Endometrial Adenocarcinoma With Pulmonary Recurrence

Description

We present the case of an 83-year-old woman with a history of grade 1 stage IB endometrial cancer (endometrial adenocarcinoma) (figure 1) involving the lower uterine segment. She underwent robotic hysterectomy with right salpingo-oophorectomy followed by brachytherapy. A year and a half later, she presented with difficulty in breathing. A chest X-ray showed 8 mm nodular density in the right lower lobe. The above finding was confirmed with CT. Given the concern for a malignant lesion, positron emission tomography/CT scan was performed, which revealed two metabolically active lung nodules, measuring 1.2 cm in the right middle lobe and other in the right lower lobe measuring 1.2 cm (figure 2). Video-assisted thoracoscopic wedge resection of the right lower lobe lung nodule was performed. The frozen section and histopathology revealed papillary adenocarcinoma (figures 3 and 4); nuclear staining was positive for oestrogen receptors and negative for thyroid...

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Cervical ganglioneuroma: clinical and radiological features of a rare tumour

Description

Ganglioneuromas are rare benign tumours of neurogenic origin that most frequently develop in the cervical sympathetic chain,1 2 with genetic associations demonstrated with Neurofibromatosis type 1  (NF-1). We report the case of a 41-year-old woman with a history of cavum neoplasm at the age of 23. This tumour was classified after assessment of extension as T1N0M0 (tumour, node, metastases). Pathological examination of a biopsy concluded to a keratinising squamous cell carcinoma. The patient was then irradiated (2D Cobalt radiotherapy). The patient presented with gait trouble that appeared a few weeks ago. Clinical examination found a Brown-Séquard syndrome with paresis and loss of proprioception on the left side, and loss of pain and temperature sensation on the right side. Medullar MRI (figures 1 and 2) showed an intradural extramedullary well-circumscribed mass with an hourglass shape from C5 to C6 extending through the...

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Rare cause of pulmonary cavitation in a 75-year-old man

A 75-year-old man of Asian descent presented to the acute medical unit with signs and symptoms suggestive of a community-acquired pneumonia. He had multiple comorbidities and was relatively immunocompromised as a result. Initial investigations supported the diagnosis of community-acquired pneumonia complicated by a cavitating lung lesion, and the patient was treated as per hospital guidelines. He continued to deteriorate despite appropriate therapy and developed a hydropneumothorax, requiring the insertion of a chest drain. A diagnosis of pulmonary mucormycosis (Rhizopus microsporus) was made based on microbiology results from pleural aspirate, and patient was treated with intravenous antifungals. The patient was referred to the thoracic team for consideration of surgical intervention but was not suitable due to his multiple comorbidities. This case highlighted the importance of early consideration of fungal infection in patients with multiple risk factors and the need for aggressive therapy to ensure the best outcome.

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Intradiploic cephalocele: a rare entity at a rare site

Description

A 52-year-old woman presented with complaints of non-specific headache. The patient had a history of head injury 1 year ago. Clinical neurological examination was nil significant. The skin over the occipital region is normal. No prior investigations were done immediately after the injury. MRI of the brain at present showed small intradiploic cerebrospinal fluid (CSF)-filled defect with herniation of foliae of the right cerebellar hemisphere (figure 1). The rest of the brain parenchyma revealed no abnormality and no skull fracture was seen. Features were suggestive of intradiploic cephalocele involving cerebellar foliae.

Figure 1

Axial Fluid attenuated inversion recovery (A), T2 (B), coronal T2 (C) and sagittal T1 (D) images at the level of the cerebellum showing small calvarial defect in the occipital bone on the right side with intradiploic herniation of the right cerebellar foliae (black arrows).

A cephalocele is...

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Sternocleidomastoid tumour in neonate: fibromatosis colli

Description

We report a case of a 4-week-old female neonate who was admitted to the hospital for a anterior right lump of the neck, perceived by his mother the day before. The mother also noticed a preferential tilting of the head towards right. He was an otherwise full-term healthy baby, with a history of instrumented delivery. There was no fever, trauma or respiratory symptoms/signs. Family history was irrelevant. On examination, the neck swelling was a small firm, partially mobile, no warm on touch and apparently painless mass, with approximately 1.5–2 cm soft tissue mass, attached to the right sternocleidomastoid muscle. There was no restriction of neck movements. Ultrasonography (USG) revealed a 13 mm fusiform thickening of the right sternocleidomastoid muscle, with maintained structure of muscle fibres (figures 1 and 2). No cervical lymphadenopathy, signs of infiltration or other anomalies were found (figures 1 and...

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Ninety-year-old man with hypereosinophilia, lymphadenopathies and pruritus

We report a case of a 90-year-old man with hypereosinophilia, lymphadenopathies and skin lesions, namely lichenification and pruritus. An aetiological investigation was performed, and a bone marrow (BM) biopsy and aspirate showed a hypercellular marrow with hypereosinophilia without dysmorphia or abnormal elements, and the BM and inguinal node's immunophenotyping denied any presence of abnormal lymphoid cell population. The inguinal node biopsy revealed a multinodular proliferation of large cells S100 and CD1a⁺, and a diagnosis of Langerhans cell histiocytosis was made. The hypereosinophilia and skin lesions were managed with corticotherapy with substantial improvement of cutaneous lesions and lymphadenopathies and normalisation of eosinophil count. Finally, to define if it is a single or multisystem disease, a skin biopsy will be necessary.

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Efficacy of adjuvant radiotherapy in the intracranial hemangiopericytoma

Abstract

We retrospectively evaluated an efficacy of adjuvant radiotherapy (RT) in the intracranial hemangiopericytoma (HPC) and analyzed prognostic factors influencing treatment outcomes. Among 49 patients diagnosed as localized intracranial HPC between 1995 and 2016, 31 patients received adjuvant RT after surgery; 26 with fractionated RT and 5 with stereotactic radiosurgery using Gamma Knife. After gross total resection (GTR) (n = 32) and subtotal resection (STR) (n = 17), histopathological grade was confirmed to be grade II (n = 9) or grade III (n = 40). The median follow-up period was 50 months (range 3–216 months). The local recurrence was defined as intracranial relapse within 15 mm and regional recurrence as beyond 15 mm from the margin of surgical bed. The 10-year overall survival (OS) and progression-free survival (PFS) were 69.9 and 34.4%, respectively. The 10-year local, regional, and distant failure-free rates were 56.6, 88.2, and 73.3%, respectively. Local tumor control was better with GTR followed by RT than GTR alone (p = 0.056), while there was no difference in OS. Local tumor control and OS after STR plus RT were equivalent to those after GTR alone. There were no differences in distant metastasis-free survival (DMFS) among GTR plus RT, GTR alone, and STR plus RT. Tumor volume > 40 cm³ was associated with poor PFS (p = 0.024). The local tumor recurrence was reduced by adjuvant RT after surgery. But OS or DMFS was not improved with adjuvant RT. PFS was better in the tumor with small volume at diagnosis.

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Efficacy of adjuvant radiotherapy in the intracranial hemangiopericytoma

Abstract

We retrospectively evaluated an efficacy of adjuvant radiotherapy (RT) in the intracranial hemangiopericytoma (HPC) and analyzed prognostic factors influencing treatment outcomes. Among 49 patients diagnosed as localized intracranial HPC between 1995 and 2016, 31 patients received adjuvant RT after surgery; 26 with fractionated RT and 5 with stereotactic radiosurgery using Gamma Knife. After gross total resection (GTR) (n = 32) and subtotal resection (STR) (n = 17), histopathological grade was confirmed to be grade II (n = 9) or grade III (n = 40). The median follow-up period was 50 months (range 3–216 months). The local recurrence was defined as intracranial relapse within 15 mm and regional recurrence as beyond 15 mm from the margin of surgical bed. The 10-year overall survival (OS) and progression-free survival (PFS) were 69.9 and 34.4%, respectively. The 10-year local, regional, and distant failure-free rates were 56.6, 88.2, and 73.3%, respectively. Local tumor control was better with GTR followed by RT than GTR alone (p = 0.056), while there was no difference in OS. Local tumor control and OS after STR plus RT were equivalent to those after GTR alone. There were no differences in distant metastasis-free survival (DMFS) among GTR plus RT, GTR alone, and STR plus RT. Tumor volume > 40 cm³ was associated with poor PFS (p = 0.024). The local tumor recurrence was reduced by adjuvant RT after surgery. But OS or DMFS was not improved with adjuvant RT. PFS was better in the tumor with small volume at diagnosis.

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Sexual Health Issues for the Young Adult with Cancer: An International Symposium Held During the First Global Adolescents and Young Adults Cancer Congress (Edinburgh, United Kingdom)

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Sexual Health Issues for the Young Adult with Cancer: An International Symposium Held During the First Global Adolescents and Young Adults Cancer Congress (Edinburgh, United Kingdom)

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Correction to: Dietary intake of soy and cruciferous vegetables and treatment-related symptoms in Chinese-American and non-Hispanic White breast cancer survivors

Abstract

In the original publication, the values provided for the isoflavone and glucosinolate intake variables were incorrectly labeled in Table 1. The correct values of 6.3 mg/day for isoflavone intake, and 20.4 mg/day and 50.1 mg/day for glucosinolate intake are provided in this erratum.

