGFR1 inhibitors in squamous cell lung cancers. To estimate the potential applicability of anti FGFR1 therapies in squamous cell carcinomas of the head and neck, we studied patterns of FGFR1 amplification using fluorescence in situ hybridization (FISH).

Materials and methods

A tissue microarray was constructed from 453 primary treatment-naive squamous cell carcinomas of the head and neck regions with histopathological and clinical follow-up data [including oral cavity (n = 222), oropharynx (n = 126), and larynx (n = 105)]. FGFR1 and centromere 8 copy numbers were assessed by dual-color FISH. FGFR1 amplification was defined as a copy number ratio FGFR1: centromere 8 ≥ 2.0. HPV sequencing and p16 immunohistochemistry (IHC) were applied to FGFR1-amplified cancers.

Results

FISH analysis was successful in 297 (66%) of the 453 cancers. FGFR1 amplification was found in 6% of analyzable tumors, and was more frequent in tumors of the oral cavity (13/133 amplified, 10%), than cancers of other localizations (1/79 oropharynx, 4/85 larynx; p = 0.007 and 0.159, respectively). One out of 18 FGFR1 amplified cancers was HPV positive. No associations were found between FGFR1 amplification and tumor phenotype or p16 IHC.

Conclusions

Head and neck cancers are recurrently affected by FGFR1 amplification, with a predominance in cancers of the oral cavity. Finding only one HPV positive and FGFR1 amplified cancer argues against a causal relationship between HPV and FGFR1 amplifications.

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Survival benefit of mantle cell lymphoma patients enrolled in clinical trials; a joint study from the LYSA group and French cancer registries

Abstract

Purpose

Mantle cell lymphoma (MCL) is a rare non-Hodgkin's lymphoma entity with a poor prognosis. Therapeutic advances have improved the survival of patients enrolled in clinical trials; however, their impact on patients outside clinical trials remains unclear. In this work, we compared patient outcome inside and outside clinical trials.

Methods

We identified MCL patients recorded in six French population-based registries between 2008 and 2012 to perform a comparison with patients enrolled in two prospective multicenter MCL clinical trials conducted by the LYSA group during the same period. Variables associated with inclusion in a clinical trial were identified using a logistic regression. Pohar-Perme estimator and Nelson et al. flexible parametric model was used to estimate net survival probabilities and prognosis factors on excess mortality.

Results

A total of 312 registry patients were compared to the 372 patients enrolled in LYSA clinical trials. Patients included in clinical trials were younger (median age 60 vs 74, p < 0.001). Age and Ann Arbor stage IV were independently associated with enrollment [OR = 0.09 (0.06–0.12) and OR = 1.61 (1.11–2.34), respectively]. The 4 year net survival was better in clinical trials [79.9% (75.9–84.7) vs 60.3% (53.6–67.0)]. This result was confirmed in multivariate analysis in patients older than 65 years with a lower excess mortality rate [0.33 (0.17–0.66)].

Conclusions

MCL included in trials are highly selected patients who are not representative of MCL patients who are encountered in everyday practice. With widened inclusion criteria, clinical trial patients could be more representative of the general population.

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Prevalence of fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell carcinomas of the head and neck

Abstract

Background

FGFR1 is a receptor tyrosine kinases involved in tumor growth signaling, survival, and differentiation in many solid cancer types. There is growing evidence that FGFR1 amplification might predict therapy response to FGFR1 inhibitors in squamous cell lung cancers. To estimate the potential applicability of anti FGFR1 therapies in squamous cell carcinomas of the head and neck, we studied patterns of FGFR1 amplification using fluorescence in situ hybridization (FISH).

Materials and methods

A tissue microarray was constructed from 453 primary treatment-naive squamous cell carcinomas of the head and neck regions with histopathological and clinical follow-up data [including oral cavity (n = 222), oropharynx (n = 126), and larynx (n = 105)]. FGFR1 and centromere 8 copy numbers were assessed by dual-color FISH. FGFR1 amplification was defined as a copy number ratio FGFR1: centromere 8 ≥ 2.0. HPV sequencing and p16 immunohistochemistry (IHC) were applied to FGFR1-amplified cancers.

