Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 23 Οκτωβρίου 2017
Recall of Fertility Discussion by Adolescent Female Cancer Patients: A Survey-Based Pilot Study
Recall of Fertility Discussion by Adolescent Female Cancer Patients: A Survey-Based Pilot Study
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Age-related changes in cyclic phosphatidic acid-induced hyaluronic acid synthesis in human fibroblasts
Abstract
Hyaluronic acid is a major component of the extracellular matrix, which is important for skin hydration. As aging brings skin dehydration, we aimed to clarify the mRNA expression of hyaluronic acid-related proteins in human skin fibroblasts from donors of various ages (range 0.7–69 years). Previously, we reported that cyclic phosphatidic acid (cPA), a unique phospholipid mediator, stimulated the expression of HAS2 and increased hyaluronic acid synthesis in human skin fibroblasts (donor age: 3 days). In this study, we measured the mRNA expression of hyaluronic acid-related proteins: hyaluronan synthase (HAS) 1–3, hyaluronidase-1, -2, and hyaluronic acid-binding protein (versican). In addition, we tested whether cPA could increase hyaluronic acid synthesis in skin fibroblasts derived from donors of various ages. The expression of HAS1, 3, hyaluronidase-1, and -2 did not change with aging. However, the mRNA expression of versican decreased with aging. Although it is thought that the amount of hyaluronic acid in the dermis decreases with aging, the mRNA expression of HAS2 was increased. But the amount of hyaluronic acid secreted by fibroblasts did not increase with aging. This suggests that the activity and/or protein expression of HAS2 decrease with aging. Furthermore, we observed that cPA caused the increase of hyaluronic acid synthesis at any age, and this effect was increased with aging. These results suggest that aging made the fibroblasts more sensitive to cPA treatment. Therefore, cPA represents a suitable candidate for the health maintenance and improvement of the skin by increasing the level of hyaluronic acid in the dermis.
from Cancer via ola Kala on Inoreader http://ift.tt/2yK7b8i
via IFTTT
Age-related changes in cyclic phosphatidic acid-induced hyaluronic acid synthesis in human fibroblasts
Abstract
Hyaluronic acid is a major component of the extracellular matrix, which is important for skin hydration. As aging brings skin dehydration, we aimed to clarify the mRNA expression of hyaluronic acid-related proteins in human skin fibroblasts from donors of various ages (range 0.7–69 years). Previously, we reported that cyclic phosphatidic acid (cPA), a unique phospholipid mediator, stimulated the expression of HAS2 and increased hyaluronic acid synthesis in human skin fibroblasts (donor age: 3 days). In this study, we measured the mRNA expression of hyaluronic acid-related proteins: hyaluronan synthase (HAS) 1–3, hyaluronidase-1, -2, and hyaluronic acid-binding protein (versican). In addition, we tested whether cPA could increase hyaluronic acid synthesis in skin fibroblasts derived from donors of various ages. The expression of HAS1, 3, hyaluronidase-1, and -2 did not change with aging. However, the mRNA expression of versican decreased with aging. Although it is thought that the amount of hyaluronic acid in the dermis decreases with aging, the mRNA expression of HAS2 was increased. But the amount of hyaluronic acid secreted by fibroblasts did not increase with aging. This suggests that the activity and/or protein expression of HAS2 decrease with aging. Furthermore, we observed that cPA caused the increase of hyaluronic acid synthesis at any age, and this effect was increased with aging. These results suggest that aging made the fibroblasts more sensitive to cPA treatment. Therefore, cPA represents a suitable candidate for the health maintenance and improvement of the skin by increasing the level of hyaluronic acid in the dermis.
http://ift.tt/2yK7b8i
Leiomyosarcoma presenting as 'idiopathic unilateral lower limb lymphoedema
A 74-year-old woman presented with an 8-year history of unilateral swelling of her right lower limb, which was thought to be 'idiopathic' lymphoedema until she noticed a painless swelling in her right groin. Physical examination showed a painless, non-pulsatile, deep-seated mass in her right proximal thigh with significant lymphoedema distally. MRI scan showed a large mass at her right inguinal region, involving the common femoral vein. Histological examination on complete excision revealed leiomyosarcoma. It is important to exclude proximal obstructive lesion before making a diagnosis of unilateral idiopathic lower limb lymphoedema.
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Rhomboencephalosynapsis
Description
A baby boy was born to healthy, unrelated parents at 34 weeks gestation by caesarean section in view of an antenatal ultrasound diagnosis of hydrocephalus. Mother had a previous miscarriage at 13 weeks gestation of a twin pregnancy. At birth, the boy weighed 2.47 kg, was well and did not require resuscitation. Pregnancy was unremarkable with no significant events. At birth, a large head circumference was noted, but fontanelles were soft. The Apgar score was 9 at 1 and 10 min, baby had a good cry and was moving all four limbs. A CT scan of brain was done at 1-day old which showed obstructive hydrocephalus at the level of the cerebral aqueduct. A ventriculoperitoneal (VP) shunt was inserted at 1-week old. The boy showed slow development over the subsequent years, he never suffered from seizures, however required growth hormone therapy. A small atrial septal defect was noted on echocardiogram. An...
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Giant mediastinal parathyroid adenoma presenting as bilateral brown tumour of mandible: a rare presentation of primary hyperparathyroidism
Hyperparathyroidism (HPT) is becoming increasingly common endocrinopathy in clinical practice. Nowadays, it is mostly diagnosed in subclinical or early clinical stage. Bony involvement in HPT has seen significant fall in incidence. Brown tumour of bone is exceptionally rare as a first manifestation of primary HPT (PHPT). Its radiological and histopathological features may be mistaken for other bony pathologies. If possibility of underlying HPT is overlooked the disease is bound to recur after surgery adding to morbidity of the patient. Here we present a case of bilateral brown tumour of mandible which was mistakenly treated as giant cell granuloma by surgical curettage. That the patient was harbouring an ectopic parathyroid adenoma with hypercalcemia causing non-specific symptoms was missed by the referring physician. This led to recurrence of the lesion. On subsequent evaluation, a giant mediastinal parathyroid adenoma causing PHPT was detected at our centre and was removed via mini sternotomy approach.
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Transcatheter valve implantation to inferior vena cava to control carcinoid symptoms
Severe carcinoid syndrome and carcinoid heart disease in neuroendocrine tumours can have a significant impact on a patient's quality of life and are a major cause of morbidity and mortality. We present a novel approach to managing a patient with medically uncontrollable carcinoid syndrome. Inferior and superior vena cava placement of transcatheter heart valves has been used to treat patients with right heart failure due to severe tricuspid and pulmonary regurgitation. However, this procedure has not been attempted to specifically reduce hormone secretion, primarily from the liver, in order to control carcinoid syndrome symptoms. We attempted this procedure in a patient with severe carcinoid disease and tricuspid regurgitation as a bridge to later definitive therapy. The procedure was technically successful, but did not improve carcinoid symptoms. The possible reasons for the failure are discussed here.
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Birt-Hogg-Dube syndrome: awareness is important!
Birt-Hogg-Dubé (BHD) is a rare syndrome of inherited renal cell carcinomas, characterised by cutaneous lesions and pulmonary cysts and pneumothorax in a vast majority of the patients. Awareness of this syndrome is important in order to refer patients for genetic counselling and personalised follow-up as soon as possible. We describe a case of a 30-year-old female referred to our institution due to incidental discovery of solid bilateral renal masses. Renal biopsies were consistent with chromophobe tumour, and bilateral nephrectomy was performed. Gross examination revealed deformed kidneys with 28 brown and solid lesions, size variable between 0.1 and 6 cm, histologically corresponding to renal cell carcinomas, chromophobe type. Genetic test was required that showed a c.573delGAinsT frameshift mutation in heterozigosity at the folliculin gene, consistent with BHD diagnosis.
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Idiopathic catastrophic thrombosis with happy ending
A 59-year-old male patient suffered three life-threatening instent thromboses after an initial resuscitation due to an ST-segment elevation myocardial infarction of the anterior cardiac wall. With a high-risk profile for heparin-induced thrombocytopenia (HIT), he was placed on argatroban after the second reinfarction. Under this apparently appropriate treatment, a third reinfarction occurred, and the patient had to undergo high-risk cardiac bypass surgery. Later on, a deep vein thrombosis and an intracardiac thrombus formed. Despite a positive screening test for HIT and a single positive result in the heparin-induced platelet aggregation test, we are not convinced that HIT was the only underlying cause for this 'catastrophic thrombotic syndrome'. We speculate that a massive generation of thrombin, reflected in consistently high D dimers and the need of copious amounts of a direct thrombin inhibitor, triggered the set of events. With this case report, we want to raise awareness for cardiac complications in patients with complex clotting disorders and share our experience in the diagnostic and therapeutic management of such an unusual scenario.
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Neuroendocrine tumour in pancreatic dorsal agenesis: a rare association
Pancreatic dorsal agenesis (PDA) is a rare congenital anomaly, usually asymptomatic, that can present with abdominal pain, pancreatitis, diabetes mellitus and jaundice. Pancreatic tumours in PDA background are extremely rare, and when they occur are mainly pancreatic ductal adenocarcinoma. We present a case of a 48-year-old female patient with incidental detection of a 26x20 mm nodular lesion of the cephalic pancreas on ultrasound. Surgery was performed and gross examination revealed PDA with a tumour developed around the Wirsung duct. Histology showed a neuroendocrine tumour G1 with neural and vascular invasion. Two and half years later, the patient is alive and without tumour relapse. Awareness of the association of PDA and pancreatic tumours is fundamental in order to develop personalised follow-up programmes.
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Adverse reaction with suvorexant for insomnia: acute worsening of depression with emergence of suicidal thoughts
A 59-year-old woman on daily peritoneal dialysis for end-stage renal failure received care at an outpatient psychiatric clinic for her diagnoses that include major depressive disorder, generalised anxiety disorder and insomnia disorder. Although there was partial improvement in the patient's mood and anxiety symptoms with antidepressant treatment, insomnia remained a persistent complaint despite adequate trials of different sleep medications. The novel hypnotic, suvorexant (Belsomra, Merck & Co.) was then initiated at the recommended bedtime dose of 10 mg and was followed by a 15 mg dose the following night. Within an hour after taking her second suvorexant dose, the severity of patient's depression symptoms worsened and was accompanied by new onset of suicidal thoughts.