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Disparities in cancer outcomes across age, sex, and race/ethnicity among patients with pancreatic cancer

Abstract

Age, sex, and racial/ethnic disparities exist, but are understudied in pancreatic adenocarcinoma (PDAC). We used the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database to determine whether survival and treatment disparities persist after adjusting for demographic and clinical characteristics. Our study included PDAC patients diagnosed between 1992 and 2011. We used Cox regression to compare survival across age, sex, and race/ethnicity within early-stage and late-stage cancer subgroups, adjusting for marital status, urban location, socioeconomics, SEER region, comorbidities, stage, lymph node status, tumor location, tumor grade, diagnosis year, and treatment received. We used logistic regression to compare differences in treatment received across age, sex, and race/ethnicity. Among 20,896 patients, 84% were White, 9% Black, 5% Asian, and 2% Hispanic. Median age was 75; 56% were female and 53% had late-stage cancer. Among early-stage patients in the adjusted Cox model, older patient subgroups had worse survival compared with ages 66–69 (HR > 1.1, P < 0.01 for groups >69); no survival differences existed between sexes. Black (HR = 1.1, P = 0.01) and Hispanic (HR = 1.2, P < 0.01) patients had worse survival compared with White. Among late-stage cancer patients, patients over age 84 had worse survival than those aged 66–69 (HR = 1.1, P < 0.01), and males (HR = 1.08, P < 0.01) had worse survival than females; there were no racial/ethnic differences. Older age and minority race/ethnicity were associated with lower likelihood of receiving chemotherapy, radiation, and/or surgery. Age and racial/ethnic disparities in survival outcomes and treatment received exist for PDAC patients; these disparities persist after adjusting for differences in demographic and clinical characteristics.

Disparities in pancreatic cancer outcomes exists, but are not fully understood. Our research uses SEER–Medicare data to determine which factors contribute to the differences in treatment receipt and survival outcomes among age, sex, and racial/ethnic subgroups. Our conclusion that disparities continue to persist after adjusting for various covariates highlights the need for additional research in this area.

http://ift.tt/2AOPgLl

Disparities in cancer outcomes across age, sex, and race/ethnicity among patients with pancreatic cancer

Abstract

Age, sex, and racial/ethnic disparities exist, but are understudied in pancreatic adenocarcinoma (PDAC). We used the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database to determine whether survival and treatment disparities persist after adjusting for demographic and clinical characteristics. Our study included PDAC patients diagnosed between 1992 and 2011. We used Cox regression to compare survival across age, sex, and race/ethnicity within early-stage and late-stage cancer subgroups, adjusting for marital status, urban location, socioeconomics, SEER region, comorbidities, stage, lymph node status, tumor location, tumor grade, diagnosis year, and treatment received. We used logistic regression to compare differences in treatment received across age, sex, and race/ethnicity. Among 20,896 patients, 84% were White, 9% Black, 5% Asian, and 2% Hispanic. Median age was 75; 56% were female and 53% had late-stage cancer. Among early-stage patients in the adjusted Cox model, older patient subgroups had worse survival compared with ages 66–69 (HR > 1.1, P < 0.01 for groups >69); no survival differences existed between sexes. Black (HR = 1.1, P = 0.01) and Hispanic (HR = 1.2, P < 0.01) patients had worse survival compared with White. Among late-stage cancer patients, patients over age 84 had worse survival than those aged 66–69 (HR = 1.1, P < 0.01), and males (HR = 1.08, P < 0.01) had worse survival than females; there were no racial/ethnic differences. Older age and minority race/ethnicity were associated with lower likelihood of receiving chemotherapy, radiation, and/or surgery. Age and racial/ethnic disparities in survival outcomes and treatment received exist for PDAC patients; these disparities persist after adjusting for differences in demographic and clinical characteristics.

Disparities in pancreatic cancer outcomes exists, but are not fully understood. Our research uses SEER–Medicare data to determine which factors contribute to the differences in treatment receipt and survival outcomes among age, sex, and racial/ethnic subgroups. Our conclusion that disparities continue to persist after adjusting for various covariates highlights the need for additional research in this area.

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Ticagrelor inhibits platelet–tumor cell interactions and metastasis in human and murine breast cancer

Abstract

Activated platelets promote the proliferation and metastatic potential of cancer cells. Platelet activation is largely mediated through ADP engagement of purinergic P2Y12 receptors on platelets. We examined the potential of the reversible P2Y12 inhibitor ticagrelor, an agent used clinically to prevent cardiovascular and cerebrovascular events, to reduce tumor growth and metastasis. In vitro, MCF-7, MDA-MB-468, and MDA-MB-231 human mammary carcinoma cells exhibited decreased interaction with platelets treated with ticagrelor compared to untreated platelets. Prevention of tumor cell–platelet interactions through pretreatment of platelets with ticagrelor did not improve natural killer cell-mediated tumor cell killing of K562 myelogenous leukemia target cells. Additionally, ticagrelor had no effect on proliferation of 4T1 mouse mammary carcinoma cells co-cultured with platelets, or on primary 4T1 tumor growth. In an orthotopic 4T1 breast cancer model, ticagrelor (10 mg/kg), but not clopidogrel (10 mg/kg) or saline, resulted in reduced metastasis and improved survival. Ticagrelor treatment was associated with a marked reduction in tumor cell–platelet aggregates in the lungs at 10, 30 and 60 min post-intravenous inoculation. These findings suggest a role for P2Y12-mediated platelet activation in promoting metastasis, and provide support for the use of ticagrelor in the prevention of breast cancer spread.

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Ticagrelor inhibits platelet–tumor cell interactions and metastasis in human and murine breast cancer

Abstract

Activated platelets promote the proliferation and metastatic potential of cancer cells. Platelet activation is largely mediated through ADP engagement of purinergic P2Y12 receptors on platelets. We examined the potential of the reversible P2Y12 inhibitor ticagrelor, an agent used clinically to prevent cardiovascular and cerebrovascular events, to reduce tumor growth and metastasis. In vitro, MCF-7, MDA-MB-468, and MDA-MB-231 human mammary carcinoma cells exhibited decreased interaction with platelets treated with ticagrelor compared to untreated platelets. Prevention of tumor cell–platelet interactions through pretreatment of platelets with ticagrelor did not improve natural killer cell-mediated tumor cell killing of K562 myelogenous leukemia target cells. Additionally, ticagrelor had no effect on proliferation of 4T1 mouse mammary carcinoma cells co-cultured with platelets, or on primary 4T1 tumor growth. In an orthotopic 4T1 breast cancer model, ticagrelor (10 mg/kg), but not clopidogrel (10 mg/kg) or saline, resulted in reduced metastasis and improved survival. Ticagrelor treatment was associated with a marked reduction in tumor cell–platelet aggregates in the lungs at 10, 30 and 60 min post-intravenous inoculation. These findings suggest a role for P2Y12-mediated platelet activation in promoting metastasis, and provide support for the use of ticagrelor in the prevention of breast cancer spread.

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Cardiovascular safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients: a prospective evaluation

Future Oncology, Ahead of Print.


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Are redheads at an increased risk of melanoma?

Future Oncology, Ahead of Print.


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Decoding oral cancer conundrums from ‘bad luck’ point of view

Future Oncology, Ahead of Print.


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Comparison of three prognostic models for predicting cancer-specific survival among patients with gastrointestinal stromal tumors

Future Oncology, Ahead of Print.


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Thymidylate synthase: a predictive biomarker in resected colorectal liver metastases receiving 5-FU treatment

Future Oncology, Ahead of Print.


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What treatments should be skipped or intensified in localized rectal cancer?

Future Oncology, Ahead of Print.


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Kompetenzbasierte Ausbildung im „geschützten Umfeld“: vom Schonraum zum Realraum

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 12-19
DOI: 10.1055/s-0043-105257

„Lernen im geschützten Umfeld" ist ein häufig gebrauchter, aber unklarer Begriff im Rahmen der anästhesiologischen postgradualen Weiterbildung. Dieser Artikel beleuchtet seine Bedeutung in der Anästhesiologie – einschließlich Lehr- und Lernstrategien, wie kompetenzorientierte und simulationsbasierte Ausbildung. Ein Versuch der Klassifikation von Simulatoren und Unterrichtsmethoden sowie deren Probleme bei der Umsetzung runden den Beitrag ab.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Behandlung im Voraus planen – Bedeutung für die Intensiv- und Notfallmedizin

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 62-70
DOI: 10.1055/s-0042-118690

Behandlung im Voraus planen (BVP) – im Englischen Advance Care Planning (ACP) – etabliert sich auch in Deutschland als ein neues Konzept zur Realisierung wirksamer Patientenverfügungen. Das Konzept beinhaltet Prozesse zur Ermittlung, Dokumentation und Umsetzung von Behandlungswünschen für den Fall, dass die Betroffenen nicht (mehr) selbst entscheiden können.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Begünstigt Kaudalanästhesie postoperative Komplikationen nach Hypospadie-OP?

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 6-7
DOI: 10.1055/s-0043-123122

Georg Thieme Verlag KG Stuttgart · New York

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„Lernen im geschützten Umfeld“: Implementierung in die Fort- und Weiterbildung

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 35-46
DOI: 10.1055/s-0043-105259

Aktuelle Aus- und Fortbildungskonzepte in der Akut- oder Notfallmedizin beinhalten Simulations- und Skill-Trainings unter Berücksichtigung von Methoden und Mechanismen der Fehler- und Zwischenfallprävention wie Human Factors, Shared mental Models und Closed-Loop-Communication. Immer noch ungeklärt ist die Frage nach der optimalen Kombination der einzelnen Methoden und Inhalte eines Fortbildungsprogramms in Abhängigkeit von individuellen Abteilungen eines Krankenhauses und dem einzelnen Mitarbeiter bzw. seinem individuellen Ausbildungsstand. Ein von uns angebotenes Konzept ist das „Lernen im geschützten Umfeld": Hier werden Teilnehmer und Patient vor den negativen Auswirkungen einer konventionellen klinisch-praktischen Ausbildungssituation beschützt. Gleichzeitig profitieren die Teilnehmer in unserem Fortbildungsprogramm von standardisierten Kursmodellen. Das Ziel der optimalen Vorbereitung auf die klinische Tätigkeit und einer möglichst praktischen bzw. wirklichkeitsnahen Aus- und Fortbildung wird durch eine ständige Re-Evaluation der Inhalte und Methoden komplettiert. Die Implementierung eines solchen multimodalen Teamtrainings ist für jede Institution individuell anzupassen. Die Methoden zur Implementierung sollten standardisiert angewendet werden. Wir empfehlen eine Curriculumsentwicklung auf Grundlage des „Kern-Zyklus". Auf dieser Basis gelingt die Kombination aus „Lernen im geschützten Umfeld" und Zwischenfalltraining zur optimalen Vorbereitung auf eine akutmedizinische, klinische Tätigkeit mit dem Ziel einer höchstmöglichen Patientensicherheit.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Hyperchlorämie ist mit akutem Nierenversagen nach SAB verbunden

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 7-8
DOI: 10.1055/s-0043-123121

Georg Thieme Verlag KG Stuttgart · New York

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Lernen im geschützten Umfeld

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 10-11
DOI: 10.1055/s-0043-122170

Georg Thieme Verlag KG Stuttgart · New York

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Etomidat-Analogon mit verringerter Nebennierensuppression

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 8-8
DOI: 10.1055/s-0043-117029

Georg Thieme Verlag KG Stuttgart · New York

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Simulation als Fortbildungsmethode zur Professionalisierung von Teams

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 20-33
DOI: 10.1055/s-0043-105261

Simulation ist eine Methode, virtuelle Lernumgebungen zu erzeugen. Mittels Simulation können Technical Skills, aber auch Soft Skills wie die Funktionsfähigkeit von Teams sehr gut vermittelt werden. Dieser Team-Aspekt wird nachfolgend vor dem Hintergrund spezifischer Trainingsmethoden näher beleuchtet. Der Artikel bezieht sich dabei auf „Zwischenfalltrainings", die in den Zentren der Autoren einen großen Anteil des Kursangebotes einnehmen.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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The Same Procedure As Last Year?