Results

FISH analysis was successful in 297 (66%) of the 453 cancers. FGFR1 amplification was found in 6% of analyzable tumors, and was more frequent in tumors of the oral cavity (13/133 amplified, 10%), than cancers of other localizations (1/79 oropharynx, 4/85 larynx; p = 0.007 and 0.159, respectively). One out of 18 FGFR1 amplified cancers was HPV positive. No associations were found between FGFR1 amplification and tumor phenotype or p16 IHC.

Conclusions

Head and neck cancers are recurrently affected by FGFR1 amplification, with a predominance in cancers of the oral cavity. Finding only one HPV positive and FGFR1 amplified cancer argues against a causal relationship between HPV and FGFR1 amplifications.

http://ift.tt/2i3uIuU

Survival benefit of mantle cell lymphoma patients enrolled in clinical trials; a joint study from the LYSA group and French cancer registries

Abstract

Purpose

Mantle cell lymphoma (MCL) is a rare non-Hodgkin's lymphoma entity with a poor prognosis. Therapeutic advances have improved the survival of patients enrolled in clinical trials; however, their impact on patients outside clinical trials remains unclear. In this work, we compared patient outcome inside and outside clinical trials.

Methods

We identified MCL patients recorded in six French population-based registries between 2008 and 2012 to perform a comparison with patients enrolled in two prospective multicenter MCL clinical trials conducted by the LYSA group during the same period. Variables associated with inclusion in a clinical trial were identified using a logistic regression. Pohar-Perme estimator and Nelson et al. flexible parametric model was used to estimate net survival probabilities and prognosis factors on excess mortality.

Results

A total of 312 registry patients were compared to the 372 patients enrolled in LYSA clinical trials. Patients included in clinical trials were younger (median age 60 vs 74, p < 0.001). Age and Ann Arbor stage IV were independently associated with enrollment [OR = 0.09 (0.06–0.12) and OR = 1.61 (1.11–2.34), respectively]. The 4 year net survival was better in clinical trials [79.9% (75.9–84.7) vs 60.3% (53.6–67.0)]. This result was confirmed in multivariate analysis in patients older than 65 years with a lower excess mortality rate [0.33 (0.17–0.66)].

Conclusions

MCL included in trials are highly selected patients who are not representative of MCL patients who are encountered in everyday practice. With widened inclusion criteria, clinical trial patients could be more representative of the general population.

http://ift.tt/2gvtWmP

Exposure–response analyses of trastuzumab emtansine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane

Abstract

Purpose

In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-free survival (PFS) and overall survival (OS) versus capecitabine plus lapatinib (control) in previously treated human epidermal growth factor receptor 2-positive advanced breast cancer. Using EMILIA data, we evaluated the T-DM1 exposure–response relationship.

Methods

Exposure–response relationships were examined with four exposure metrics [model-predicted and observed minimum concentration (C _min) and area under the concentration–time curve from time zero to day 21 of T-DM1 at cycle 1] and multiple efficacy (OS, PFS, objective response rate) and safety (grade ≥ 3 adverse events, grade ≥ 3 thrombocytopenia, grade ≥ 3 hepatotoxicity) endpoints.

Results

An apparent exposure–response trend was observed between model-predicted exposure metrics and efficacy; trends for observed exposure metrics were shallower and often not significant. Although median OS and PFS were numerically longer in patients with higher versus lower model-predicted cycle 1 C _min, OS and PFS hazard ratios for T-DM1-treated patients in the lowest exposure quartile (Q1) versus control were < 1 after adjusting for baseline risk factors (e.g., ECOG status, tumor burden, measurable disease, and number of disease sites). No meaningful exposure–response relationship was observed for any safety endpoints.

Conclusion

Exposure–response relationships for efficacy were inconsistent across exposure metrics; model-predicted cycle 1 C _min showed the strongest exposure–response trend. The Q1 subgroup based on model-predicted cycle 1 C _min had numerically similar or better OS and PFS versus control following covariate adjustment. The approved T-DM1 dose (3.6 mg/kg every 3 weeks) has a positive benefit–risk ratio versus control, even for the T-DM1 Q1 subgroup.

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Exposure–response analyses of trastuzumab emtansine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane

Abstract

Purpose

In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-free survival (PFS) and overall survival (OS) versus capecitabine plus lapatinib (control) in previously treated human epidermal growth factor receptor 2-positive advanced breast cancer. Using EMILIA data, we evaluated the T-DM1 exposure–response relationship.