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Case of tumoral calcinosis on images: a rare clinicopathological entity
Description
We are presenting a case of tumoral calcinosis (TC) diagnosed on histopathology with characteristic X-ray, CT and MRI images. We acknowledge that although radiological and pathological descriptions are suggested as diagnostic criteria, mostly the term TC is saved for the condition caused by hereditary metabolic dysfunction of phosphate regulation associated with massive periarticular masses. Our patient had a normal phosphate. On review of literature, normophosphatemic TC has also been described.1
An 81-year-old Caucasian woman presented with left wrist pain and swelling, which first began approximately 3–4 years ago. As per patient, she saw her physician regarding this 1 year ago and was diagnosed with gout. Physical examination showed 4x3 cm left-sided volar ulnar wrist mass (figure 1).
Figure 1
Patient's picture showing swelling on the left wrist.
The patient's vital signs and rest of the examination were within normal limits....
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Metastatic meningioma: a rare cause of mediastinal lymphadenopathy.
Description
A 69-year-old man with known, stable atypical meningioma of the brain diagnosed 5 years previously presented with severe shortness of breath. The patient had previously been treated with surgery and radiotherapy to the brain. Chest X-ray revealed bulky mediastinal lymphadenopathy (figure 1). CT (figure 2) confirmed mediastinal and upper abdominal lymphadenopathy in addition to multiple pulmonary emboli. The patient underwent an endoscopic ultrasound and fine-needle aspiration (EUS-FNA), an established technique that enables prompt cytological sampling and assessment.1
Figure 1
Chest X-ray.
Figure 2
Contrast-enhanced CT image showing adenopathy at the level of the aortic arch.
The EUS-FNA preparations showed sheets and clusters of bland, polygonal epithelioid cells (figure 3). These demonstrated strong immunohistochemical positivity (figure 4) for epithelial membrane antigen. The final immunopanel was strongly supportive...
http://ift.tt/2xj2IWN
Olfactory nerve hypertrophy: a clue to the presence of ipsilateral megalencephaly
Description
A boy aged 4 years presented with refractory focal seizures since 9 months of age. The seizures involved the left side of the body and consisted of clonic movements with frequent generalisation. MRI brain showed abnormal area with poor grey-white differentiation involving the right frontal lobe, especially the basifrontal region and the temporal lobe (figure 1A,B) suggesting the presence of a frontotemporal developmental malformation. Interestingly olfactory nerve hypertrophy was also noted on the same side (figure 1C,D). Video-electroencephalogram study demonstrated concurrence of the interictal (figure 2A) and ictal data (figure 2B) with the MRI defined abnormality. An 18-fluoro-2-deoxy-D-glucose positron emission tomography/CT of the brain showed severe right frontotemporal hypometabolism. The boy underwent a disconnection procedure involving the right frontal lobe sparing the motor cortex and the temporal lobe. Histopathology of the abnormal brain obtained during the surgery showed large...
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Necrotising pneumonia following influenza due to PVL-negative Staphylococcus aureus in a 64-year-old woman
Description
A 64-year-old immunocompetent woman presented to our institution during the 2016–2017 influenza A(H3N2) epidemic for cough and fever. She presented 10 days ago with an influenza syndrome, treated with ibuprofen 400 mg/day for 7 days. As the fever continued, with blood-streaked sputum, amoxicillin with clavulanic acid was prescribed for 3 days and then ceftriaxone (1 g/day). She had elevated transaminases and C reactive protein (184 mg/L). A chest X-ray was performed, showing a left pneumonia (figure 1A), and the patient was admitted in the infectious disease unit. There was no respiratory failure. Amphoric breath sound was heard at the top of the right lung. Antibiotics were modified, as levofloxacine (500 mg twice daily) was added to cefotaxime (1 g/8 hours). A CT scan of the chest was performed (figure 1B,C), showing a bifocal pneumonia involving the upper right and lower left lobes, and excavated bilateral nodules. The bronchoalveolar lavage showed a positive influenza...
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Correction: Out of the blue--finger ischaemia and occult colorectal cancer
Schattner A. Out of the blue finger ischaemia and occult colorectal cancer. BMJ Case Rep 2017 (Epub ahead of print 8 Mar 2017). doi:10.1136/bcr-2016-218779
The correct title of the article is: Out of the blue—finger ischaemia and occult colorectal cancer.
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Heart irradiation reduces microvascular density and accumulation of HSPA1 in mice
Abstract
Purpose
Improvement of radiotherapy techniques reduces the exposure of normal tissues to ionizing radiation. However, the risk of radiation-related late effects remains elevated. In the present study, we investigated long-term effects of radiation on heart muscle morphology.
Materials and methods
We established a mouse model to study microvascular density (MVD), deposition of collagen fibers, and changes in accumulation of heat shock 70 kDa protein 1 (HSPA1) in irradiated heart tissue. Hearts of C57BL/6 mice received a single dose of X‑ray radiation in the range 0.2–16 Gy. Analyses were performed 20, 40, and 60 weeks after irradiation.
Results
Reduction in MD was revealed as a long-term effect observed 20–60 weeks after irradiation. Moreover, a significant and dose-dependent increase in accumulation of HSPA1, both cytoplasmic and nuclear, was observed in heart tissues collected 20 weeks after irradiation. We also noticed an increase in collagen deposition in hearts treated with higher doses.
Conclusions
This study shows that some changes induced by radiation in the heart tissue, such as reduction in microvessel density, increase in collagen deposition, and accumulation of HSPA1, are observed as long-term effects which might be associated with late radiation cardiotoxicity.
http://ift.tt/2z33Gen
Surgical Resection Does Not Improve Survival in Multifocal Intrahepatic Cholangiocarcinoma: A Comparison of Surgical Resection with Intra-Arterial Therapies
Abstract
Background
Multifocal intrahepatic cholangiocarcinoma (ICC) has traditionally been treated with surgical resection when amenable. Intra-arterial therapy (IAT) for multifocal ICC has not been directly compared with surgical resection.
Methods
A single-center, retrospective review of consecutive patients treated for multifocal ICC was conducted. Patients with distant metastases or treatment with systemic chemotherapy alone were excluded. Patients were divided into two groups: surgical resection versus IAT; IAT included transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and hepatic arterial infusion (HAI) pump therapy. Subjects were also analyzed by surgical resection, TACE, and HAI pump therapy.
Results
Overall, 116 patients with multifocal ICC were studied, 57 in the surgical resection group and 59 in the IAT group (TACE = 41, HAI pump = 16, TARE = 2). The IAT group was characterized by a higher incidence of bilobar disease (88.1% vs. 47.4%, p < 0.001), larger tumors (median 10.6 vs. 7.5 cm, p = 0.004), higher incidence of macrovascular invasion (44.1% vs. 24.6%, p = 0.027), and higher rate of nodal metastases (57.6% vs. 28.6%, p = 0.002). Median overall survival for surgical resection was 20 months versus 16 months for IAT (p = 0.627). Multivariate analysis found that macrovascular invasion [hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.56–4.09] and non-receipt of systemic chemotherapy (HR 3.81, 95% CI 2.23–6.52) were independent poor prognostic risk factors. Surgical resection was not associated with a survival advantage over IAT on multivariate analysis (p = 0.242).
Conclusion
Despite selection bias for use of surgical resection compared with IAT, no survival advantage was conferred in the treatment of multifocal ICC.
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Long-Term Outcomes After R0 Resection of Synchronous Peritoneal Metastasis from Colorectal Cancer Without Cytoreductive Surgery or Hyperthermic Intraperitoneal Chemotherapy
Abstract
Background
The National Comprehensive Cancer Network (NCCN) guidelines for colon cancer recently added the following footnote regarding the therapeutic strategy for peritoneal metastases: "If R0 resection can be achieved, surgical resection of isolated peritoneal disease may be considered at experienced centers." This study investigated the efficacy of R0 resection of peritoneal metastasis from colorectal cancer without cytoreductive surgery or hyperthermic intraperitoneal chemotherapy (HIPEC).
Methods
This retrospective cohort study was conducted at a single-institution tertiary care cancer center. Among 496 consecutive M1c colorectal cancer patients, R0 resection was achieved for 94 patients (19%). The subjects were 78 consecutive patients with colorectal cancer and simultaneous peritoneal metastasis but no other distant metastases who underwent R0 resection at the National Cancer Center Hospital from 1971 to 2016 (16% of all M1c patients). Overall survival (OS) was investigated, and clinicopathologic variables were analyzed for prognostic significance.
Results
No perioperative mortality was noted. The 3-year OS rate was 45%, and the 5-year OS rate was 28.7%. The median survival time was 33.4 months. Notably, 17 patients survived for more than 5 years, and 9 of these patients did not receive any chemotherapy. Multivariate analysis showed cancer location in the colon and harvesting of 12 or more lymph nodes to be independent factors associated with a better prognosis.
Conclusions
From the perspective of long-term outcomes and no perioperative mortality, R0 resection of peritoneal metastasis from colorectal cancer, without complete peritonectomy or HIPEC, appeared to be an acceptable therapeutic option for some patients with peritoneal metastasis.
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Surgical Resection Does Not Improve Survival in Multifocal Intrahepatic Cholangiocarcinoma: A Comparison of Surgical Resection with Intra-Arterial Therapies
Abstract
Background
Multifocal intrahepatic cholangiocarcinoma (ICC) has traditionally been treated with surgical resection when amenable. Intra-arterial therapy (IAT) for multifocal ICC has not been directly compared with surgical resection.
Methods
A single-center, retrospective review of consecutive patients treated for multifocal ICC was conducted. Patients with distant metastases or treatment with systemic chemotherapy alone were excluded. Patients were divided into two groups: surgical resection versus IAT; IAT included transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and hepatic arterial infusion (HAI) pump therapy. Subjects were also analyzed by surgical resection, TACE, and HAI pump therapy.
Results
Overall, 116 patients with multifocal ICC were studied, 57 in the surgical resection group and 59 in the IAT group (TACE = 41, HAI pump = 16, TARE = 2). The IAT group was characterized by a higher incidence of bilobar disease (88.1% vs. 47.4%, p < 0.001), larger tumors (median 10.6 vs. 7.5 cm, p = 0.004), higher incidence of macrovascular invasion (44.1% vs. 24.6%, p = 0.027), and higher rate of nodal metastases (57.6% vs. 28.6%, p = 0.002). Median overall survival for surgical resection was 20 months versus 16 months for IAT (p = 0.627). Multivariate analysis found that macrovascular invasion [hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.56–4.09] and non-receipt of systemic chemotherapy (HR 3.81, 95% CI 2.23–6.52) were independent poor prognostic risk factors. Surgical resection was not associated with a survival advantage over IAT on multivariate analysis (p = 0.242).