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 9-9
DOI: 10.1055/s-0043-123165

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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„Das Kind hat einen Fremdkörper verschluckt“ – was tun?

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 48-60
DOI: 10.1055/s-0042-120991

Sowohl Ingestions- als auch Aspirationsunfälle sind häufige Ereignisse bei Kindern. Sie können unmittelbar lebensbedrohlich sein oder bei fehlender direkter Bedrohung dennoch erhebliche langfristige Beeinträchtigungen für die Kinder verursachen. Der Beitrag zeigt die diagnostischen und therapeutischen Möglichkeiten und Notwendigkeiten auf, durch die eine bestmögliche Sicherheit und möglichst geringe Folgeschäden zu gewährleisten sind.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Neurologischer Schaden nach Wirbelsäulen-OP

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 71-75
DOI: 10.1055/s-0043-122628

Schlichtungsstellen für Arzthaftpflichtfragen bieten Patienten, Ärzten und Versicherern eine Möglichkeit, Arzthaftungsstreitigkeiten außergerichtlich zu klären. In der Rubrik „Fälle der Schlichtungsstelle" stellen wir abgeschlossene Fälle aus der Schlichtungsstelle für Arzthaftpflichtfragen der norddeutschen Ärztekammern vor.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Entwicklung neuer Antibiotika: Endpunkte klinischer Studien teils ungeeignet

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 5-6
DOI: 10.1055/s-0043-117062

Georg Thieme Verlag KG Stuttgart · New York

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Atemübungen schützen ältere Patienten vor gefährlichen Lungenentzündungen

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 753-753
DOI: 10.1055/s-0043-121213

Georg Thieme Verlag KG Stuttgart · New York

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Interventionen zur präoperativen Unterstützung geriatrischer Patienten mit Frailty

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 777-783
DOI: 10.1055/s-0043-104684

Der stetig zu beobachtende demografische Wandel geht mit veränderten Anforderungen an die Patientenbetreuung einher. Ältere Patienten weisen häufig einen erhöhten Behandlungsbedarf und eine höhere Komplexität des klinischen Gesamtbildes auf. Dieser Umstand ist – abgesehen von der Routineversorgung – besonders dann zu beachten, wenn eine angedachte Intervention zu schweren und potenziell lebensbedrohlichen Komplikationen führen kann.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Therapiebegrenzung: DIVI empfiehlt neuen Dokumentationsbogen

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 752-753
DOI: 10.1055/s-0043-119947

Georg Thieme Verlag KG Stuttgart · New York

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Zervikale Plexusblockaden

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 806-813
DOI: 10.1055/s-0043-115204

Eine vollständige Blockade des Plexus cervicalis ist weder erwünscht noch ausreichend für eine chirurgische Anästhesie in der vorderen Halsregion. Supplementierungen durch Opioide oder topische Lokalanästhetika sind daher häufig. Die Blockade beteiligter Hirnnerven und des Truncus sympathicus verbessert möglicherweise die Anästhesiequalität, führt aber auch zu typischen Nebenwirkungen. Dieser Beitrag liefert anatomisches Hintergrundwissen und stellt Indikationen vor – auch außerhalb der Karotischirurgie.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Warum und wie sollte ich Frailty erfassen? – ein Ansatz für die Anästhesieambulanz

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 765-776
DOI: 10.1055/s-0043-104682

Frailty (Gebrechlichkeit) ist eine Einschränkung der physiologischen Reserve bei älteren Patienten mit schwerwiegenden individuellen und sozioökonomischen Folgen. Multiple Aspekte der Patientenbehandlung sowie das Outcome werden durch Frailty nachhaltig beeinflusst. Obwohl mehr als 60 Messinstrumente existieren, sind die Erfassung und Berücksichtigung funktioneller Assessments in der klinischen Routine unzureichend umgesetzt. Das interdisziplinäre und interprofessionelle Verständnis, warum und wie Frailty beurteilt werden sollte, ist die Grundlage für die dauerhafte Implementierung. Der Artikel zeigt die Auswirkungen von Frailty und Vorteile einer Früherkennung auf und gibt einen Überblick über die wichtigsten Instrumente, die in der Frailty-Erkennung und -Bewertung verwendet werden können. Die frühe präoperative Detektion bietet ein vielfältiges Optimierungspotenzial für die peri- und intraoperative Versorgung. Verschiedene Frailty-Assessment-Tools körperlicher, kognitiver und psychosozialer Domänen werden vorgestellt und diskutiert. Frailty-Assessments variieren immens in Bezug auf die erforderliche Zeit, die Ausrüstung und das Fachwissen zur Durchführung. Wir empfehlen mindestens einen Test für die einzelnen Dimensionen von Frailty, um ein holistisches Bild der geriatrischen Patienten zu erhalten. Die Bewertung von Frailty sollte übergreifend in die interdisziplinären Strukturen der klinischen Routine implementiert werden, um die Patientensicherheit sowie das kurz- und langfristige Outcome zu verbessern.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Vielen Dank!

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 754-754
DOI: 10.1055/s-0043-121256

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

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Die meisten Todesbescheinigungen weisen Fehler auf

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 752-752
DOI: 10.1055/s-0043-121621

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

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Patienten mit Frailty: Anästhesiologie in der Verantwortung

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 756-757
DOI: 10.1055/s-0043-117836

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

http://ift.tt/2CZUV77

Cardiovascular safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients: a prospective evaluation

Future Oncology, Ahead of Print.


http://ift.tt/2ANhZjv

Are redheads at an increased risk of melanoma?

Future Oncology, Ahead of Print.


http://ift.tt/2D27ZZV

Decoding oral cancer conundrums from ‘bad luck’ point of view

Future Oncology, Ahead of Print.


http://ift.tt/2AO53tS

Comparison of three prognostic models for predicting cancer-specific survival among patients with gastrointestinal stromal tumors

Future Oncology, Ahead of Print.


http://ift.tt/2D27Up5

Thymidylate synthase: a predictive biomarker in resected colorectal liver metastases receiving 5-FU treatment

Future Oncology, Ahead of Print.


http://ift.tt/2AO501a

What treatments should be skipped or intensified in localized rectal cancer?

Future Oncology, Ahead of Print.


http://ift.tt/2D1ZSfE

Antitumor effects of blocking protein neddylation in T315I-BCR-ABL leukemia cells and leukemia stem cells

Imatinib (IM) revolutionized the treatment of chronic myeloid leukemia (CML) but drug resistance and disease recurrence remain a challenge. In this study, we suggest a novel strategy based on blocking protein neddylation to address BCR-ABL point mutations and leukemia stem cells (LSCs) that lie at the root of IM-resistant recurrences. Based on the finding that the NEDD8-activating enzyme subunit NAE1 is overexpressed in CML cells, we hypothesized that the function of certain neddylation-dependent protein substrates might be targeted to therapeutic ends in IM-resistant CML cells and LSCs. In support of this hypothesis, we demonstrated that the NAE1 inhibitor MLN4924 induced G2/M-phase arrest and apoptosis in bulk CML cells with wild-type p53, regardless of their T315I mutation status in BCR-ABL. Moreover, MLN4924 inhibited the survival and self-renewal of primary human CML CD34+ cells and LSCs in CML-bearing mice via accumulation of p27kip1 in the nucleus. Notably, p27kip1 silencing attenuated the suppressive effect of MLN4924 on the maintenance of LSCs in CML-bearing mice. Taken together, our findings offer a preclinical proof of concept for targeting protein neddylation as a novel therapeutic strategy to override mutational and LSC-derived IM resistance in CML.

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KRAS oncoprotein expression is regulated by a self-governing eIF5A-PEAK1 feed-forward regulatory loop

There remains intense interest in tractable approaches to target or silence the KRAS oncoprotein as a rational therapeutic strategy to attack pancreatic adenocarcinoma (PDAC) and other cancers which overexpress it. Here we provide evidence that accumulation of the KRAS oncoprotein is controlled by a self-regulating feed-forward regulatory loop that utilizes a unique hypusinated isoform of the translation elongation factor eIF5A and the tyrosine kinase PEAK1. Oncogenic activation of KRAS increased eIF5A-PEAK1 translational signaling, which in turn facilitated increased KRAS protein synthesis. Mechanistic investigations shows that this feed-forward positive regulatory pathway was controlled by oncogenic KRAS-driven metabolic demands, operated independently of canonical mTOR signaling, and did not involve new KRas gene transcription. Perturbing eIF5A-PEAK1 signaling, by genetic or pharmacologic strategies or by blocking glutamine synthesis, was sufficient to inhibit expression of KRAS, eIF5A, and PEAK1, attenuate cancer cell growth and migration, and block tumor formation in established preclinical mouse models of PDAC. Levels of KRAS, eIF5A, and PEAK1 protein increased during cancer progression with the highest levels of expression observed in metastatic cell populations. Combinatorial targeting of eIF5A hypusination and the RAS-ERK signaling pathway cooperated to attenuate KRAS expression and its downstream signaling along with cell growth in vitro and tumor formation in vivo. Collectively, our findings highlight a new mechanistic strategy to attenuate KRAS expression as a therapeutic strategy to target PDAC and other human cancers driven by KRAS activation.