Methods

Exposure–response relationships were examined with four exposure metrics [model-predicted and observed minimum concentration (C _min) and area under the concentration–time curve from time zero to day 21 of T-DM1 at cycle 1] and multiple efficacy (OS, PFS, objective response rate) and safety (grade ≥ 3 adverse events, grade ≥ 3 thrombocytopenia, grade ≥ 3 hepatotoxicity) endpoints.

Results

An apparent exposure–response trend was observed between model-predicted exposure metrics and efficacy; trends for observed exposure metrics were shallower and often not significant. Although median OS and PFS were numerically longer in patients with higher versus lower model-predicted cycle 1 C _min, OS and PFS hazard ratios for T-DM1-treated patients in the lowest exposure quartile (Q1) versus control were < 1 after adjusting for baseline risk factors (e.g., ECOG status, tumor burden, measurable disease, and number of disease sites). No meaningful exposure–response relationship was observed for any safety endpoints.

Conclusion

Exposure–response relationships for efficacy were inconsistent across exposure metrics; model-predicted cycle 1 C _min showed the strongest exposure–response trend. The Q1 subgroup based on model-predicted cycle 1 C _min had numerically similar or better OS and PFS versus control following covariate adjustment. The approved T-DM1 dose (3.6 mg/kg every 3 weeks) has a positive benefit–risk ratio versus control, even for the T-DM1 Q1 subgroup.

http://ift.tt/2i2PhYe

let-7d suppresses proliferation and invasion and promotes apoptosis of meningioma by targeting AEG-1

http://ift.tt/2i3f42z

Quantification of altered tissue turnover in a liquid biopsy: a proposed precision medicine tool to assess chronic inflammation and desmoplasia associated with a pro-cancerous niche and response to immuno-therapeutic anti-tumor modalities

Abstract

Immuno-therapy has begun to revolutionize cancer treatment. However, despite the significant progress achieved in regard to the duration of clinical benefits, a substantial number of patients do not respond to these therapies. To improve the outcome of patients receiving immuno-therapy, there is a need for novel biomarkers that can predict and monitor treatment. Tumor microenvironment alterations, more specifically the state of chronic inflammation and desmoplasia (tumor fibrosis), are important factors to consider in this context. Here, we discuss the potential for quantification of altered tissue turnover in a liquid biopsy as a proposed precision medicine tool to assess chronic inflammation and desmoplasia in the immuno-oncology (IO) setting. We highlight the need for novel non-invasive biomarkers in IO and the importance of addressing tumor microenvironment alterations. We focus on desmoplasia and extracellular matrix (ECM) remodeling, and how the composition of the ECM defines T-cell permissiveness in the tumor microenvironment and opens up the possibility for associated liquid biopsy biomarkers. Moreover, we address the importance of the assessment of chronic inflammation, primarily macrophage activity, in a liquid biopsy.

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Quantification of altered tissue turnover in a liquid biopsy: a proposed precision medicine tool to assess chronic inflammation and desmoplasia associated with a pro-cancerous niche and response to immuno-therapeutic anti-tumor modalities

Abstract

Immuno-therapy has begun to revolutionize cancer treatment. However, despite the significant progress achieved in regard to the duration of clinical benefits, a substantial number of patients do not respond to these therapies. To improve the outcome of patients receiving immuno-therapy, there is a need for novel biomarkers that can predict and monitor treatment. Tumor microenvironment alterations, more specifically the state of chronic inflammation and desmoplasia (tumor fibrosis), are important factors to consider in this context. Here, we discuss the potential for quantification of altered tissue turnover in a liquid biopsy as a proposed precision medicine tool to assess chronic inflammation and desmoplasia in the immuno-oncology (IO) setting. We highlight the need for novel non-invasive biomarkers in IO and the importance of addressing tumor microenvironment alterations. We focus on desmoplasia and extracellular matrix (ECM) remodeling, and how the composition of the ECM defines T-cell permissiveness in the tumor microenvironment and opens up the possibility for associated liquid biopsy biomarkers. Moreover, we address the importance of the assessment of chronic inflammation, primarily macrophage activity, in a liquid biopsy.

http://ift.tt/2hAaBjS

Quantification of altered tissue turnover in a liquid biopsy: a proposed precision medicine tool to assess chronic inflammation and desmoplasia associated with a pro-cancerous niche and response to immuno-therapeutic anti-tumor modalities