Conclusion
Despite selection bias for use of surgical resection compared with IAT, no survival advantage was conferred in the treatment of multifocal ICC.
http://ift.tt/2yE9NFf
Four-Dimensional Computed Tomography: Clinical Impact for Patients with Primary Hyperparathyroidism
Abstract
Background
In recent years, four-dimensional computed tomography (4DCT) has emerged as a new localization study for primary hyperparathyroidism (pHPT).
Objective
We aimed to assess the added value of 4DCT in our institution in the first 4 years of use.
Methods
A retrospective cohort study was conducted from February 2004 to June 2015. Since 2011, patients over 50 years of age without concordant sestamibi-SPECT (SeS) and ultrasound (US) findings underwent 4DCT. Imaging results, surgical findings, histopathology, and postoperative biochemistry were collected.
Results
A total of 536 parathyroid operations in 510 patients were performed during the study period. The overall cure rate was 99.2% after reoperation in some patients, and the overall sensitivity for SeS was 76.0%, and 74.8% for US. Since 2011, 100 patients without concordant SeS/US findings have undergone 4DCT, with a sensitivity of 72.9%. This is in comparison to the sensitivities for SeS (48.3%) and US (52.3%). 4DCT was more sensitive in patients with persistent/recurrent disease (60.0% compared with SeS 43.8% and US 36.4%) and patients with multigland disease (67.4% compared with SeS 40.9% and US 42.1%). Comparison between outcomes in the pre- versus post-CT era demonstrated no difference in the initial cure rate (95.4 vs. 95.9%, p = 0.85) or the rate of minimally invasive parathyroidectomies (74.5 vs. 79.9%, p = 0.22).
Conclusion
Parathyroid 4DCT can aid surgical planning in cases without concordant SeS/US findings; however, the introduction of 4DCT as a second-line test did not change our overall cure rate or rate of minimally invasive parathyroidectomy. The role of 4DCT as the primary localization study for pHPT merits further investigation.
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Pre-operative Axillary Ultrasound-Guided Needle Sampling in Breast Cancer: Comparing the Sensitivity of Fine Needle Aspiration Cytology and Core Needle Biopsy
Abstract
Background
Pre-operative ultrasound-guided needle sampling (UNS) of abnormal axillary lymph nodes in breast cancer can identify patients with axillary metastases and therefore rationalize patient care and inform decision-making. To obtain tissue diagnosis, UNS can be performed by either fine needle aspiration (FNA) or core needle biopsy (CNB). However, few studies have compared the sensitivity of these techniques and the majority show no difference.
Methods
All node-positive patients (those with micro- and macrometastases but not isolated tumor cells) treated at a tertiary referral center between January 2012 and December 2015 were retrospectively identified from pathology records. The result of the first axillary UNS performed on each patient was compared with postoperative histopathology results. The UNS method used was according to individual radiologist preference.
Results
A total of 215 patients underwent FNA (1 patient had bilateral breast cancer and underwent bilateral FNA), and 92 underwent CNB. Sensitivity of CNB was significantly higher than FNA (83.7 vs. 69.0%, P = 0.008). The false-negative rate in the FNA group was therefore higher than in the CNB group by a factor of 2.5. There was no difference in inadequacy rate between the two techniques. There were no complications in the FNA group, and only one hematoma (which did not require operative intervention) in the CNB group.
Conclusions
CNB is safe and should be the preferred technique for UNS to improve sensitivity.
http://ift.tt/2yEZ4dQ
Long-Term Outcomes After R0 Resection of Synchronous Peritoneal Metastasis from Colorectal Cancer Without Cytoreductive Surgery or Hyperthermic Intraperitoneal Chemotherapy
Abstract
Background
The National Comprehensive Cancer Network (NCCN) guidelines for colon cancer recently added the following footnote regarding the therapeutic strategy for peritoneal metastases: "If R0 resection can be achieved, surgical resection of isolated peritoneal disease may be considered at experienced centers." This study investigated the efficacy of R0 resection of peritoneal metastasis from colorectal cancer without cytoreductive surgery or hyperthermic intraperitoneal chemotherapy (HIPEC).
Methods
This retrospective cohort study was conducted at a single-institution tertiary care cancer center. Among 496 consecutive M1c colorectal cancer patients, R0 resection was achieved for 94 patients (19%). The subjects were 78 consecutive patients with colorectal cancer and simultaneous peritoneal metastasis but no other distant metastases who underwent R0 resection at the National Cancer Center Hospital from 1971 to 2016 (16% of all M1c patients). Overall survival (OS) was investigated, and clinicopathologic variables were analyzed for prognostic significance.
Results
No perioperative mortality was noted. The 3-year OS rate was 45%, and the 5-year OS rate was 28.7%. The median survival time was 33.4 months. Notably, 17 patients survived for more than 5 years, and 9 of these patients did not receive any chemotherapy. Multivariate analysis showed cancer location in the colon and harvesting of 12 or more lymph nodes to be independent factors associated with a better prognosis.
Conclusions
From the perspective of long-term outcomes and no perioperative mortality, R0 resection of peritoneal metastasis from colorectal cancer, without complete peritonectomy or HIPEC, appeared to be an acceptable therapeutic option for some patients with peritoneal metastasis.
http://ift.tt/2zLvq4o
Stereotactic Body Radiation Therapy for Isolated Local Recurrence After Surgical Resection of Pancreatic Ductal Adenocarcinoma Appears to be Safe and Effective
Abstract
Background
A standardized treatment regimen for unresectable isolated local recurrence (ILR) of pancreatic ductal adenocarcinoma has not been established. This study evaluated the outcomes for patients with ILR who underwent stereotactic body radiation therapy (SBRT).
Methods
The records of patients with ILR who underwent SBRT between 2010 and 2016 were retrospectively reviewed. Symptom palliation and treatment-related toxicity were recorded. Associations between patient or treatment characteristics and overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) were assessed.
Results
The study identified 51 patients who received SBRT for ILR. Of the 51 patients, 26 (51%) had not received radiation therapy before SBRT. The median OS was 36 months after diagnosis. From the first day of SBRT, the median OS, PFS, and LPFS were respectively 16, 7, and 10 months. Patients with a recurrence-free interval of 9 months or longer after surgery had superior OS (P = 0.019). Maintenance chemotherapy after SBRT was associated with superior OS (P < 0.001) and LPFS (P = 0.027). In the multivariable analysis, poorly differentiated tumor grade [hazard ratio (HR) 11.274], positive surgical margins (HR 0.126), and reception of maintenance chemotherapy (HR 0.141) were independently associated with OS. Positive surgical margins (HR 0.255) and maintenance chemotherapy (HR 0.299) were associated with improved LPFS. Of 16 patients, 10 (63%) experienced abdominal pain relief after SBRT. Four patients (8%) experienced grade 3 gastrointestinal toxicity, and one patient experienced grade 4 gastrointestinal toxicity.
Conclusions
Use of SBRT for ILR improved pain for a majority of the patients with acceptable acute and late toxicity. The findings show that SBRT is a feasible treatment for select patients with ILR. For those who receive SBRT, maintenance chemotherapy should be considered.
http://ift.tt/2gElEwi
Awareness and Knowledge Levels of 18-Year-Old and Older Individuals Regarding Human Papillomavirus (HPV) and HPV Vaccine in Hatay, Turkey
Abstract
The aim of this study was to evaluate the knowledge and awareness levels of 18-year-old and older women and men on HPV infection, HPV vaccine, and the potential risk factors in Hatay, Turkey. In our study, it was found that overall 27.0 and 23.2% of the participants reported having heard of HPV infection and HPV vaccine. The rate of participants who had heard of HPV infection and HPV vaccine was higher in women than in men (p < 0.000). Thirteen percent of the participants was aware of the fact that HPV triggers cervical cancer, 10.2% penile cancer, and 16.7% genital warts, respectively. The overall vaccination rate of the participants was 2.7%. When the total knowledge score of the participants about HPV infection and HPV vaccine was evaluated according to independent variables, it was found that being a woman, urbanization, and having a high level of education had a positive effect on knowledge score, while never having heard of HPV infection and HPV vaccine had a negative effect on knowledge score (p < 0.000). It was determined in the linear regression model that gender, educational status, residential area, and having heard of HPV infection before influenced knowledge levels. It was determined that the relation between these variables and the total knowledge scores of the participants was statistically significant (p < 0.05). It was also determined that women who had higher educational levels, those who were living in urban areas, and those who had heard HPV infection before had higher knowledge levels. The level of knowledge of the participants about HPV infection and HPV vaccine was found to be very low. Having adequate knowledge about HPV infection and increasing the acceptance of HPV vaccination in public will play an important role in decreasing the rate of mortality and morbidity of the different HPV-associated cancers in women and men.
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Awareness and Knowledge Levels of 18-Year-Old and Older Individuals Regarding Human Papillomavirus (HPV) and HPV Vaccine in Hatay, Turkey
Abstract
The aim of this study was to evaluate the knowledge and awareness levels of 18-year-old and older women and men on HPV infection, HPV vaccine, and the potential risk factors in Hatay, Turkey. In our study, it was found that overall 27.0 and 23.2% of the participants reported having heard of HPV infection and HPV vaccine. The rate of participants who had heard of HPV infection and HPV vaccine was higher in women than in men (p < 0.000). Thirteen percent of the participants was aware of the fact that HPV triggers cervical cancer, 10.2% penile cancer, and 16.7% genital warts, respectively. The overall vaccination rate of the participants was 2.7%. When the total knowledge score of the participants about HPV infection and HPV vaccine was evaluated according to independent variables, it was found that being a woman, urbanization, and having a high level of education had a positive effect on knowledge score, while never having heard of HPV infection and HPV vaccine had a negative effect on knowledge score (p < 0.000). It was determined in the linear regression model that gender, educational status, residential area, and having heard of HPV infection before influenced knowledge levels. It was determined that the relation between these variables and the total knowledge scores of the participants was statistically significant (p < 0.05). It was also determined that women who had higher educational levels, those who were living in urban areas, and those who had heard HPV infection before had higher knowledge levels. The level of knowledge of the participants about HPV infection and HPV vaccine was found to be very low. Having adequate knowledge about HPV infection and increasing the acceptance of HPV vaccination in public will play an important role in decreasing the rate of mortality and morbidity of the different HPV-associated cancers in women and men.
http://ift.tt/2xiVked
HALO-109–301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer
Future Oncology, Ahead of Print.
http://ift.tt/2gFjbBP
An updated review of the JAK1/2 inhibitor (ruxolitinib) in the Philadelphia-negative myeloproliferative neoplasms
Future Oncology, Ahead of Print.
http://ift.tt/2yDOrbd
HALO-109–301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer
Future Oncology, Ahead of Print.