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Antitumor effects of blocking protein neddylation in T315I-BCR-ABL leukemia cells and leukemia stem cells

Imatinib (IM) revolutionized the treatment of chronic myeloid leukemia (CML) but drug resistance and disease recurrence remain a challenge. In this study, we suggest a novel strategy based on blocking protein neddylation to address BCR-ABL point mutations and leukemia stem cells (LSCs) that lie at the root of IM-resistant recurrences. Based on the finding that the NEDD8-activating enzyme subunit NAE1 is overexpressed in CML cells, we hypothesized that the function of certain neddylation-dependent protein substrates might be targeted to therapeutic ends in IM-resistant CML cells and LSCs. In support of this hypothesis, we demonstrated that the NAE1 inhibitor MLN4924 induced G2/M-phase arrest and apoptosis in bulk CML cells with wild-type p53, regardless of their T315I mutation status in BCR-ABL. Moreover, MLN4924 inhibited the survival and self-renewal of primary human CML CD34+ cells and LSCs in CML-bearing mice via accumulation of p27kip1 in the nucleus. Notably, p27kip1 silencing attenuated the suppressive effect of MLN4924 on the maintenance of LSCs in CML-bearing mice. Taken together, our findings offer a preclinical proof of concept for targeting protein neddylation as a novel therapeutic strategy to override mutational and LSC-derived IM resistance in CML.

http://ift.tt/2mrpWGT

KRAS oncoprotein expression is regulated by a self-governing eIF5A-PEAK1 feed-forward regulatory loop

There remains intense interest in tractable approaches to target or silence the KRAS oncoprotein as a rational therapeutic strategy to attack pancreatic adenocarcinoma (PDAC) and other cancers which overexpress it. Here we provide evidence that accumulation of the KRAS oncoprotein is controlled by a self-regulating feed-forward regulatory loop that utilizes a unique hypusinated isoform of the translation elongation factor eIF5A and the tyrosine kinase PEAK1. Oncogenic activation of KRAS increased eIF5A-PEAK1 translational signaling, which in turn facilitated increased KRAS protein synthesis. Mechanistic investigations shows that this feed-forward positive regulatory pathway was controlled by oncogenic KRAS-driven metabolic demands, operated independently of canonical mTOR signaling, and did not involve new KRas gene transcription. Perturbing eIF5A-PEAK1 signaling, by genetic or pharmacologic strategies or by blocking glutamine synthesis, was sufficient to inhibit expression of KRAS, eIF5A, and PEAK1, attenuate cancer cell growth and migration, and block tumor formation in established preclinical mouse models of PDAC. Levels of KRAS, eIF5A, and PEAK1 protein increased during cancer progression with the highest levels of expression observed in metastatic cell populations. Combinatorial targeting of eIF5A hypusination and the RAS-ERK signaling pathway cooperated to attenuate KRAS expression and its downstream signaling along with cell growth in vitro and tumor formation in vivo. Collectively, our findings highlight a new mechanistic strategy to attenuate KRAS expression as a therapeutic strategy to target PDAC and other human cancers driven by KRAS activation.

http://ift.tt/2qR6wA1

Serum Copper Homeostasis in Hypertensive Intracerebral Hemorrhage and its Clinical Significance

Abstract

This study was to investigate the alterations of serum copper homeostasis after hypertensive intracerebral hemorrhage (ICH), which is not yet clear. We recruited 85 hypertensive ICH patients and determined their serum levels of total copper (TCu), small molecule copper (SMC), and ceruloplasmin (Cp). Sera from 32 healthy persons and 12 primary hypertension patients were collected and analyzed as well. Serum TCu levels in ICH patients were tested at three time points (on admission, day 3, and day 7) and found to be higher than that in hypertension patients (p < 0.05). The serum SMC levels in hypertension patients and ICH patients at three time points were higher than that in healthy controls (p < 0.05). Higher serum SMC levels on days 3 and 7 were associated with death in the hospital. Additionally, higher serum SMC levels on the seventh day were associated with poor outcome at discharge. High serum Cp levels on admission, as well as low serum Cp levels on the seventh day, were associated with death in the hospital (p = 0.002 and p = 0.034, respectively). Our findings indicated that declines in serum Cp and increases in serum SMC are correlated with lethal or poor outcome in hypertensive ICH patients, possibly as a result of contributions to secondary injury of brain after hemorrhage due to impairment of iron transport and enhanced oxidative stress.

http://ift.tt/2D2XrZs

Serum Copper Homeostasis in Hypertensive Intracerebral Hemorrhage and its Clinical Significance

Abstract

This study was to investigate the alterations of serum copper homeostasis after hypertensive intracerebral hemorrhage (ICH), which is not yet clear. We recruited 85 hypertensive ICH patients and determined their serum levels of total copper (TCu), small molecule copper (SMC), and ceruloplasmin (Cp). Sera from 32 healthy persons and 12 primary hypertension patients were collected and analyzed as well. Serum TCu levels in ICH patients were tested at three time points (on admission, day 3, and day 7) and found to be higher than that in hypertension patients (p < 0.05). The serum SMC levels in hypertension patients and ICH patients at three time points were higher than that in healthy controls (p < 0.05). Higher serum SMC levels on days 3 and 7 were associated with death in the hospital. Additionally, higher serum SMC levels on the seventh day were associated with poor outcome at discharge. High serum Cp levels on admission, as well as low serum Cp levels on the seventh day, were associated with death in the hospital (p = 0.002 and p = 0.034, respectively). Our findings indicated that declines in serum Cp and increases in serum SMC are correlated with lethal or poor outcome in hypertensive ICH patients, possibly as a result of contributions to secondary injury of brain after hemorrhage due to impairment of iron transport and enhanced oxidative stress.

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Kartagener’s syndrome: a case report

Kartagener's syndrome is a subset of primary ciliary dyskinesia, an autosomal recessive inherited disorder characterized by the clinical triad of chronic sinusitis, bronchiectasis, and situs inversus. Abnormal...

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Are prognostic indices for brain metastases of melanoma still valid in the stereotactic era?

Malignant melanoma brain metastases (MBM) are the third most common cause for brain metastases (BM). Historically Whole-brain radiotherapy (WBRT) was considered the goldstandard of treatment even though melano...

http://ift.tt/2CZtLMR

Are prognostic indices for brain metastases of melanoma still valid in the stereotactic era?

Malignant melanoma brain metastases (MBM) are the third most common cause for brain metastases (BM). Historically Whole-brain radiotherapy (WBRT) was considered the goldstandard of treatment even though melano...

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High intraoperative inspiratory oxygen fraction and risk of major respiratory complications

British Journal of Anaesthesia, 2017; 119(1): 140–9, DOI 10.1093/bja/aex128

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Reviewer Lists for Neuro-Oncology

The following lists refer to the number of times reviewed within the 12-month period ending October 31, 2017. The names of Editorial Board members and Editorial Team members are excluded from the lists.

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Highlights from the Literature

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Forthcoming Meetings

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Response to Harreld re: “Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology Committee”

What is lost in the letter by Harreld is the mandate of the RAPNO committee and the purpose of the proposed recommendations. Our goal, as a committee, was to develop consensus recommendations on the response assessment for use in clinical trials of patients with medulloblastoma and other seeding tumors, which could then be tested prospectively. Committee recommendations were based on scientific justification where this exists in peer-reviewed literature, or based upon the extensive experience of leaders in the field who are members of this group. Rather than recommend advanced imaging sequences utilized in limited institutions, we proposed recommendations that can be utilized at most institutions and that will allow uniformity and quality data collection. This approach is also in line with the Brain Tumor Drug Development Coalition Imaging Standardization Steering Committee and their recommendations. ¹ As such, it required compromise from the committee members in order to be applicable and feasible for the majority of institutions.

http://ift.tt/2CV7srT

Control versus cognition: the changing paradigm of adjuvant therapy for resected brain metastasis

Twenty years ago, Patchell and colleagues¹ demonstrated that whole-brain radiotherapy (WBRT) mitigates relapse both in the surgical bed and elsewhere in the brain and prevents death from neurologic causes in patients with resected brain metastasis. Therefore, postoperative WBRT became the standard of care.

http://ift.tt/2CZs1U2

Synergy of vaccination and agonist OX40 treatment—toward a mechanism-driven combination of glioma immunotherapy

See the article by Jahan et al on pages44–54.

http://ift.tt/2CYVn4U

The impact of surgery in molecularly defined low-grade glioma: an integrated clinical, radiological, and molecular analysis

Abstract

Background

Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes.

Methods

We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model.

Results

Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1–5.0 cm³) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002–1.02; P = 0.016) per cm³ increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1–5.0 cm) already negatively affected OS.

Conclusion

Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.

http://ift.tt/2CUXmXU

Longitudinal assessment of late-onset neurologic conditions in survivors of childhood central nervous system tumors: a Childhood Cancer Survivor Study report

Abstract

Background

Survivors of childhood central nervous system (CNS) tumors experience high rates of treatment-related neurologic sequelae. Whether survivors continue to be at increased risk for new events as they age is unknown.

Methods

Adverse neurologic health conditions in 5-year survivors of CNS tumors from the Childhood Cancer Survivor Study (n = 1876) were evaluated longitudinally at a median 23.0 years from diagnosis (range, 5.1–38.9), median age at last evaluation 30.3 years (range, 6.1–56.4). Multivariable regression estimated hazard ratios (HRs) and 95% CIs.