Abstract

Immuno-therapy has begun to revolutionize cancer treatment. However, despite the significant progress achieved in regard to the duration of clinical benefits, a substantial number of patients do not respond to these therapies. To improve the outcome of patients receiving immuno-therapy, there is a need for novel biomarkers that can predict and monitor treatment. Tumor microenvironment alterations, more specifically the state of chronic inflammation and desmoplasia (tumor fibrosis), are important factors to consider in this context. Here, we discuss the potential for quantification of altered tissue turnover in a liquid biopsy as a proposed precision medicine tool to assess chronic inflammation and desmoplasia in the immuno-oncology (IO) setting. We highlight the need for novel non-invasive biomarkers in IO and the importance of addressing tumor microenvironment alterations. We focus on desmoplasia and extracellular matrix (ECM) remodeling, and how the composition of the ECM defines T-cell permissiveness in the tumor microenvironment and opens up the possibility for associated liquid biopsy biomarkers. Moreover, we address the importance of the assessment of chronic inflammation, primarily macrophage activity, in a liquid biopsy.

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The identification of Lynch syndrome in Congolese colorectal cancer patients.

The identification of Lynch syndrome in Congolese colorectal cancer patients.

Bull Cancer. 2017 Oct 05;:

Authors: Poaty H, Aba Gandzion C, Soubeyran I, Gassaye D, Peko JF, Nkoua Bon JB, Gombé Mbalawa C

Abstract
BACKGROUND: We aimed to investigate the prevalence of Lynch syndrome as one of hereditary causes of colorectal cancer (CRC) among young Congolese individuals affected by the CRC, and to define methods for diagnosis in Congo Brazzaville.
METHODS: We conducted a transversal cohort study of 34 patients having a CRC with a family history for a period of eight years. They were selected among 89 CRCs of any type from the Bethesda guidelines criteria combined with pedigrees. Mismatch repair (MMR) genes alterations were researched by immunohistochemistry (IHC).
RESULTS: We identified with the Bethesda criteria a total of 38.2% (34/89) patients having familial CRC with a confidence interval (CI) of 95%=[0.34-0.41]. Only 14.7% (5/34) 95% CI=[0.34-2.32] patients showed MMR immunodeficiency involving firstly MLH1 protein then MSH2 protein. These data account for 5.6% (5/89) 95% CI=[0.15-0.33] of patients affected by Lynch syndrome with an earlier median age of 35 years (range 20 to 47 years).
CONCLUSION: The prevalence of Lynch syndrome found in Brazzaville is comparable to that is found in northern countries. The combined Bethesda guidelines, pedigree and IHC is an accessible and good alternative method for the positive diagnosis of Lynch syndrome in current practice in Congo.

PMID: 28988047 [PubMed - as supplied by publisher]

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Modified staging system for pulmonary carcinoids on the basis of lung cancer TNM system

Abstract

Background

Pulmonary carcinoids are being staged along the lines of lung cancer American Joint Committee on Cancer (AJCC) staging system. The current study evaluated the prognostic value of a modified staging system for patients with pulmonary carcinoid.

Patients and methods

Surveillance, Epidemiology and End Results (SEER) database (2004–2014) was searched through SEER*Stat program. Through recursive partitioning analysis and subsequent decision tree formation, suggested stages were constructed. Overall survival analyses were performed through Kaplan–Meier analysis. The cancer-specific Cox regression hazard (adjusted for age, gender, race, sub-site and surgery) was calculated and pairwise comparisons of hazard ratios were conducted.

Results

A total of 6395 pulmonary carcinoid patients were recruited in the period from 2004–2014. Pairwise hazard ratio comparisons among different AJCC 8th stages were conducted and all comparisons were non-significant except for stage IIB vs. stage IIIA and stage IIIA vs. stage IIIB. Pairwise hazard ratio comparisons among different modified staging system stages were conducted and all comparisons were significant except for stage III vs. stage IV. C-statistic (using death from pulmonary carcinoid as the dependent variable) for AJCC 8th staging system was: 0.794 (SE 0.013; 95% CI 0.769–0.818); for AJCC 7th staging system was: 0.789 (SE 0.013; 95% CI 0.764–0.815), while c-statistic for the modified staging system was: 0.802 (SE 0.012; 95% CI 0.778–0.827).

Conclusion

The proposed modified staging system provided a simpler yet prognostically more relevant classification of pulmonary carcinoids compared to AJCC staging systems (both 7th and 8th editions).