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Prenatal methamphetamine exposure is associated with corticostriatal white matter changes in neonates
Abstract
Diffusion tensor imaging (DTI) studies have shown that prenatal exposure to methamphetamine is associated with alterations in white matter microstructure, but to date no tractography studies have been performed in neonates. The striato-thalamo-orbitofrontal circuit and its associated limbic-striatal areas, the primary circuit responsible for reinforcement, has been postulated to be dysfunctional in drug addiction. This study investigated potential white matter changes in the striatal-orbitofrontal circuit in neonates with prenatal methamphetamine exposure. Mothers were recruited antenatally and interviewed regarding methamphetamine use during pregnancy, and DTI sequences were acquired in the first postnatal month. Target regions of interest were manually delineated, white matter bundles connecting pairs of targets were determined using probabilistic tractography in AFNI-FATCAT, and fractional anisotropy (FA) and diffusion measures were determined in white matter connections. Regression analysis showed that increasing methamphetamine exposure was associated with reduced FA in several connections between the striatum and midbrain, orbitofrontal cortex, and associated limbic structures, following adjustment for potential confounding variables. Our results are consistent with previous findings in older children and extend them to show that these changes are already evident in neonates. The observed alterations are likely to play a role in the deficits in attention and inhibitory control frequently seen in children with prenatal methamphetamine exposure.
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Awareness and Knowledge Levels of 18-Year-Old and Older Individuals Regarding Human Papillomavirus (HPV) and HPV Vaccine in Hatay, Turkey
Abstract
The aim of this study was to evaluate the knowledge and awareness levels of 18-year-old and older women and men on HPV infection, HPV vaccine, and the potential risk factors in Hatay, Turkey. In our study, it was found that overall 27.0 and 23.2% of the participants reported having heard of HPV infection and HPV vaccine. The rate of participants who had heard of HPV infection and HPV vaccine was higher in women than in men (p < 0.000). Thirteen percent of the participants was aware of the fact that HPV triggers cervical cancer, 10.2% penile cancer, and 16.7% genital warts, respectively. The overall vaccination rate of the participants was 2.7%. When the total knowledge score of the participants about HPV infection and HPV vaccine was evaluated according to independent variables, it was found that being a woman, urbanization, and having a high level of education had a positive effect on knowledge score, while never having heard of HPV infection and HPV vaccine had a negative effect on knowledge score (p < 0.000). It was determined in the linear regression model that gender, educational status, residential area, and having heard of HPV infection before influenced knowledge levels. It was determined that the relation between these variables and the total knowledge scores of the participants was statistically significant (p < 0.05). It was also determined that women who had higher educational levels, those who were living in urban areas, and those who had heard HPV infection before had higher knowledge levels. The level of knowledge of the participants about HPV infection and HPV vaccine was found to be very low. Having adequate knowledge about HPV infection and increasing the acceptance of HPV vaccination in public will play an important role in decreasing the rate of mortality and morbidity of the different HPV-associated cancers in women and men.
http://ift.tt/2xiVked
Prenatal methamphetamine exposure is associated with corticostriatal white matter changes in neonates
Abstract
Diffusion tensor imaging (DTI) studies have shown that prenatal exposure to methamphetamine is associated with alterations in white matter microstructure, but to date no tractography studies have been performed in neonates. The striato-thalamo-orbitofrontal circuit and its associated limbic-striatal areas, the primary circuit responsible for reinforcement, has been postulated to be dysfunctional in drug addiction. This study investigated potential white matter changes in the striatal-orbitofrontal circuit in neonates with prenatal methamphetamine exposure. Mothers were recruited antenatally and interviewed regarding methamphetamine use during pregnancy, and DTI sequences were acquired in the first postnatal month. Target regions of interest were manually delineated, white matter bundles connecting pairs of targets were determined using probabilistic tractography in AFNI-FATCAT, and fractional anisotropy (FA) and diffusion measures were determined in white matter connections. Regression analysis showed that increasing methamphetamine exposure was associated with reduced FA in several connections between the striatum and midbrain, orbitofrontal cortex, and associated limbic structures, following adjustment for potential confounding variables. Our results are consistent with previous findings in older children and extend them to show that these changes are already evident in neonates. The observed alterations are likely to play a role in the deficits in attention and inhibitory control frequently seen in children with prenatal methamphetamine exposure.
http://ift.tt/2zKSqjO
The evidence base for circulating tumour DNA blood-based biomarkers for the early detection of cancer: a systematic mapping review
Abstract
Background
The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types.
Methods
The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded.
Results
The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods).
Conclusion
We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection.
http://ift.tt/2xjMUDc
Coping and adjustment in men with prostate cancer: a systematic review of qualitative studies
Abstract
Purpose
Prostate cancer (PCa) is one of the most common forms of cancer amongst males. Men's coping responses are an important determinant of functioning and adjustment to this disease. Previous qualitative research exists in this area, but the current review sought to systematically review and summarise these studies.
Methods
A systematic review was conducted to identify studies concerned with men's coping strategies in their attempts to live with PCa. A search of relevant electronic databases was conducted to identify studies that met inclusion criteria for this review. Methodological quality assessment was also undertaken for each included study.
Results
One hundred twenty-one publications were identified for initial screening, and 18 studies were included in the review. A total of five coping strategy categories or 'meta-themes' were identified across included studies. These categories were labelled 'avoidance, minimisation, and withdrawal', 'directing cognition and attention', 'reframing masculinity and seeking support', 'retain pre-illness identity and lifestyle', and 'symptom/side-effect management'.
Conclusions
A range of coping strategies were reported by men with PCa. Some of these strategies appear to be partially influenced by gender roles and masculinities. Coping meta-themes reported in this review have also been found in other research on men's coping. Strategies relating to flexible interpretation of gender roles/masculinities may be a particularly relevant category of coping responses due to the hypothesised beneficial impact of flexibility on psychological well-being.
Implications for cancer survivors
PCa survivors utilise a range of coping strategies, and the types of strategies used may have implications for men's well-being. The ability to be flexible in both coping responses used, and in the view of oneself as a man may be particularly important skills in meeting the challenges associated with this disease.
http://ift.tt/2xiPdGE
Significance of a frozen section analysis of the ureteral margin in bladder cancer patients treated with radical cystectomy and neoadjuvant chemotherapy
Abstract
Although the clinical utility of a frozen section analysis (FSA) at the time of radical cystectomy (RC) has already been established, its significance and utility in bladder cancer patients receiving neoadjuvant chemotherapy (NAC) have not yet been fully evaluated. We identified 458 patients (937 ureters) who underwent open RC for bladder cancer at our 7 Japanese institutions between 2004 and 2015. Among these patients, 139 (284 ureters) received NAC before RC (NAC group), while 319 (653 ureters) underwent RC alone (non-NAC group). FSA was performed on 356 out of 937 (38.0%) ureters and 179 out of 458 (39.1%) patients. FSA was positive in 30 out of 356 (8.4%) ureters and its sensitivity, specificity, and accuracy were 89.3, 98.5, and 97.8%, respectively. In the NAC group, FSA was performed on 138 out of 284 (48.6%) ureters and 68 out of 139 (48.9%) patients. FSA was positive in 8 out of 138 ureters (5.8%), and its sensitivity, specificity, and accuracy were 77.8, 99.2, and 97.8%, respectively. In the non-NAC group, FSA was performed on 218 out of 653 (33.4%) ureters and 111 out of 319 (34.8%) patients. FSA was positive in 22 out of 218 (10.1%) ureters, and its sensitivity, specificity, and accuracy were 94.7, 98.0, and 97.7%, respectively. No correlation was observed between preoperative clinical factors and FSA positivity in the NAC group; however, in the non-NAC group, the incidence of FSA positivity in the ureters of patients with concomitant CIS in TUR-BT specimens was 8/41 (19.5%), which was significantly higher than that in their counterpart (14/177, 7.9%, p = 0.033). Even in the era of NAC in the management of bladder cancer patients, the performance of FSA does not change and FSA at the time of RC may provide useful diagnostic information.
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Prognostic significance of the preoperative neutrophil-to-lymphocyte ratio for complete resection of thymoma
Abstract
Purpose
The preoperative peripheral neutrophil-to-lymphocyte ratio (NLR) is associated with a poor prognosis for various cancers. We evaluated the prognostic role of the preoperative NLR in patients with thymoma.
Methods
We reviewed the medical records of 254 patients who underwent resection of thymic epithelial tumors at our institution. Patients were excluded if they had received steroid therapy, neoadjuvant therapy, or incomplete resection, or if they had thymic carcinoma or Good's syndrome, recurrence of thymoma, or missing data. The NLR was measured preoperatively, and outcomes of patients with a low (< 1.96) vs those with a high (≥ 1.96) NLR were compared statistically.
Results
Of 159 eligible patients, 59 (37.1%) had a high NLR and 100 (62.9%) had a low NLR. Overall survival (OS), recurrence-free survival (RFS), disease-specific survival (DSS), disease-related survival (DRS), and the cumulative incidence of recurrence (CIR) differed significantly between the groups. Multivariate analyses revealed that a high NLR was independently associated with disease-related survival and a cumulative incidence of recurrence. A high NLR was also associated with a higher risk of recurrence of Masaoka stage I or II thymoma.
Conclusions
An elevated preoperative NLR was associated with poor outcomes after thymoma resection. Thus, the NLR may be a useful biomarker of the postoperative prognosis of thymoma.