Results

From 5 to 30 years post diagnosis, cumulative incidence increased for seizures from 27% to 41%, motor impairment 21% to 35%, and hearing loss 9% to 23%. Risks were elevated compared with siblings (eg, seizures HR: 12.7; 95% CI: 9.6–16.7; motor impairment HR: 7.6; 95% CI: 5.8–9.9; hearing loss HR: 18.4; 95% CI: 13.1–25.9). Regional brain doses of radiation therapy were associated with development of new deficits (eg, frontal ≥50 Gy and motor impairment HR: 2.0; 95% CI: 1.2–3.4). Increased risk for motor impairment was also associated with tumor recurrence (HR: 2.6; 95% CI: 1.8–3.8), development of a meningioma (HR: 2.3; 95% CI: 0.9–5.4), and stroke (HR: 14.9; 95% CI: 10.4–21.4). Seizure risk was doubled by recurrence (HR: 2.3; 95% CI: 1.6–3.2), meningioma (HR: 2.6; 95% CI: 1.1–6.5), and stroke (HR: 2.0; 95% CI: 1.1–3.4).

Conclusions

CNS tumor survivors remain at risk for new-onset adverse neurologic events across their lifespans at a rate greater than siblings. Cranial radiation, stroke, tumor recurrence, and development of meningioma were independently associated with late-onset adverse neurologic sequelae.

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Inability of positive phase II clinical trials of investigational treatments to subsequently predict positive phase III clinical trials in glioblastoma

Abstract

Background

Glioblastoma is the most common primary malignant brain tumor in adults, but effective therapies are lacking. With the scarcity of positive phase III trials, which are increasing in cost, we examined the ability of positive phase II trials to predict statistically significant improvement in clinical outcomes of phase III trials.

Methods

A PubMed search was conducted to identify phase III clinical trials performed in the past 25 years for patients with newly diagnosed or recurrent glioblastoma. Trials were excluded if they did not examine an investigational chemotherapy or agent, if they were stopped early owing to toxicity, if they lacked prior phase II studies, or if a prior phase II study was negative.

Results

Seven phase III clinical trials in newly diagnosed glioblastoma and 4 phase III clinical trials in recurrent glioblastoma met the inclusion criteria. Only 1 (9%) phase III study documented an improvement in overall survival and changed the standard of care.

Conclusion

The high failure rate of phase III trials demonstrates the urgent need to increase the reliability of phase II trials of treatments for glioblastoma. Strategies such as the use of adaptive trial designs, Bayesian statistics, biomarkers, volumetric imaging, and mathematical modeling warrant testing. Additionally, it is critical to increase our expectations of phase II trials so that positive findings increase the probability that a phase III trial will be successful.

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Prognostic relevance of genetic alterations in diffuse lower-grade gliomas

Abstract

Background

Diffuse lower-grade gliomas (LGGs) are genetically classified into 3 distinct subtypes based on isocitrate dehydrogenase (IDH) mutation status and codeletion of chromosome 1p and 19q (1p/19q). However, the subtype-specific effects of additional genetic lesions on survival are largely unknown.

Methods

Using Cox proportional hazards regression modeling, we investigated the subtype-specific effects of genetic alterations and clinicopathological factors on survival in each LGG subtype, in a Japanese cohort of LGG cases fully genotyped for driver mutations and copy number variations associated with LGGs (n = 308). The results were validated using a dataset from 414 LGG cases available from The Cancer Genome Atlas (TCGA).

Results

In Oligodendroglioma, IDH-mutant and 1p/19q codeleted, NOTCH1 mutations (P = 0.0041) and incomplete resection (P = 0.0019) were significantly associated with shorter survival. In Astrocytoma, IDH-mutant, PIK3R1 mutations (P = 0.0014) and altered retinoblastoma pathway genes (RB1, CDKN2A, and CDK4) (P = 0.013) were independent predictors of poor survival. In IDH-wildtype LGGs, co-occurrence of 7p gain, 10q loss, mutation in the TERT promoter (P = 0.024), and grade III histology (P < 0.0001) independently predicted poor survival. IDH-wildtype LGGs without any of these factors were diagnosed at a younger age (P = 0.042), and were less likely to have genetic lesions characteristic of glioblastoma, in comparison with other IDH-wildtype LGGs, suggesting that they likely represented biologically different subtypes. These results were largely confirmed in the cohort of TCGA.

Conclusions

Subtype-specific genetic lesions can be used to stratify patients within each LGG subtype. enabling better prognostication and management.

http://ift.tt/2CTXozj

Dissecting human gliomas by single-cell RNA sequencing

Abstract

Diffuse gliomas are the most common human primary brain tumors and remain incurable. They are complex entities in which diverse genetic and nongenetic effects determine tumor biology and clinical course. Our current understanding of gliomas in patients is primarily based on genomic and transcriptomic methods that have profiled them as bulk, providing critical information yet masking the diversity of cells within each tumor. Recent advances in single-cell DNA and RNA profiling have paved the way to studying tumors at cellular resolution. Here, we review initial studies deploying single-cell analysis in clinical glioma samples, with a focus on RNA expression profiling. We highlight how these studies provide new insights into glioma biology, tumor heterogeneity, cancer cell lineages, cancer stem cell programs, the tumor microenvironment, and glioma classification.

http://ift.tt/2CXEdVa

Activation of WEE1 confers resistance to PI3K inhibition in glioblastoma

Abstract

Background

Oncogenic activation of phosphatidylinositol-3 kinase (PI3K) signaling plays a pivotal role in the development of glioblastoma (GBM). However, pharmacological inhibition of PI3K has so far not been therapeutically successful due to adaptive resistance through a rapid rewiring of cancer cell signaling. Here we identified that WEE1 is activated after transient exposure to PI3K inhibition and confers resistance to PI3K inhibition in GBM.

Methods

Patient-derived glioma-initiating cells and established GBM cells were treated with PI3K inhibitor or WEE1 inhibitor alone or in combination, and cell proliferation was evaluated by CellTiter-Blue assay. Cell apoptosis was analyzed by TUNEL, annexin V staining, and blotting of cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase. Both subcutaneous xenograft and orthotropic xenograft studies were conducted to evaluate the effects of the combination on tumorigenesis; the tumor growth was monitored by bioluminescence imaging, and tumor tissue was analyzed by immunohistochemistry to validate signaling changes.

Results

PI3K inhibition activates WEE1 kinase, which in turn phosphorylates cell division control protein 2 homolog (Cdc2) at Tyr15 and inhibits Cdc2 activity, leading to G2/M arrest in a p53-independent manner. WEE1 inhibition abrogated the G2/M arrest and propelled cells to prematurely enter into mitosis and consequent cell death through mitotic catastrophe and apoptosis. Additionally, combination treatment significantly suppressed tumor growth in a subcutaneous model but not in an intracranial model due to limited blood–brain barrier penetration.

Conclusions

Our findings highlight WEE1 as an adaptive resistant gene activated after PI3K inhibition, and inhibition of WEE1 potentiated the effectiveness of PI3K targeted inhibition, suggesting that a combinational inhibition of WEE1 and PI3K might allow successful targeted therapy in GBM.

http://ift.tt/2mdCosI

CD70, a novel target of CAR T-cell therapy for gliomas

Abstract

Background

Cancer immunotherapy represents a promising treatment approach for malignant gliomas but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified cluster of differentiation (CD)70 as a novel immunosuppressive ligand and glioma target.

Methods

Normal tissues derived from 52 different organs and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression. The association between CD70 and patients' overall survival and its impact on T-cell death was also evaluated. Human and mouse CD70-specific chimeric antigen receptors (CARs) were tested respectively against human primary GBMs and murine glioma lines. The antitumor efficacies of these CARs were also examined in orthotopic xenograft and syngeneic models.

Results

CD70 was not detected in peripheral and brain normal tissues but was constitutively overexpressed by isocitrate dehydrogenase (IDH) wild-type primary LGGs and GBMs in the mesenchymal subgroup and recurrent tumors. CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T-cell death. To explore the potential for therapeutic targeting of this newly identified immunosuppressive axis in GBM tumors, we demonstrate that both human and mouse CD70-specific CAR T cells recognize primary CD70+ GBM tumors in vitro and mediate the regression of established GBM in xenograft and syngeneic models without illicit effect.

Conclusion

These studies identify a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas.

http://ift.tt/2CWeZ9D

Comment on “Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology Committee”

I read with interest and trepidation "Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology Committee" ¹ —interest because at St Jude we invest significant time and expertise in researching and optimizing pediatric neuro-oncologic imaging; trepidation because I was a member of this committee but felt compelled to withdraw because I felt that 2 recommendations were counter to existing evidence and potentially detrimental to patient care.

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Reviewer Lists for Neuro-Oncology

The following lists refer to the number of times reviewed within the 12-month period ending October 31, 2017. The names of Editorial Board members and Editorial Team members are excluded from the lists.

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Forthcoming Meetings

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The impact of surgery in molecularly defined low-grade glioma: an integrated clinical, radiological, and molecular analysis

Abstract

Background

Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes.

Methods

We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model.

Results

Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1–5.0 cm³) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002–1.02; P = 0.016) per cm³ increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1–5.0 cm) already negatively affected OS.

Conclusion

Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.

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Response to Harreld re: “Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology Committee”

What is lost in the letter by Harreld is the mandate of the RAPNO committee and the purpose of the proposed recommendations. Our goal, as a committee, was to develop consensus recommendations on the response assessment for use in clinical trials of patients with medulloblastoma and other seeding tumors, which could then be tested prospectively. Committee recommendations were based on scientific justification where this exists in peer-reviewed literature, or based upon the extensive experience of leaders in the field who are members of this group. Rather than recommend advanced imaging sequences utilized in limited institutions, we proposed recommendations that can be utilized at most institutions and that will allow uniformity and quality data collection. This approach is also in line with the Brain Tumor Drug Development Coalition Imaging Standardization Steering Committee and their recommendations. ¹ As such, it required compromise from the committee members in order to be applicable and feasible for the majority of institutions.