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Modified staging system for pulmonary carcinoids on the basis of lung cancer TNM system

Abstract

Background

Pulmonary carcinoids are being staged along the lines of lung cancer American Joint Committee on Cancer (AJCC) staging system. The current study evaluated the prognostic value of a modified staging system for patients with pulmonary carcinoid.

Patients and methods

Surveillance, Epidemiology and End Results (SEER) database (2004–2014) was searched through SEER*Stat program. Through recursive partitioning analysis and subsequent decision tree formation, suggested stages were constructed. Overall survival analyses were performed through Kaplan–Meier analysis. The cancer-specific Cox regression hazard (adjusted for age, gender, race, sub-site and surgery) was calculated and pairwise comparisons of hazard ratios were conducted.

Results

A total of 6395 pulmonary carcinoid patients were recruited in the period from 2004–2014. Pairwise hazard ratio comparisons among different AJCC 8th stages were conducted and all comparisons were non-significant except for stage IIB vs. stage IIIA and stage IIIA vs. stage IIIB. Pairwise hazard ratio comparisons among different modified staging system stages were conducted and all comparisons were significant except for stage III vs. stage IV. C-statistic (using death from pulmonary carcinoid as the dependent variable) for AJCC 8th staging system was: 0.794 (SE 0.013; 95% CI 0.769–0.818); for AJCC 7th staging system was: 0.789 (SE 0.013; 95% CI 0.764–0.815), while c-statistic for the modified staging system was: 0.802 (SE 0.012; 95% CI 0.778–0.827).

Conclusion

The proposed modified staging system provided a simpler yet prognostically more relevant classification of pulmonary carcinoids compared to AJCC staging systems (both 7th and 8th editions).

http://ift.tt/2g11Xe5

Quantification of altered tissue turnover in a liquid biopsy: a proposed precision medicine tool to assess chronic inflammation and desmoplasia associated with a pro-cancerous niche and response to immuno-therapeutic anti-tumor modalities

Abstract

Immuno-therapy has begun to revolutionize cancer treatment. However, despite the significant progress achieved in regard to the duration of clinical benefits, a substantial number of patients do not respond to these therapies. To improve the outcome of patients receiving immuno-therapy, there is a need for novel biomarkers that can predict and monitor treatment. Tumor microenvironment alterations, more specifically the state of chronic inflammation and desmoplasia (tumor fibrosis), are important factors to consider in this context. Here, we discuss the potential for quantification of altered tissue turnover in a liquid biopsy as a proposed precision medicine tool to assess chronic inflammation and desmoplasia in the immuno-oncology (IO) setting. We highlight the need for novel non-invasive biomarkers in IO and the importance of addressing tumor microenvironment alterations. We focus on desmoplasia and extracellular matrix (ECM) remodeling, and how the composition of the ECM defines T-cell permissiveness in the tumor microenvironment and opens up the possibility for associated liquid biopsy biomarkers. Moreover, we address the importance of the assessment of chronic inflammation, primarily macrophage activity, in a liquid biopsy.

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Quantification of altered tissue turnover in a liquid biopsy: a proposed precision medicine tool to assess chronic inflammation and desmoplasia associated with a pro-cancerous niche and response to immuno-therapeutic anti-tumor modalities

Abstract

Immuno-therapy has begun to revolutionize cancer treatment. However, despite the significant progress achieved in regard to the duration of clinical benefits, a substantial number of patients do not respond to these therapies. To improve the outcome of patients receiving immuno-therapy, there is a need for novel biomarkers that can predict and monitor treatment. Tumor microenvironment alterations, more specifically the state of chronic inflammation and desmoplasia (tumor fibrosis), are important factors to consider in this context. Here, we discuss the potential for quantification of altered tissue turnover in a liquid biopsy as a proposed precision medicine tool to assess chronic inflammation and desmoplasia in the immuno-oncology (IO) setting. We highlight the need for novel non-invasive biomarkers in IO and the importance of addressing tumor microenvironment alterations. We focus on desmoplasia and extracellular matrix (ECM) remodeling, and how the composition of the ECM defines T-cell permissiveness in the tumor microenvironment and opens up the possibility for associated liquid biopsy biomarkers. Moreover, we address the importance of the assessment of chronic inflammation, primarily macrophage activity, in a liquid biopsy.

http://ift.tt/2hAaBjS