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Significance of a frozen section analysis of the ureteral margin in bladder cancer patients treated with radical cystectomy and neoadjuvant chemotherapy
Abstract
Although the clinical utility of a frozen section analysis (FSA) at the time of radical cystectomy (RC) has already been established, its significance and utility in bladder cancer patients receiving neoadjuvant chemotherapy (NAC) have not yet been fully evaluated. We identified 458 patients (937 ureters) who underwent open RC for bladder cancer at our 7 Japanese institutions between 2004 and 2015. Among these patients, 139 (284 ureters) received NAC before RC (NAC group), while 319 (653 ureters) underwent RC alone (non-NAC group). FSA was performed on 356 out of 937 (38.0%) ureters and 179 out of 458 (39.1%) patients. FSA was positive in 30 out of 356 (8.4%) ureters and its sensitivity, specificity, and accuracy were 89.3, 98.5, and 97.8%, respectively. In the NAC group, FSA was performed on 138 out of 284 (48.6%) ureters and 68 out of 139 (48.9%) patients. FSA was positive in 8 out of 138 ureters (5.8%), and its sensitivity, specificity, and accuracy were 77.8, 99.2, and 97.8%, respectively. In the non-NAC group, FSA was performed on 218 out of 653 (33.4%) ureters and 111 out of 319 (34.8%) patients. FSA was positive in 22 out of 218 (10.1%) ureters, and its sensitivity, specificity, and accuracy were 94.7, 98.0, and 97.7%, respectively. No correlation was observed between preoperative clinical factors and FSA positivity in the NAC group; however, in the non-NAC group, the incidence of FSA positivity in the ureters of patients with concomitant CIS in TUR-BT specimens was 8/41 (19.5%), which was significantly higher than that in their counterpart (14/177, 7.9%, p = 0.033). Even in the era of NAC in the management of bladder cancer patients, the performance of FSA does not change and FSA at the time of RC may provide useful diagnostic information.
http://ift.tt/2gEu9Y8
Prognostic significance of the preoperative neutrophil-to-lymphocyte ratio for complete resection of thymoma
Abstract
Purpose
The preoperative peripheral neutrophil-to-lymphocyte ratio (NLR) is associated with a poor prognosis for various cancers. We evaluated the prognostic role of the preoperative NLR in patients with thymoma.
Methods
We reviewed the medical records of 254 patients who underwent resection of thymic epithelial tumors at our institution. Patients were excluded if they had received steroid therapy, neoadjuvant therapy, or incomplete resection, or if they had thymic carcinoma or Good's syndrome, recurrence of thymoma, or missing data. The NLR was measured preoperatively, and outcomes of patients with a low (< 1.96) vs those with a high (≥ 1.96) NLR were compared statistically.
Results
Of 159 eligible patients, 59 (37.1%) had a high NLR and 100 (62.9%) had a low NLR. Overall survival (OS), recurrence-free survival (RFS), disease-specific survival (DSS), disease-related survival (DRS), and the cumulative incidence of recurrence (CIR) differed significantly between the groups. Multivariate analyses revealed that a high NLR was independently associated with disease-related survival and a cumulative incidence of recurrence. A high NLR was also associated with a higher risk of recurrence of Masaoka stage I or II thymoma.
Conclusions
An elevated preoperative NLR was associated with poor outcomes after thymoma resection. Thus, the NLR may be a useful biomarker of the postoperative prognosis of thymoma.
http://ift.tt/2yFXI2m
Isolation and characterization of three new anti-proliferative Sesquiterpenes from Polygonum barbatum and their mechanism via apoptotic pathway
Abstract
Background
The emergence of chemoresistant cancers and toxicity related to existing chemotherapeutic agents, demand the search for new pharmacophore with enhanced anti-cancer activity and least toxicity. For this purpose, three new sesquiterpenes were isolated from ethyl acetate fraction of the aerial parts of the plant Polygonum barbatum and evaluated for their anti-cancer potential.
Methods
The structural elucidation and characterization of the isolated compounds 1–3 were performed using various spectroscopic techniques such as mass, UV, IR, and extensive 1D/2D–NMR spectroscopy. Furthermore, the compounds 1–3 were subjected to screening of anti-cancer activity against different cell lines followed by brief analysis of apoptotic and anti-angiogenic potentials of the potent hit against non-small cell lung carcinoma cell line.
Results
All the compounds 1–3 were subjected to anti-proliferative potential against non-small cell lung carcinoma (NCI-H460), breast cancer (MCF-7), cervical cancer (HeLa) and normal mouse fibroblast (NIH-3 T3) cell lines. Among these, compound 3 was found to be more cytotoxic against NCI-H460 and MCF-7 cells (IC50 = 17.86 ± 0.72 and 11.86 ± 0.46 μM respectively). When compared with the standard drug cisplatin compound 3 was found to have more potent activity against NCI-H460 (IC50 = 19 ± 1.24 μM) as compared to MCF-7 cell lines (IC50 = 9.62 ± 0.5 μM). Compound 3 induced apoptosis in NCI-H460 cells in a dose dependent manner. It significantly downregulated, the expression of anti-apoptotic (BCL-2 L1 and p53) and increased the expression of pro-apoptotic (BAK and BAX) genes. Besides apoptosis, it also significantly reduced the cell migration and downregulated the angiogenic genes (i.e. VEGF and COX-2), thereby, inhibiting angiogenesis in NCI-H460 cells.
Conclusion
Compound 3 possesses potent anti-proliferative potential as well as induced apoptosis and inhibited the cell migration of the cancerous cells by altering the gene expression, responsible for it.
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Whether intermediate-risk stage 1A, grade 1/2, endometrioid endometrial cancer patients with lesions larger than 2 cm warrant lymph node dissection?
Abstract
Background
Our research aimed to investigate whether lymphadenectomy was required in patients with intermediate-risk endometrioid endometrial cancer (EEC).
Methods
Between 1989 and 2015, 1009 patients with intermediate-risk EEC: grade 1 or 2 tumor, <50% myometrial invasion, and a tumor diameter ≥ 2 cm and 818 low-risk patients with grade 1 or 2 tumor, <50% myometrial invasion, and a tumor diameter < 2 cm were enrolled in this study. The rate and risk factors of node metastasis were evaluated and compared between the two risk groups. Survival data were analyzed in patients with intermediate-risk EEC with or without lymphadenectomy.
Results
In all, 624 of 1009 (61.8%) patients with intermediate-risk EEC underwent pelvic ± para-aortic lymphadenectomy with a nodal metastasis rate of 1.9% (12/624), whereas 394 of 818 (48.2%) patients with low-risk EEC underwent pelvic ± para-aortic lymphadenectomy with a nodal metastasis rate of 0.3% (1/394) (p = 0.021). Notably, intermediate-risk EEC patients with a microcystic, elongated and fragmented (MELF) pattern of invasion, lymphatic vascular space invasion (LVSI), diffuse lesions, or lesions located in the cornua were more likely to have node metastasis. The 5-year overall cancer-related survival and the recurrence-free survival rates of the 742 intermediate-risk EEC patients who were followed for more than 3 years were 99.4% and 94.7%, respectively. In intermediate-risk group, 6 patients (6/443, 1.4%) with lymphadenectomy and 9 patients (9/299, 3.0%) without lymphadenectomy recurred, with a mean recurrence time of 38.3 and 18.7 months respectively. The five-year overall and recurrence-free survival rates of intermediate-risk patients with and without lymphadenectomy were similar (100% vs 98.9%, p = 0.351; 95.2% vs 93.3%, p = 0.464).
Conclusion
Patients with intermediate-risk EEC have low nodal metastasis rate and a favorable outcome whether lymphadenectomy is performed or not. Omission of lymphadenectomy may be a reasonable option in the surgical management of patients with intermediate-risk EEC.
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18 F- FDG PET/CT helps differentiate autoimmune pancreatitis from pancreatic cancer
Abstract
Background
18F-FDG PET/CT could satisfactorily show pancreatic and extra-pancreatic lesions in AIP, which can be mistaken for pancreatic cancer (PC). This study aimed to identify 18F-FDG PET/CT findings that might differentiate AIP from PC.
Methods
FDG-PET/CT findings of 26 AIP and 40 PC patients were reviewed. Pancreatic and extra-pancreatic lesions related findings, including maximum standardized uptake values (SUVmax) and patterns of FDG uptake, were identified and compared.
Results
All 26 patients with AIP had increased pancreatic FDG uptake. Focal abnormal pancreatic FDG activities were found in 38/40 (95.00%) PC patients, while longitudinal were found in 18/26 (69.23%) AIP patients. SUVmax was significantly different between AIP and PC, both in early and delayed PET/CT scans (p < 0.05). AUCs were 0.700 (early SUVmax), 0.687 (delayed SUVmax), 0.683 (early lesions/liver SUVmax), and 0.715 (delayed lesion/liver SUVmax). Bile duct related abnormalities were found in 12/26 (46.15%) AIP and 10/40 (25.00%) PC patients, respectively. Incidentally, salivary and prostate gland SUVmax in AIP patients were higher compared with those of PC patients (p < 0.05). In males,an inverted "V" shaped high FDG uptake in the prostate was more frequent in AIP than PC patients (56.00%, 14/25 vs. 5.71%, 2/35). Increased FDG activity in extra-pancreatic bile duct was present in 4/26 of AIP patients, while was observed in none of the PC patients. Only in AIP patients, both diffuse pancreatic FDG accumulation and increased inverted "V" shaped FDG uptake in the prostate could be found simultaneously.
Conclusions
18F-FDG PET/CT findings might help differentiate AIP from PC.
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Bitter Melon prevents the development of 4-NQO-induced oral squamous cell carcinoma in an immunocompetent mouse model by modulating immune signalling
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and tobacco is one of the most common factors for HNSCC of the oral cavity. We have previously observed that bitter melon (Momordica charantia) extract (BME) exerts anti-proliferative activity against several cancers including HNSCC. In this study, we investigated the preventive role of BME in 4-nitroquinoline 1-oxide (4-NQO) carcinogen-induced HNSCC. We observed that BME feeding significantly reduced the incidence of 4-NQO induced oral cancer in a mouse model. Histological analysis suggested control 4-NQO treated mouse tongues showed neoplastic changes ranging from moderate dysplasia to invasive squamous cell carcinoma, whereas no significant dysplasia was observed in the BME-fed mouse tongues. We also examined the global transcriptome changes in normal vs. carcinogen-induced tongue cancer tissues, and following BME feeding. Gene ontology and pathway analyses revealed a signature of biological processes including "immune system process" that is significantly dysregulated in 4-NQO-induced oral cancer. We identified elevated expression of pro-inflammatory genes, s100a9, IL23a, IL-1beta and immune check point gene PDCD1/PD1, during oral cancer development. Interestingly, BME treatment significantly reduced their expression. Enhancement of MMP9 ("ossification" pathway) was noted during carcinogenesis, which was reduced in BME-fed mouse tongue tissues. Our study demonstrates the preventive effect of BME in 4-NQO-induced carcinogenesis. Identification of pathways that involved in carcinogen-induced oral cancer provides useful information for prevention strategies. Together, our data strongly suggest the potential clinical benefits of BME as a chemopreventive agent in the control or delay of carcinogen-induced HNSCC development and progression.