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Extent of surgery in low-grade gliomas: an old question in a new context

See the article by Wijnenga et al on pages 103–112

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Control versus cognition: the changing paradigm of adjuvant therapy for resected brain metastasis

Twenty years ago, Patchell and colleagues¹ demonstrated that whole-brain radiotherapy (WBRT) mitigates relapse both in the surgical bed and elsewhere in the brain and prevents death from neurologic causes in patients with resected brain metastasis. Therefore, postoperative WBRT became the standard of care.

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via IFTTT

Synergy of vaccination and agonist OX40 treatment—toward a mechanism-driven combination of glioma immunotherapy

See the article by Jahan et al on pages44–54.

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Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location

Abstract

Background

The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis.

Methods

Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection.

Results

We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival.

Conclusion

These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis.

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Inability of positive phase II clinical trials of investigational treatments to subsequently predict positive phase III clinical trials in glioblastoma

Abstract

Background

Glioblastoma is the most common primary malignant brain tumor in adults, but effective therapies are lacking. With the scarcity of positive phase III trials, which are increasing in cost, we examined the ability of positive phase II trials to predict statistically significant improvement in clinical outcomes of phase III trials.

Methods

A PubMed search was conducted to identify phase III clinical trials performed in the past 25 years for patients with newly diagnosed or recurrent glioblastoma. Trials were excluded if they did not examine an investigational chemotherapy or agent, if they were stopped early owing to toxicity, if they lacked prior phase II studies, or if a prior phase II study was negative.

Results

Seven phase III clinical trials in newly diagnosed glioblastoma and 4 phase III clinical trials in recurrent glioblastoma met the inclusion criteria. Only 1 (9%) phase III study documented an improvement in overall survival and changed the standard of care.

Conclusion

The high failure rate of phase III trials demonstrates the urgent need to increase the reliability of phase II trials of treatments for glioblastoma. Strategies such as the use of adaptive trial designs, Bayesian statistics, biomarkers, volumetric imaging, and mathematical modeling warrant testing. Additionally, it is critical to increase our expectations of phase II trials so that positive findings increase the probability that a phase III trial will be successful.

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Prognostic relevance of genetic alterations in diffuse lower-grade gliomas

Abstract

Background

Diffuse lower-grade gliomas (LGGs) are genetically classified into 3 distinct subtypes based on isocitrate dehydrogenase (IDH) mutation status and codeletion of chromosome 1p and 19q (1p/19q). However, the subtype-specific effects of additional genetic lesions on survival are largely unknown.

Methods

Using Cox proportional hazards regression modeling, we investigated the subtype-specific effects of genetic alterations and clinicopathological factors on survival in each LGG subtype, in a Japanese cohort of LGG cases fully genotyped for driver mutations and copy number variations associated with LGGs (n = 308). The results were validated using a dataset from 414 LGG cases available from The Cancer Genome Atlas (TCGA).

Results

In Oligodendroglioma, IDH-mutant and 1p/19q codeleted, NOTCH1 mutations (P = 0.0041) and incomplete resection (P = 0.0019) were significantly associated with shorter survival. In Astrocytoma, IDH-mutant, PIK3R1 mutations (P = 0.0014) and altered retinoblastoma pathway genes (RB1, CDKN2A, and CDK4) (P = 0.013) were independent predictors of poor survival. In IDH-wildtype LGGs, co-occurrence of 7p gain, 10q loss, mutation in the TERT promoter (P = 0.024), and grade III histology (P < 0.0001) independently predicted poor survival. IDH-wildtype LGGs without any of these factors were diagnosed at a younger age (P = 0.042), and were less likely to have genetic lesions characteristic of glioblastoma, in comparison with other IDH-wildtype LGGs, suggesting that they likely represented biologically different subtypes. These results were largely confirmed in the cohort of TCGA.

Conclusions

Subtype-specific genetic lesions can be used to stratify patients within each LGG subtype. enabling better prognostication and management.

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Agonist OX40 immunotherapy improves survival in glioma-bearing mice and is complementary with vaccination with irradiated GM-CSF–expressing tumor cells

Abstract

Background

Glioma immunotherapy is an active area of clinical investigation. Glioma-associated immunosuppression remains an obstacle to efficacious immunotherapy, and combination approaches are likely necessary for durable success. OX40 is a member of the tumor necrosis factor receptor superfamily that is upregulated on activated lymphocytes, ligation of which results in enhanced activity and may be active against cancer. We sought to confirm the efficacy of agonist anti-OX40 immunotherapy against glioma and hypothesized that it is complementary with irradiated whole tumor cell vaccination.

Methods

GL261 tumor cells were implanted into the right frontal lobes of syngeneic mice, which were then treated with controls, agonist anti-OX40 monoclonal antibody, vaccination with subcutaneous injection of irradiated granulocyte macrophage colony stimulating factor (GM-CSF)–expressing GL261 cells (GVAX), or vaccination + agonist anti-OX40 therapy. Animals were followed for survival. On day 18, splenocytes were harvested for enzyme-linked immunosorbent spot analyses and brains were harvested for immunohistochemistry and flow cytometry analyses of infiltrating lymphocytes.

Results

Combination immunotherapy with GVAX and systemic agonist anti-OX40 monoclonal antibody improved survival by 14 days over controls (median survival 36 vs 22 days, P < 0.00005). Systemically, T helper cell type 1 (Th1) antitumor immunity was enhanced significantly by combination therapy. In the brain, combination immunotherapy increased the percentage of Th1 CD4+ T lymphocytes and reduced the fraction that were Th2. In the brain, vaccination improved the ratio of CD8+ to FoxP3+ T lymphocytes, while combination immunotherapy reversed intracranial T-lymphocyte exhaustion, reducing their coexpression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) as well as PD-1 and lymphocyte-activation gene 3 (LAG-3).

Conclusions

Anti-OX40 immunotherapy is active against intracranial glioma and synergizes with GVAX. Vaccination and anti-OX40 immunotherapy are mechanistically complementary, particularly in the glioma microenvironment.

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Dissecting human gliomas by single-cell RNA sequencing

Abstract

Diffuse gliomas are the most common human primary brain tumors and remain incurable. They are complex entities in which diverse genetic and nongenetic effects determine tumor biology and clinical course. Our current understanding of gliomas in patients is primarily based on genomic and transcriptomic methods that have profiled them as bulk, providing critical information yet masking the diversity of cells within each tumor. Recent advances in single-cell DNA and RNA profiling have paved the way to studying tumors at cellular resolution. Here, we review initial studies deploying single-cell analysis in clinical glioma samples, with a focus on RNA expression profiling. We highlight how these studies provide new insights into glioma biology, tumor heterogeneity, cancer cell lineages, cancer stem cell programs, the tumor microenvironment, and glioma classification.

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Activation of WEE1 confers resistance to PI3K inhibition in glioblastoma

Abstract

Background

Oncogenic activation of phosphatidylinositol-3 kinase (PI3K) signaling plays a pivotal role in the development of glioblastoma (GBM). However, pharmacological inhibition of PI3K has so far not been therapeutically successful due to adaptive resistance through a rapid rewiring of cancer cell signaling. Here we identified that WEE1 is activated after transient exposure to PI3K inhibition and confers resistance to PI3K inhibition in GBM.

Methods

Patient-derived glioma-initiating cells and established GBM cells were treated with PI3K inhibitor or WEE1 inhibitor alone or in combination, and cell proliferation was evaluated by CellTiter-Blue assay. Cell apoptosis was analyzed by TUNEL, annexin V staining, and blotting of cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase. Both subcutaneous xenograft and orthotropic xenograft studies were conducted to evaluate the effects of the combination on tumorigenesis; the tumor growth was monitored by bioluminescence imaging, and tumor tissue was analyzed by immunohistochemistry to validate signaling changes.

Results

PI3K inhibition activates WEE1 kinase, which in turn phosphorylates cell division control protein 2 homolog (Cdc2) at Tyr15 and inhibits Cdc2 activity, leading to G2/M arrest in a p53-independent manner. WEE1 inhibition abrogated the G2/M arrest and propelled cells to prematurely enter into mitosis and consequent cell death through mitotic catastrophe and apoptosis. Additionally, combination treatment significantly suppressed tumor growth in a subcutaneous model but not in an intracranial model due to limited blood–brain barrier penetration.

Conclusions

Our findings highlight WEE1 as an adaptive resistant gene activated after PI3K inhibition, and inhibition of WEE1 potentiated the effectiveness of PI3K targeted inhibition, suggesting that a combinational inhibition of WEE1 and PI3K might allow successful targeted therapy in GBM.

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CD70, a novel target of CAR T-cell therapy for gliomas

Abstract

Background

Cancer immunotherapy represents a promising treatment approach for malignant gliomas but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified cluster of differentiation (CD)70 as a novel immunosuppressive ligand and glioma target.

Methods

Normal tissues derived from 52 different organs and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression. The association between CD70 and patients' overall survival and its impact on T-cell death was also evaluated. Human and mouse CD70-specific chimeric antigen receptors (CARs) were tested respectively against human primary GBMs and murine glioma lines. The antitumor efficacies of these CARs were also examined in orthotopic xenograft and syngeneic models.

Results

CD70 was not detected in peripheral and brain normal tissues but was constitutively overexpressed by isocitrate dehydrogenase (IDH) wild-type primary LGGs and GBMs in the mesenchymal subgroup and recurrent tumors. CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T-cell death. To explore the potential for therapeutic targeting of this newly identified immunosuppressive axis in GBM tumors, we demonstrate that both human and mouse CD70-specific CAR T cells recognize primary CD70+ GBM tumors in vitro and mediate the regression of established GBM in xenograft and syngeneic models without illicit effect.

Conclusion

These studies identify a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas.

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Neurological complications of new chemotherapy agents

Abstract

This last decade has yielded more robust development of cancer treatments and first-in-class agents than ever before. Since 2006, nearly one hundred new drugs have received regulatory approval for the treatment of hematological and solid organ neoplasms. Moreover, older conventional therapies have received approval for new clinical indications and are being used in combination with these newer small-molecule targeted treatments. The nervous system is vulnerable to many of the traditional cancer therapies, manifesting both already well-described acute and chronic toxicities. However, newer agents may produce toxicities that may seem indistinguishable from the underlying cancer. Early recognition of neurotoxicities from new therapeutics is vital to avoid irreversible neurological injury. This review focuses on cancer therapies in use in the last 10 years and approved by the FDA from January 2006 through January 1, 2017.

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MerTK as a therapeutic target in glioblastoma

Abstract

Background

Glioma-associated macrophages and microglia (GAMs) are components of the glioblastoma (GBM) microenvironment that express MerTK, a receptor tyrosine kinase that triggers efferocytosis and can suppress innate immune responses. The aim of the study was to define MerTK as a therapeutic target using an orally bioavailable inhibitor, UNC2025.

Methods

We examined MerTK expression in tumor cells and macrophages in matched patient GBM samples by double-label immunohistochemistry. UNC2025-induced MerTK inhibition was studied in vitro and in vivo.

Results

MerTK/CD68+ macrophages increased in recurrent tumors while MerTK/glial fibrillary acidic protein–positive tumor cells did not. Pharmacokinetic studies showed high tumor exposures of UNC2025 in a syngeneic orthotopic allograft mouse GBM model. The same model mice were randomized to receive vehicle, daily UNC2025, fractionated external beam radiotherapy (XRT), or UNC2025/XRT. Although median survival (21, 22, 35, and 35 days, respectively) was equivalent with or without UNC2025, bioluminescence imaging (BLI) showed significant growth delay with XRT/UNC2025 treatment and complete responses in 19%. The responders remained alive for 60 days and showed regression to 1%–10% of pretreatment BLI tumor burden; 5 of 6 were tumor free by histology. In contrast, only 2% of 98 GBM mice of the same model treated with XRT survived 50 days and none survived 60 days. UNC2025 also reduced CD206+ macrophages in mouse tumor samples.

Conclusions

These results suggest that MerTK inhibition combined with XRT has a therapeutic effect in a subset of GBM. Further mechanistic studies are warranted.

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RE: Long-term Safety of Pregnancy Following Breast Cancer According to Estrogen Receptor Status

We read the article by Lambertini et al. with great interest (1). This case–control study showed that, at a median follow-up of 7.2 years for women with a history of estrogen receptor (ER)–positive or ER-negative breast cancer (BC), there was no difference in disease-free survival between women who became pregnant and those who did not. Overall survival (OS) of the ER-positive patients was unaffected by pregnancy (hazard ratio [HR] = 0.84, 95% confidence interval [CI] = 0.60 to 1.18, P = .32), but, surprisingly, ER-negative patients who became pregnant had a longer median survival than those who did not (HR = 0.57, 95% CI = 0.36 to 0.90, P = .01). While these results appear reassuring to the many young BC survivors who so desperately wish to become pregnant, we are concerned about a possible source of bias that would be almost impossible to eliminate in a retrospective study of this nature.

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Response

We would like to thank Ozturk Topcu and colleagues for their interest in our study investigating the safety of pregnancy in patients with history of breast cancer (1). They pointed out a possible bias in our study results as patients desiring a pregnancy might have undergone imaging tests to exclude subclinical metastatic disease prior to attempting pregnancy.

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The European Society of Regional Anaesthesia and Pain Therapy/American Society of Regional Anesthesia and Pain Medicine Recommendations on Local Anesthetics and Adjuvants Dosage in Pediatric Regional Anesthesia

Background and Objectives Dosage of local anesthetics (LAs) used for regional anesthesia in children is not well determined. In order to evaluate and come to a consensus regarding some of these controversial topics, The European Society of Regional Anaesthesia and Pain Therapy (ESRA) and the American Society of Regional Anesthesia and Pain Medicine (ASRA) developed a Joint Committee Practice Advisory on Local Anesthetics and Adjuvants Dosage in Pediatric Regional Anesthesia. Methods Representatives from both ASRA and ESRA composed the joint committee practice advisory. Evidence-based recommendations were based on a systematic search of the literature. In cases where no literature was available, expert opinion was elicited. Results Spinal anesthesia with bupivacaine can be performed with a dose of 1 mg/kg for newborn and/or infant and a dose of 0.5 mg/kg in older children (>1 year of age). Tetracaine 0.5% is recommended for spinal anesthesia (dose, 0.07–0.13 mL/kg). Ultrasound-guided upper-extremity peripheral nerve blocks (eg, axillary, infraclavicular, interscalene, supraclavicular) in children can be performed successfully and safely using a recommended LA dose of bupivacaine or ropivacaine of 0.5 to 1.5 mg/kg. Dexmedetomidine can be used as an adjunct to prolong the duration of peripheral nerve blocks in children. Conclusions High-level evidence is not yet available to guide dosage of LA used in regional blocks in children. The ASRA/ESRA recommendations intend to provide guidance in order to reduce the large variability of LA dosage currently observed in clinical practice. Accepted for publication August 20, 2017. Address correspondence to: Santhanam Suresh, MD, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E Chicago Ave, Chicago, IL 60611 (e-mail: ssuresh@luriechildrens.org). Identification of institution(s) where work is attributed: Ann & Robert H. Lurie Children's Hospital of Chicago Northwestern University, Chicago, IL; and Department of Anesthesiology at Rhode Island Hospital, Alpert School of Medicine, Brown University, Providence, RI. The authors declare no conflict of interest. Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.

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Epidural Hematoma Following Interlaminar Epidural Injection in Patient Taking Aspirin

Objective We present a case report of a patient who developed an epidural hematoma following an interlaminar epidural steroid injection with no risk factors aside from old age and aspirin use for secondary prevention. Case Report A 79-year-old man developed an epidural hematoma requiring surgical treatment following an uncomplicated interlaminar epidural steroid injection performed for neurogenic claudication. In the periprocedural period, he continued aspirin for secondary prophylaxis following a myocardial infarction. Conclusions For patients taking aspirin for primary or secondary prophylaxis, the American Society of Regional Anesthesia and Pain Medicine antiplatelet and anticoagulation guidelines for spine and pain procedures recommend a shared assessment and risk stratification when deciding to hold the medication for intermediate-risk neuraxial procedures. Cases such as this serve to highlight the importance of giving careful consideration to medical optimization of a patient even when a low- or intermediate-risk procedure is planned. Accepted for publication September 2, 2017. Address correspondence to: Rebecca A. Sanders, MD, 200 First Street SW, Rochester, MN 55901 (e-mail: Sanders.rebecca@mayo.edu). The authors declare no conflict of interest. A case abstract was presented at the 2016 Annual Meeting of the American Academy of Pain Medicine; February 18 to 21, 2016; Palm Springs, CA. Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.

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Prone Position, Cerebral Oximetry, and Delirium

No abstract available

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High-intensity focused ultrasound in the treatment of breast tumours

Mirjam CL Peek and Feng Wu

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Novel devices for implant-based breast reconstruction: is the use of meshes to support the lower pole justified in terms of benefits? A review of the evidence

Lorna Jane Cook and Tibor Kovacs

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Novel techniques for intraoperative assessment of margin involvement

Dorin Dumitru, Michael Douek and John R Benson

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Update on intraoperative radiotherapy: new challenges and issues

Emanuela Esposito and Michael Douek

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Novel devices for implant-based breast reconstruction: is the use of meshes to support the lower pole justified in terms of benefits? A review of the evidence

Lorna Jane Cook and Tibor Kovacs

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Novel techniques for intraoperative assessment of margin involvement

Dorin Dumitru, Michael Douek and John R Benson

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High-intensity focused ultrasound in the treatment of breast tumours

Mirjam CL Peek and Feng Wu

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Update on intraoperative radiotherapy: new challenges and issues

Emanuela Esposito and Michael Douek

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Negative regulators of cell death pathways in cancer: perspective on biomarkers and targeted therapies

Abstract

Cancer is a primary cause of human fatality and conventional cancer therapies, e.g., chemotherapy, are often associated with adverse side-effects, tumor drug-resistance, and recurrence. Molecularly targeted therapy, composed of small-molecule inhibitors and immunotherapy (e.g., monoclonal antibody and cancer vaccines), is a less harmful alternative being more effective against cancer cells whilst preserving healthy tissues. Drug-resistance, however, caused by negative regulation of cell death signaling pathways, is still a challenge. Circumvention of negative regulators of cell death pathways or development of predictive and response biomarkers is, therefore, quintessential. This review critically discusses the current state of knowledge on targeting negative regulators of cell death signaling pathways including apoptosis, ferroptosis, necroptosis, autophagy, and anoikis and evaluates the recent advances in clinical and preclinical research on biomarkers of negative regulators. It aims to provide a comprehensive platform for designing efficacious polytherapies including novel agents for restoring cell death signaling pathways or targeting alternative resistance pathways to improve the chances for antitumor responses. Overall, it is concluded that nonapoptotic cell death pathways are a potential research arena for drug discovery, development of novel biomarkers and targeted therapies.

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Effects of concentrated long-chain omega-3 polyunsaturated fatty acid supplementation before radical prostatectomy on prostate cancer proliferation, inflammation, and quality of life: study protocol for a phase IIb, randomized, double-blind, placebo-controlled trial

Abstract

Background

Prostate cancer is the most commonly diagnosed cancer in north-American men. Few dietary or lifestyle interventions have been tested to prevent prostate cancer progression. Omega-3 fatty acid supplementation represents a promising intervention for prostate cancer patients. The aim of the study is to evaluate the effects of long-chain omega-3 polyunsaturated fatty acids (LCn3), more precisely eicosapentaenoic acid monoacylglyceride (MAG-EPA) supplementation, on prostate cancer proliferation, inflammation mediators and quality of life among men who will undergo radical prostatectomy.