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A survey among breast cancer specialists on the low uptake of therapeutic prevention with tamoxifen or raloxifene
With this survey, we aimed to address the reasons why physicians are reluctant to prescribe breast cancer preventive therapy with the selective oestrogens receptor modulators (SERMs) tamoxifen or raloxifene despite a strong evidence of efficacy. A self-administered 5-point Likert questionnaire was given during breast cancer meetings in Europe or sent via email to rank the importance of 10 pre-defined reasons for low uptake of SERMs for breast cancer therapeutic prevention. Analyses tested the associations between the stated reasons and physician characteristics such as gender, age, country of work and specialty. Of 246 delivered questionnaires, 27 were incomplete and were excluded from analysis. Overall, there was a small variability in response scores, with a tendency for physicians to give moderate importance (score=3) to all 10 statements. However, the top five reasons were: the expected greater preventive effectiveness of aromatase inhibitors (70.3% with score>3), difficulty applying current risk models in clinical practice (69.9%), the lack of clarity on the most appropriate physician for prevention advice (68.4%), the lack of reliable short-term biomarkers of effectiveness (67.5%) and the lack of commercial interest in therapeutic prevention (66.0%). The lack of reliable short-term biomarkers showed a tendency to discriminate between medical oncologists and other breast specialists (OR=2.42, 95% CI, 0.93-6.25). This survey highlights the complexity of prescribing decisions among physicians in this context. Coupled with the known barriers among eligible women, these data may help to identify strategies to increase uptake of breast cancer therapeutic prevention.
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Whether intermediate-risk stage 1A, grade 1/2, endometrioid endometrial cancer patients with lesions larger than 2 cm warrant lymph node dissection?
Abstract
Background
Our research aimed to investigate whether lymphadenectomy was required in patients with intermediate-risk endometrioid endometrial cancer (EEC).
Methods
Between 1989 and 2015, 1009 patients with intermediate-risk EEC: grade 1 or 2 tumor, <50% myometrial invasion, and a tumor diameter ≥ 2 cm and 818 low-risk patients with grade 1 or 2 tumor, <50% myometrial invasion, and a tumor diameter < 2 cm were enrolled in this study. The rate and risk factors of node metastasis were evaluated and compared between the two risk groups. Survival data were analyzed in patients with intermediate-risk EEC with or without lymphadenectomy.
Results
In all, 624 of 1009 (61.8%) patients with intermediate-risk EEC underwent pelvic ± para-aortic lymphadenectomy with a nodal metastasis rate of 1.9% (12/624), whereas 394 of 818 (48.2%) patients with low-risk EEC underwent pelvic ± para-aortic lymphadenectomy with a nodal metastasis rate of 0.3% (1/394) (p = 0.021). Notably, intermediate-risk EEC patients with a microcystic, elongated and fragmented (MELF) pattern of invasion, lymphatic vascular space invasion (LVSI), diffuse lesions, or lesions located in the cornua were more likely to have node metastasis. The 5-year overall cancer-related survival and the recurrence-free survival rates of the 742 intermediate-risk EEC patients who were followed for more than 3 years were 99.4% and 94.7%, respectively. In intermediate-risk group, 6 patients (6/443, 1.4%) with lymphadenectomy and 9 patients (9/299, 3.0%) without lymphadenectomy recurred, with a mean recurrence time of 38.3 and 18.7 months respectively. The five-year overall and recurrence-free survival rates of intermediate-risk patients with and without lymphadenectomy were similar (100% vs 98.9%, p = 0.351; 95.2% vs 93.3%, p = 0.464).
Conclusion
Patients with intermediate-risk EEC have low nodal metastasis rate and a favorable outcome whether lymphadenectomy is performed or not. Omission of lymphadenectomy may be a reasonable option in the surgical management of patients with intermediate-risk EEC.
http://ift.tt/2z2XtPv
18 F- FDG PET/CT helps differentiate autoimmune pancreatitis from pancreatic cancer
Abstract
Background
18F-FDG PET/CT could satisfactorily show pancreatic and extra-pancreatic lesions in AIP, which can be mistaken for pancreatic cancer (PC). This study aimed to identify 18F-FDG PET/CT findings that might differentiate AIP from PC.
Methods
FDG-PET/CT findings of 26 AIP and 40 PC patients were reviewed. Pancreatic and extra-pancreatic lesions related findings, including maximum standardized uptake values (SUVmax) and patterns of FDG uptake, were identified and compared.
Results
All 26 patients with AIP had increased pancreatic FDG uptake. Focal abnormal pancreatic FDG activities were found in 38/40 (95.00%) PC patients, while longitudinal were found in 18/26 (69.23%) AIP patients. SUVmax was significantly different between AIP and PC, both in early and delayed PET/CT scans (p < 0.05). AUCs were 0.700 (early SUVmax), 0.687 (delayed SUVmax), 0.683 (early lesions/liver SUVmax), and 0.715 (delayed lesion/liver SUVmax). Bile duct related abnormalities were found in 12/26 (46.15%) AIP and 10/40 (25.00%) PC patients, respectively. Incidentally, salivary and prostate gland SUVmax in AIP patients were higher compared with those of PC patients (p < 0.05). In males,an inverted "V" shaped high FDG uptake in the prostate was more frequent in AIP than PC patients (56.00%, 14/25 vs. 5.71%, 2/35). Increased FDG activity in extra-pancreatic bile duct was present in 4/26 of AIP patients, while was observed in none of the PC patients. Only in AIP patients, both diffuse pancreatic FDG accumulation and increased inverted "V" shaped FDG uptake in the prostate could be found simultaneously.
Conclusions
18F-FDG PET/CT findings might help differentiate AIP from PC.
http://ift.tt/2iw91E5
Hepatic artery infusion chemotherapy using mFOLFOX versus transarterial chemoembolization for massive unresectable hepatocellular carcinoma: a prospective non-randomized study
Abstract
Background
Transarterial chemoembolization (TACE) is recommended as the standard care for unresectable hepatocellular carcinoma (HCC) at Barcelona Clinic Liver Cancer (BCLC) stage A–B. However, the efficacy of TACE on large (≥ 10 cm) stage A–B HCC is far from satisfactory, and it is proposed that hepatic artery infusion chemotherapy (HAIC) might be a better first-line treatment of this disease. Hence, we compared the safety and efficacy of HAIC with the modified FOLFOX (mFOLFOX) regimen and those of TACE in patients with massive unresectable HCC.
Methods
A prospective, non-randomized, phase II study was conducted on patients with massive unresectable HCC. The protocol involved HAIC with the mFOLFOX regimen (oxaliplatin, 85 mg/m2 intra-arterial infusion; leucovorin, 400 mg/m2 intra-arterial infusion; and fluorouracil, 400 mg/m2 bolus infusion and 2400 mg/m2 continuous infusion) every 3 weeks and TACE with 50 mg of epirubicin, 50 mg of lobaplatin, 6 mg of mitomycin, and lipiodol and polyvinyl alcohol particles. The tumor responses, time-to-progression (TTP), and safety were assessed.
Results
A total of 79 patients were recruited for this study: 38 in the HAIC group and 41 in the TACE group. The HAIC group exhibited higher partial response and disease control rates than did the TACE group (52.6% vs. 9.8%, P < 0.001; 83.8% vs. 52.5%, P = 0.004). The median TTPs for the HAIC and TACE groups were 5.87 and 3.6 months (hazard radio [HR] = 2.35, 95% confidence interval [CI] = 1.16–4.76, P = 0.015). More patients in the HAIC group than in the TACE group underwent resection (10 vs. 3, P = 0.033). The proportions of grade 3–4 adverse events (AE) and serious adverse events (SAE) were lower in the HAIC group than in the TACE group (grade 3–4 AEs: 13 vs. 27, P = 0.007; SAEs: 6 vs. 15, P = 0.044). More patients in the TACE group than in the HAIC group had the study treatment terminated early due to intolerable treatment-related adverse events or the withdrawal of consent (10 vs. 2, P = 0.026).
Conclusions
HAIC with mFOLFOX yielded significantly better treatment responses and less serious toxicity than did TACE. HAIC might represent a feasible and promising first-line treatment for patients with massive unresectable HCC.
http://ift.tt/2z3naQ8
Heart irradiation reduces microvascular density and accumulation of HSPA1 in mice
Abstract
Purpose
Improvement of radiotherapy techniques reduces the exposure of normal tissues to ionizing radiation. However, the risk of radiation-related late effects remains elevated. In the present study, we investigated long-term effects of radiation on heart muscle morphology.
Materials and methods
We established a mouse model to study microvascular density (MVD), deposition of collagen fibers, and changes in accumulation of heat shock 70 kDa protein 1 (HSPA1) in irradiated heart tissue. Hearts of C57BL/6 mice received a single dose of X‑ray radiation in the range 0.2–16 Gy. Analyses were performed 20, 40, and 60 weeks after irradiation.
Results
Reduction in MD was revealed as a long-term effect observed 20–60 weeks after irradiation. Moreover, a significant and dose-dependent increase in accumulation of HSPA1, both cytoplasmic and nuclear, was observed in heart tissues collected 20 weeks after irradiation. We also noticed an increase in collagen deposition in hearts treated with higher doses.
Conclusions
This study shows that some changes induced by radiation in the heart tissue, such as reduction in microvessel density, increase in collagen deposition, and accumulation of HSPA1, are observed as long-term effects which might be associated with late radiation cardiotoxicity.
http://ift.tt/2z33Gen
Chemical meningitis related to intra-CSF liposomal cytarabine
CNS Oncology, Ahead of Print.
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Chemical meningitis related to intra-CSF liposomal cytarabine
CNS Oncology, Ahead of Print.
http://ift.tt/2i1oHLt
HALO-109–301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer
Future Oncology, Ahead of Print.