Methods/design

We propose a phase IIb, randomized, double-blind placebo-controlled trial of MAG-EPA supplementation for 130 men who will undergo radical prostatectomy as treatment for a prostate cancer of Gleason score ≥ 7 in an academic cancer center in Quebec City. Participants will be randomized to 6 capsules of 625 mg of fish oil (MAG-EPA) per capsule containing 500 mg of EPA daily or to identically looking capsules of high oleic acid sunflower oil (HOSO) as placebo. The intervention begins 4 to 10 weeks prior to radical prostatectomy (baseline) and continues for one year after surgery. The primary endpoint is the proliferative index (Ki-67) measured in prostate cancer cells at radical prostatectomy. A secondary endpoint includes prostate tissue levels of inflammatory mediators (cytokines and proteins) at time of radical prostatectomy. Changes in blood levels of inflammatory mediators, relative to baseline levels, at time of radical prostatectomy and 12 months after radical prostatectomy will also be evaluated. Secondary endpoints also include important aspects of psychosocial functioning and quality of life such as depression, anxiety, sleep disturbances, fatigue, cognitive complaints and prostate cancer-specific quality of life domains. The changes in these outcomes, relative to baseline levels, will be evaluated at 3, 6, 9 and 12 months after radical prostatectomy.

Discussion

The results from this trial will provide crucial information to clarify the role of omega-3 supplementation on prostate cancer proliferation, inflammation and quality of life.

Trial registration

ClinicalTrials.gov Identifier: NCT02333435. Registered on December 17, 2014. Last updated September 6, 2016.

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RCC2 over-expression in tumor cells alters apoptosis and drug sensitivity by regulating Rac1 activation

Abstract

Background

Small GTP binding protein Rac1 is a component of NADPH oxidases and is essential for superoxide-induced cell death. Rac1 is activated by guanine nucleotide exchange factors (GEFs), and this activation can be blocked by regulator of chromosome condensation 2 (RCC2), which binds the switch regions of Rac1 to prevent access from GEFs.

Methods

Three cancer cell lines with up- or down-regulation of RCC2 were used to evaluate cell proliferation, apoptosis, Rac1 signaling and sensitivity to a group of nine chemotherapeutic drugs. RCC2 expression in lung cancer and ovarian cancer were studied using immunochemistry stain of tumor tissue arrays.

Results

Forced RCC2 expression in tumor cells blocked spontaneous- or Staurosporine (STS)-induced apoptosis. In contrast, RCC2 knock down in these cells resulted in increased apoptosis to STS treatment. The protective activity of RCC2 on apoptosis was revoked by a constitutively activated Rac1, confirming a role of RCC2 in apoptosis by regulating Rac1. In an immunohistochemistry evaluation of tissue microarray, RCC2 was over-expressed in 88.3% of primary lung cancer and 65.2% of ovarian cancer as compared to non-neoplastic lung and ovarian tissues, respectively. Because chemotherapeutic drugs can kill tumor cells by activating Rac1/JNK pathway, we suspect that tumors with RCC2 overexpression would be more resistant to these drugs. Tumor cells with forced RCC2 expression indeed had significant difference in drug sensitivity compared to parental cells using a panel of common chemotherapeutic drugs.

Conclusions

RCC2 regulates apoptosis by blocking Rac1 signaling. RCC2 expression in tumor can be a useful marker for predicting chemotherapeutic response.

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CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension

Abstract

Background

The prognostic variability of thyroid carcinomas has led to the search for accurate biomarkers at the molecular level. Follicular thyroid carcinoma (FTC) is a typical example of differentiated thyroid carcinomas (DTC) in which challenges are faced in the differential diagnosis.

Methods

We used high-throughput paired-end RNA sequencing technology to study four cases of FTC with different degree of capsular invasion: two minimally invasive (mFTC) and two widely invasive FTC (wFTC). We searched by genes differentially expressed between mFTC and wFTC, in an attempt to find biomarkers of thyroid cancer diagnosis and/or progression. Selected biomarkers were validated by real-time quantitative PCR in 137 frozen thyroid samples and in an independent dataset (TCGA), evaluating the diagnostic and the prognostic performance of the candidate biomarkers.

Results

We identified 17 genes significantly differentially expressed between mFTC and wFTC. C1QL1, LCN2, CRABP1 and CILP were differentially expressed in DTC in comparison with normal thyroid tissues. LCN2 and CRABP1 were also differentially expressed in DTC when compared with follicular thyroid adenoma. Additionally, overexpression of LCN2 and C1QL1 were found to be independent predictors of extrathyroidal extension in DTC.

Conclusions

We conclude that the underexpression of CRABP1 and the overexpression of LCN2 may be useful diagnostic biomarkers in thyroid tumours with questionable malignity, and the overexpression of LCN2 and C1QL1 may be useful for prognostic purposes.

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Metformin, Asian ethnicity and risk of prostate cancer in type 2 diabetes: a systematic review and meta-analysis

Abstract

Background

Metformin is associated with a reduced risk of some cancers but its effect on prostate cancer is unclear. Some studies suggest only Asians derive this benefit. Therefore, we undertook a systematic review with particular attention to ethnicity.

Methods

Medline, Embase, Scopus, Web of Science, and EBM Reviews were searched from inception to 2015. Two reviewers identified and abstracted articles. Studies were pooled using random effects model and stratified by Western- vs Asian-based populations.

Results

We identified 482 studies; 26 underwent full review. Of Western-based studies (n = 23), two were randomized trials and 21 were observational studies. All Asian-based studies (n = 3) were observational. There were 1,572,307 patients, 1,171,643 Western vs 400,664 Asian. Across all studies there was no association between metformin and prostate cancer (RR: 1.01, 95%CI: 0.86-1.18, I²: 97%), with similar findings in Western-based trials (RR: 1.38, 95%CI: 0.72-2.64 I²: 15%) and observational studies (RR: 1.03 95%CI: 0.94-1.13, I²: 88%). Asian-based studies suggested a non-significant reduction (RR: 0.75, 95%CI: 0.42-1.34, I²: 90%), although these results were highly influenced by one study of almost 400,000 patients (propensity-adjusted RR: 0.47 95%CI 0.45-0.49). Removing this influential study yielded an estimate more congruent with Western-based studies (RR: 0.98 95%CI:0.71-1.36, I²: 0%).

Conclusion

There is likely no association between metformin and risk of prostate cancer, in either Western-based or Asian-based populations after removing a highly influential Asian-based study.

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The quality of working life questionnaire for cancer survivors (QWLQ-CS): factorial structure, internal consistency, construct validity and reproducibility

Abstract

Background

To assess the factorial structure, internal consistency, construct validity and reproducibility of the Quality of Working Life Questionnaire for Cancer Survivors (QWLQ-CS).

Methods

An Exploratory Factor Analysis (EFA) was performed on QWLQ-CS data from a sample of employed cancer survivors to establish the final number of items and factorial structure of the QWLQ-CS. Internal consistency was assessed using Cronbach's alpha. In a second sample of (self-)employed cancer survivors, construct validity was tested by convergent validity (correlations of QWLQ-CS with construct-related questionnaires), and discriminative validity (difference in QWLQ-CS scores between cancer survivors and employed people without cancer). In a subgroup of stable cancer survivors subtracted from the second sample, reproducibility was evaluated by Intraclass Correlation Coefficient (ICC) and Standard Error of Measurement (SEM).

Results

EFA on QWLQ-CS data of 302 cancer survivors resulted in 23 items and five factors. The internal consistency of the QWLQ-CS was Cronbach's α = 0.91. Convergent validity on data of 130 cancer survivors resulted in r = 0.61–0.70. QWLQ-CS scores of these cancer survivors statistically differed (p = 0.04) from employed people without cancer (N = 45). Reproducibility of QWLQ-CS data from 87 cancer survivors demonstrated an ICC of 0.84 and a SEM of 9.59.

Conclusions

The five-factor QWLQ-CS with 23 items and adequate internal consistency, construct validity, and reproducibility at group level can be used in clinical and occupational healthcare, and research settings.

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An oncogenic mutant of RHEB, RHEB Y35N, exhibits an altered interaction with BRAF resulting in cancer transformation

Abstract

Background

RHEB is a unique member of the RAS superfamily of small GTPases expressed in all tissues and conserved from yeast to humans. Early studies on RHEB indicated a possible RHEB-RAF interaction, but this has not been fully explored. Recent work on cancer genome databases has revealed a reoccurring mutation in RHEB at the Tyr35 position, and a recent study points to the oncogenic potential of this mutant that involves activation of RAF/MEK/ERK signaling. These developments prompted us to reassess the significance of RHEB effect on RAF, and to compare mutant and wild type RHEB.

Methods

To study RHEB-RAF interaction, and the effect of the Y35N mutation on this interaction, we used transfection, immunoprecipitation, and Western blotting techniques. We generated cell lines stably expressing RHEB WT, RHEB Y35N, and KRAS G12V, and monitored cellular transforming properties through cell proliferation, anchorage independent growth, cell cycle analysis, and foci formation assays.

Results

We observe a strong interaction between RHEB and BRAF, but not with CRAF. This interaction is dependent on an intact RHEB effector domain and RHEB-GTP loading status. RHEB overexpression decreases RAF activation of the RAF/MEK/ERK pathway and RHEB knockdown results in an increase in RAF/MEK/ERK activation. RHEB Y35N mutation has decreased interaction with BRAF, and RHEB Y35N cells exhibit greater BRAF/CRAF heterodimerization resulting in increased RAF/MEK/ERK signaling. This leads to cancer transformation of RHEB Y35N stably expressing cell lines, similar to KRAS G12 V expressing cell lines.

Conclusions

RHEB interaction with BRAF is crucial for inhibiting RAF/MEK/ERK signaling. The RHEB Y35N mutant sustains RAF/MEK/ERK signaling due to a decreased interaction with BRAF, leading to increased BRAF/CRAF heterodimerization. RHEB Y35N expressing cells undergo cancer transformation due to decreased interaction between RHEB and BRAF resulting in overactive RAF/MEK/ERK signaling. Taken together with the previously established function of RHEB to activate mTORC1 signaling, it appears that RHEB performs a dual function; one is to suppress the RAF/MEK/ERK signaling and the other is to activate mTORC1 signaling.

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