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An updated review of the JAK1/2 inhibitor (ruxolitinib) in the Philadelphia-negative myeloproliferative neoplasms
Future Oncology, Ahead of Print.
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Nitrite administration improves sepsis-induced myocardial and mitochondrial dysfunction by modulating stress signal responses
Abstract
Purpose
A specific therapeutic strategy in sepsis-induced myocardial dysfunction remains to be determined. Nitrite may have cardioprotective effects against sepsis-induced myocardial dysfunction. This study investigated the cardioprotective effects of nitrite on myocardial function, mitochondrial bioenergetics, and its underlying molecular mechanisms in severe septic rats.
Methods
Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP). After CLP, we administered normal saline (NS group) or nitrite (nitrite group) subcutaneously. We administered nitrite at different doses (0.1–10 mg/kg) to ascertain the most effective dose and examined cardiac function in an isolated heart experiment 8 h after CLP. We investigated mitochondrial bioenergetics and molecular mechanisms underlying the administration of nitrite in vitro.
Results
In isolated heart experiments, the left ventricular developed pressure (96 ± 5 mmHg) at a moderate nitrite dose (1.0 mg/kg) was significantly higher than that in the NS group (75 ± 4 mmHg, P < 0.05). Mitochondrial oxidative phosphorylation in the nitrite group was significantly higher than that in the NS group (P < 0.01). Immunoblotting revealed that nitrite significantly increased the phosphorylation of Akt (P < 0.05) and reduced the nuclear translocation of NF-κB (P < 0.05) compared with the NS group. Nitrite was also shown to improve the rate of survival in severe septic rats (P < 0.001).
Conclusions
Our results showed that a moderate nitrite dose improved septic myocardial dysfunction at organ, cellular, and molecular levels via modulation of stress signal responses, which resulted in an improvement in survival.
http://ift.tt/2z30tv9
KRAS mutation and Consensus Molecular Subtypes 2 and 3 are independently associated with reduced immune infiltration and reactivity in colorectal cancer
Purpose: KRAS mutation is a common canonical mutation in CRC, found at differing frequencies in all Consensus Molecular Subtypes (CMS). The independent immunobiological impacts of RAS mutation and CMS are unknown. Thus, we explored the immunobiological effects of KRAS mutation across the CMS spectrum. Experimental Design: Transcriptional analysis of immune genes/signatures was performed with RNA-seq using The Cancer Genome Atlas (TCGA) and the KFSYSCC data set. Multivariate analysis included KRAS status, CMS, tumour location, MSI status, and neoantigen load. Protein expression of STAT1, HLA-Class II, and CXCL10 was analysed by digital immunohistochemistry. Results: The Th1-centric co-ordinated immune response cluster (CIRC) was significantly, albeit modestly, reduced in KRAS mutant CRC in both data sets. Cytotoxic T cells, neutrophils and the interferon gamma pathway were suppressed in KRAS mutant samples. The expression of STAT1 and CXCL10, were reduced at the mRNA and protein levels. In multivariate analysis KRAS mutation, CMS2 and CMS3 were independently predictive of reduced CIRC expression. Immune response was heterogeneous across KRAS mutant CRC: CMS2 KRAS mutant samples have the lowest CIRC expression, reduced expression of the interferon gamma pathway, STAT1 and CXCL10 and reduced infiltration of cytotoxic cells and neutrophils relative to CMS1 and CMS4 and to CMS2 KRAS wild type samples in the TCGA. These trends held in the KFSYSCC data set. Conclusions: KRAS mutation is associated with suppressed Th1/cytotoxic immunity in CRC, the extent of the effect being modulated by CMS subtype. These results add a novel immunobiological dimension to the biological heterogeneity of CRC.
http://ift.tt/2yJx1ci
Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer
Purpose: Women with epithelial ovarian cancer generally have a poor prognosis, however a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths. Experimental Design: We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical, and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing. Results: Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8+ tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR-deficiency and RB1 loss were correlated and co-occurrence was significantly associated with prolonged survival. Conclusions: There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR-deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients.
http://ift.tt/2y1Enod
Comprehensive pharmacogenomic profiling of malignant pleural mesothelioma identifies a subgroup sensitive to FGFR inhibition.
Purpose: Despite intense research, treatment options for patients with mesothelioma are limited and offer only modest survival advantage. We screened a large panel of compounds in multiple mesothelioma models, and correlated sensitivity with a range of molecular features to detect biomarkers of drug response. Experimental design: We utilised a high-throughput chemical inhibitor screen in a panel of 889 cancer cell lines, including both immortalised and primary early passage mesothelioma lines, alongside comprehensive molecular characterisation using Illumina whole exome sequencing, copy number analysis and Affymetrix array whole transcriptome profiling. Subsequent validation was done using functional assays such as siRNA silencing and mesothelioma mouse xenograft models. Results: A subgroup of immortalized and primary MPM lines appeared highly sensitive to FGFR inhibition. None of these lines harboured genomic alterations of FGFR family members, but rather BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. This was confirmed in a MPM mouse xenograft model and by BAP1 knock-down and overexpression in cell line models. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. These associations were confirmed in a cohort of MPM patient samples. Conclusion: A subgroup of mesotheliomas cell lines harbour sensitivity to FGFR inhibition. BAP1 protein loss enriches for this subgroup, and could serve as a potential biomarker to select patients for FGFR inhibitor treatment. These data identify a clinically relevant MPM subgroup for consideration of FGFR therapeutics in future clinical studies.
http://ift.tt/2yJP6qF
A Phase Ib Study of Immune Biomarker Modulation with Neoadjuvant Cetuximab and TLR8 stimulation in Head and Neck Cancer to Overcome Suppressive Myeloid Signals
Purpose: The response rate of head and neck squamous cell carcinoma (HNSCC) patients to cetuximab therapy is only 15-20%, despite frequent EGFR overexpression. Since immunosuppression is common in HNSCC, we hypothesized that adding a pro-inflammatory TLR8 agonist to cetuximab therapy might result in enhanced T lymphocyte stimulation and anti-EGFR specific priming. Experimental Design: Fourteen patients with previously untreated HNSCC were enrolled in this neoadjuvant trial and treated preoperatively with 3-4 weekly doses of motolimod (2.5 mg/m2) and cetuximab. Correlative tumor and peripheral blood specimens were obtained at baseline and at the time of surgical resection and analyzed for immune biomarker changes. Preclinical in vitro studies were also performed to assess the effect of cetuximab plus motolimod on myeloid cells. Results: TLR8 stimulation skewed monocytes toward an M1 phenotype and reversed MDSC suppression of T cell proliferation in vitro. These data were validated in a prospective phase Ib neoadjuvant trial, in which fewer MDSC and increased M1 monocyte infiltration were found in TIL. Motolimod plus cetuximab also decreased induction of Treg, and reduced markers of suppression, including CTLA-4, CD73 and membrane bound TGF-β. Significantly increased circulating EGFR-specific T cells were observed, concomitant with enhanced CD8+ T cell infiltration into tumors. These T cells manifested increased TCR clonality, upregulation of the costimulatory receptor CD27, and downregulation of inhibitory receptor TIGIT. Conclusions:Enhanced inflammatory stimulation in the tumor microenvironment using a TLR agonist overcomes suppressive myeloid and regulatory cells, enhancing the cellular antitumor immune response by therapeutic mAb in HNSCC.
http://ift.tt/2y1yQxL
Multilayered omics-based analysis of a head and neck cancer model of cisplatin resistance reveals intratumoral heterogeneity and treatment-induced clonal selection
Purpose: Platinum-based drugs, in particular cisplatin (CDDP), are used for treatment of squamous cell carcinoma of the head and neck (SCCHN). Despite initial responses, CDDP treatment often results in chemoresistance, leading to therapeutic failure. The role of primary resistance at subclonal level and treatment-induced clonal selection in the development of CDDP resistance remains unknown. Experimental Design: By applying targeted next-generation sequencing, fluorescence in-situ hybridization, microarray-based transcriptome and mass spectrometry-based phosphoproteome analysis to the CDDP-sensitive SCCHN cell line FaDu, a CDDP-resistant subline and single-cell derived subclones, the molecular basis of CDDP resistance was elucidated. The causal relationship between molecular features and resistant phenotypes was determined by siRNA-based gene silencing. The clinical relevance of molecular findings was validated in SCCHN patients with recurrence after CDDP-based chemoradiation and the TCGA SCCHN dataset. Results: Evidence of primary resistance at clonal level and clonal selection by long-term CDDP treatment was established in the FaDu model. Resistance was associated with aneuploidy of chromosome 17, increased TP53 copy numbers and overexpression of the gain-of-function (GOF) mutant variant p53 R248L. siRNA-mediated knock-down established a causal relationship between mutant p53 R248L and CDDP resistance. Resistant clones were also characterized by increased activity of the PI3K-AKT-mTOR pathway. The poor prognostic value of GOF TP53 variants and mTOR pathway upregulation was confirmed in the TCGA SCCHN cohort. Conclusions: Our study demonstrates a link of intratumoral heterogeneity and clonal evolution as important mechanisms of drug resistance in SCCHN and establishes mutant GOF TP53 variants and the PI3K/mTOR pathway as molecular targets for treatment optimization.
http://ift.tt/2yJJZqs
Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain
Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular co-stimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown HER2-CARs containing the 4-1BB co-stimulatory domain confer improved tumor targeting with reduced T cell exhaustion phenotype and enhanced proliferative capacity compared to HER2-CARs containing the CD28 co-stimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo anti-tumor activity in an orthotopic xenograft models. Importantly, we demonstrated robust anti-tumor efficacy following regional intraventricular delivery of HER2-CAR T cells for treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases.
http://ift.tt/2y1yPKd
Lenalidomide enhances the function of CS1 chimeric antigen receptor redirected T cells against multiple myeloma
Purpose:Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite considerable advances in treatment. The purpose of the study was to develop novel CARs for the treatment of MM and explore combinatorial therapy using CAR T cells and immunomodulatory drugs such as lenalidomide for increasing treatment efficacy. Experimental Design: We redirected central memory T cells to express second-generation CAR specific for CS1 and adoptively transferred them into MM tumor-bearing mice to test their anti-MM activity. CS1 CAR T cells were transduced and expanded in the presence of lenalidomide in vitro. The phenotype and effector function of CS1 CAR T cells treated with and without lenalidomide were compared. Finally, CS1 CAR T cells and lenalidomide were administered to treat MM bearing mice as combinatorial therapy.Results: CS1 CAR T cells exhibited efficient antitumor activity when adoptively transferred into mice. Mechanistic studies indicated that the addition of lenalidomide during CS1 CAR T cell expansion in vitro enhanced the immune functions of CS1 CAR T cells, including cytotoxicity, memory maintenance, Th1 cytokine production, and immune synapse formation. Furthermore, lenalidomide enhanced the anti-tumor activity and persistence of adoptively transferred CS1 CAR T cells in vivo. Conclusions:The study demonstrates that lenalidomide improves the anti-MM properties of CS1-directed CAR T cells and provides a basis for a planned clinical trial using the combination of lenalidomide with engineered T cells against CS1 in relapsed myeloma.
http://ift.tt/2yK9oQT
KRAS mutation and Consensus Molecular Subtypes 2 and 3 are independently associated with reduced immune infiltration and reactivity in colorectal cancer
Purpose: KRAS mutation is a common canonical mutation in CRC, found at differing frequencies in all Consensus Molecular Subtypes (CMS). The independent immunobiological impacts of RAS mutation and CMS are unknown. Thus, we explored the immunobiological effects of KRAS mutation across the CMS spectrum. Experimental Design: Transcriptional analysis of immune genes/signatures was performed with RNA-seq using The Cancer Genome Atlas (TCGA) and the KFSYSCC data set. Multivariate analysis included KRAS status, CMS, tumour location, MSI status, and neoantigen load. Protein expression of STAT1, HLA-Class II, and CXCL10 was analysed by digital immunohistochemistry. Results: The Th1-centric co-ordinated immune response cluster (CIRC) was significantly, albeit modestly, reduced in KRAS mutant CRC in both data sets. Cytotoxic T cells, neutrophils and the interferon gamma pathway were suppressed in KRAS mutant samples. The expression of STAT1 and CXCL10, were reduced at the mRNA and protein levels. In multivariate analysis KRAS mutation, CMS2 and CMS3 were independently predictive of reduced CIRC expression. Immune response was heterogeneous across KRAS mutant CRC: CMS2 KRAS mutant samples have the lowest CIRC expression, reduced expression of the interferon gamma pathway, STAT1 and CXCL10 and reduced infiltration of cytotoxic cells and neutrophils relative to CMS1 and CMS4 and to CMS2 KRAS wild type samples in the TCGA. These trends held in the KFSYSCC data set. Conclusions: KRAS mutation is associated with suppressed Th1/cytotoxic immunity in CRC, the extent of the effect being modulated by CMS subtype. These results add a novel immunobiological dimension to the biological heterogeneity of CRC.
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Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer
Purpose: Women with epithelial ovarian cancer generally have a poor prognosis, however a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths. Experimental Design: We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical, and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing. Results: Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8+ tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR-deficiency and RB1 loss were correlated and co-occurrence was significantly associated with prolonged survival. Conclusions: There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR-deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients.
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Comprehensive pharmacogenomic profiling of malignant pleural mesothelioma identifies a subgroup sensitive to FGFR inhibition.
Purpose: Despite intense research, treatment options for patients with mesothelioma are limited and offer only modest survival advantage. We screened a large panel of compounds in multiple mesothelioma models, and correlated sensitivity with a range of molecular features to detect biomarkers of drug response. Experimental design: We utilised a high-throughput chemical inhibitor screen in a panel of 889 cancer cell lines, including both immortalised and primary early passage mesothelioma lines, alongside comprehensive molecular characterisation using Illumina whole exome sequencing, copy number analysis and Affymetrix array whole transcriptome profiling. Subsequent validation was done using functional assays such as siRNA silencing and mesothelioma mouse xenograft models. Results: A subgroup of immortalized and primary MPM lines appeared highly sensitive to FGFR inhibition. None of these lines harboured genomic alterations of FGFR family members, but rather BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. This was confirmed in a MPM mouse xenograft model and by BAP1 knock-down and overexpression in cell line models. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. These associations were confirmed in a cohort of MPM patient samples. Conclusion: A subgroup of mesotheliomas cell lines harbour sensitivity to FGFR inhibition. BAP1 protein loss enriches for this subgroup, and could serve as a potential biomarker to select patients for FGFR inhibitor treatment. These data identify a clinically relevant MPM subgroup for consideration of FGFR therapeutics in future clinical studies.
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A Phase Ib Study of Immune Biomarker Modulation with Neoadjuvant Cetuximab and TLR8 stimulation in Head and Neck Cancer to Overcome Suppressive Myeloid Signals
Purpose: The response rate of head and neck squamous cell carcinoma (HNSCC) patients to cetuximab therapy is only 15-20%, despite frequent EGFR overexpression. Since immunosuppression is common in HNSCC, we hypothesized that adding a pro-inflammatory TLR8 agonist to cetuximab therapy might result in enhanced T lymphocyte stimulation and anti-EGFR specific priming. Experimental Design: Fourteen patients with previously untreated HNSCC were enrolled in this neoadjuvant trial and treated preoperatively with 3-4 weekly doses of motolimod (2.5 mg/m2) and cetuximab. Correlative tumor and peripheral blood specimens were obtained at baseline and at the time of surgical resection and analyzed for immune biomarker changes. Preclinical in vitro studies were also performed to assess the effect of cetuximab plus motolimod on myeloid cells. Results: TLR8 stimulation skewed monocytes toward an M1 phenotype and reversed MDSC suppression of T cell proliferation in vitro. These data were validated in a prospective phase Ib neoadjuvant trial, in which fewer MDSC and increased M1 monocyte infiltration were found in TIL. Motolimod plus cetuximab also decreased induction of Treg, and reduced markers of suppression, including CTLA-4, CD73 and membrane bound TGF-β. Significantly increased circulating EGFR-specific T cells were observed, concomitant with enhanced CD8+ T cell infiltration into tumors. These T cells manifested increased TCR clonality, upregulation of the costimulatory receptor CD27, and downregulation of inhibitory receptor TIGIT. Conclusions:Enhanced inflammatory stimulation in the tumor microenvironment using a TLR agonist overcomes suppressive myeloid and regulatory cells, enhancing the cellular antitumor immune response by therapeutic mAb in HNSCC.
from Cancer via ola Kala on Inoreader http://ift.tt/2y1yQxL
via IFTTT
Multilayered omics-based analysis of a head and neck cancer model of cisplatin resistance reveals intratumoral heterogeneity and treatment-induced clonal selection
Purpose: Platinum-based drugs, in particular cisplatin (CDDP), are used for treatment of squamous cell carcinoma of the head and neck (SCCHN). Despite initial responses, CDDP treatment often results in chemoresistance, leading to therapeutic failure. The role of primary resistance at subclonal level and treatment-induced clonal selection in the development of CDDP resistance remains unknown. Experimental Design: By applying targeted next-generation sequencing, fluorescence in-situ hybridization, microarray-based transcriptome and mass spectrometry-based phosphoproteome analysis to the CDDP-sensitive SCCHN cell line FaDu, a CDDP-resistant subline and single-cell derived subclones, the molecular basis of CDDP resistance was elucidated. The causal relationship between molecular features and resistant phenotypes was determined by siRNA-based gene silencing. The clinical relevance of molecular findings was validated in SCCHN patients with recurrence after CDDP-based chemoradiation and the TCGA SCCHN dataset. Results: Evidence of primary resistance at clonal level and clonal selection by long-term CDDP treatment was established in the FaDu model. Resistance was associated with aneuploidy of chromosome 17, increased TP53 copy numbers and overexpression of the gain-of-function (GOF) mutant variant p53 R248L. siRNA-mediated knock-down established a causal relationship between mutant p53 R248L and CDDP resistance. Resistant clones were also characterized by increased activity of the PI3K-AKT-mTOR pathway. The poor prognostic value of GOF TP53 variants and mTOR pathway upregulation was confirmed in the TCGA SCCHN cohort. Conclusions: Our study demonstrates a link of intratumoral heterogeneity and clonal evolution as important mechanisms of drug resistance in SCCHN and establishes mutant GOF TP53 variants and the PI3K/mTOR pathway as molecular targets for treatment optimization.
from Cancer via ola Kala on Inoreader http://ift.tt/2yJJZqs
via IFTTT
Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain
Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular co-stimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown HER2-CARs containing the 4-1BB co-stimulatory domain confer improved tumor targeting with reduced T cell exhaustion phenotype and enhanced proliferative capacity compared to HER2-CARs containing the CD28 co-stimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo anti-tumor activity in an orthotopic xenograft models. Importantly, we demonstrated robust anti-tumor efficacy following regional intraventricular delivery of HER2-CAR T cells for treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases.
from Cancer via ola Kala on Inoreader http://ift.tt/2y1yPKd
via IFTTT
Lenalidomide enhances the function of CS1 chimeric antigen receptor redirected T cells against multiple myeloma
Purpose:Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite considerable advances in treatment. The purpose of the study was to develop novel CARs for the treatment of MM and explore combinatorial therapy using CAR T cells and immunomodulatory drugs such as lenalidomide for increasing treatment efficacy. Experimental Design: We redirected central memory T cells to express second-generation CAR specific for CS1 and adoptively transferred them into MM tumor-bearing mice to test their anti-MM activity. CS1 CAR T cells were transduced and expanded in the presence of lenalidomide in vitro. The phenotype and effector function of CS1 CAR T cells treated with and without lenalidomide were compared. Finally, CS1 CAR T cells and lenalidomide were administered to treat MM bearing mice as combinatorial therapy.Results: CS1 CAR T cells exhibited efficient antitumor activity when adoptively transferred into mice. Mechanistic studies indicated that the addition of lenalidomide during CS1 CAR T cell expansion in vitro enhanced the immune functions of CS1 CAR T cells, including cytotoxicity, memory maintenance, Th1 cytokine production, and immune synapse formation. Furthermore, lenalidomide enhanced the anti-tumor activity and persistence of adoptively transferred CS1 CAR T cells in vivo. Conclusions:The study demonstrates that lenalidomide improves the anti-MM properties of CS1-directed CAR T cells and provides a basis for a planned clinical trial using the combination of lenalidomide with engineered T cells against CS1 in relapsed myeloma.
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