Dexmedetomidine: a valuable sedative currently not widely available in the UK

British Journal of Anaesthesia, 2016; 117(2): 263–264, DOI 10.1093/bja/aew202

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Necrotic cutaneous vasculitic skin lesions: a case of atypical Henoch-Schönlein purpura in a child with heterozygosity for factor V Leiden

Description

A Caucasian boy aged 5 years presented with acute onset of a non-tender, palpable purpuric rash to his lower limbs, preceded by a mild upper respiratory tract infection. Clinical findings were consistent with Henoch-Schönlein purpura (HSP) and he was discharged with community follow-up to monitor his lesions, blood pressure and urinalysis.

However, he clinically deteriorated over the following week with two further admissions due to evolving purpuric skin lesions (figure 1) and development of severe joint pain requiring opioid analgesia. There was no clinical evidence of renal or intestinal involvement.

Figure 1

Initial presentation of the purpuric Henoch Schonlein purpura rash.

Over a subsequent 6-week period, his purpuric lesions progressed to full thickness skin necrosis (figure 2). This was confirmed by a plastic surgery assessment and he was referred for a tertiary rheumatology review. He underwent a series...

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Surgery in late melanoma adrenal metastasis

Metastatic melanoma to adrenal gland are very infrequent, being generally associated with additional evidence of systemic disease and, consequently, with short-term survival. However, the prognosis and the therapeutic management vary depending on some important oncological features. Long-term survival rates have been described after complete resection of metastatic disease. Here, we report the case of a woman aged 41 years diagnosed with a cutaneous melanoma on the right side of her paravertebral region, level III of Clark, in 2002, who underwent surgical excision of the tumour with negative margins and a negative sentinel node. She posteriorly developed pulmonary metastasis in 2006 and 2009, both resected with curative intention and in 2013, she was diagnosed with an adrenal metastasis. Therefore, she was submitted to an uneventful right laparoscopic adrenalectomy. The pathology report described metastasis of a cutaneous melanoma, negative for BRAF mutation. The patient is actually disease-free after 30 months of follow-up.

http://ift.tt/2rc0ysL

Unusual course of a haematoma of the thigh

Description

A Caucasian woman aged 56 years presented to emergency room (ER) department with leucorrhoea and fever since 48 hours. She was a smoker, had no diabetes history, no prosthetic material and denied use of injected drugs.

A month before, the patient had a closed inguinal trauma due to fall from height with a muscle strain of the anterior right thigh. Despite rest and analgesics, she went to ER several times because of progressive local pain and swelling. After 3 weeks, a local ultrasound scan showed a 3 cm size haematoma associated with probable rupture of obturator internus and rectus femoris muscles. On the following days, she developed fetid leucorrhoea associated with movements and compression of the anterior thigh. On physical examination and analyses, she had sepsis criteria and the abdomen/pelvic CT scan (figure1A, B) and MRI (figure1C, D) showed an abscess of 105x25mm size, complicated with...

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Bottom of an iceberg: undiagnosed aortic aneurysm masquerading as vocal cord palsy

Description

A previously healthy woman aged 60 years was referred to a tertiary referral cancer centre with change of voice for 1 week suspecting neoplastic aetiology on account of her tobacco chewing habit of more than 20 years. No history of voice abuse, fever or cough was there preceding the onset of the change of voice. She did not have any previous history of hospitalisation or diagnosed comorbidities. On clinical examination, her pulse rate was 82 bpm; blood pressure was 130/90 mm Hg and respiratory rate was 12/min.

Video laryngoscopy examination revealed left vocal cord palsy with no obvious lesion. A whole-body F18 FDG PET–CT scan revealed the presence of 6.6x4.8x6.7 cm lobulated sacullar aneurysm arising from the aortic arch between the origins of the left common carotid and subclavian arteries (figures 1 and 2). The likely mycotic aneurysm caused significant surrounding metabolically active inflammatory changes (figure 3). The...

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Immune Checkpoint Inhibitor Therapy: What Line of Therapy and How to Choose?

Opinion statement

Immunotherapy is now an established part of the treatment paradigm for advanced non-small cell lung cancer (NSCLC), but the line of therapy and the sequence of agents are still in flux. In this time when much is to be learned, the optimal therapy for most patients in both the first-line and previously treated settings is in the context of a clinical trial. For standard therapy, however, there are good data to support the practice of programmed death-ligand 1 (PD-L1) testing in the front-line advanced setting and to use pembrolizumab as first-line therapy for those with ≥50% PD-L1 expression. In those who have progressed after receiving platinum-based chemotherapy in the first-line, multiple PD-1/PD-L1 agents are available and currently approved, including nivolumab, pembrolizumab, and atezolizumab. There are no data to suggest that one agent is more efficacious than the others, but pembrolizumab should be reserved for patients with PD-L1 expression ≥1%. Prescribers and patients must be cognizant of the toxicity profile of these agents, as severe immune-related adverse events can occur with therapy. At this time, this practice pattern for immunotherapy in the first- and second-line can be considered the standard of care, but new data are likely to impact the role of immunotherapy as monotherapy or in combination in the near future.

http://ift.tt/2rLBTHQ

Advancing Immunotherapy in Metastatic Breast Cancer

Opinion statement

Despite many advances in the treatment of breast cancer, the development of metastatic disease remains an incurable and frequent cause of cancer death for women worldwide. An improved understanding of the role of host immunosurveillance in modulating breast cancer disease biology, as well as impressive survival benefits seen to checkpoint blockade in other malignancies have provided great hope for an expanding role of immunotherapies in breast cancer management. While these novel therapies are currently being investigated in clinical trials, signals of efficacy, and tolerability in early phase studies suggest these will eventually make their way into standard practice algorithms. Ongoing research has highlighted a high degree of intertumoural heterogeneity in tumour lymphocytic infiltrates, suggesting some tumours or subtypes are more immunogenic than others. Furthermore, tumour intrinsic mechanisms of immune evasion are beginning to be uncovered, potentially representing key therapeutic targets to use in combination with checkpoint blockade, exemplifying the emerging concept of personalised medicine approaches to immune therapies. Subsequently, different immunotherapeutic strategies may be required based on stratification by these factors—for the minority of tumours with a high level of pre-existing immunity, immune checkpoint blockade monotherapy may be sufficient. However, for the majority of tumours with lower levels of pre-existing immunity, combination approaches will likely be required to achieve maximal therapeutic effect. Results of ongoing clinical trials including combinations with chemotherapy, radiation therapy, and targeted therapies are eagerly awaited.

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Trabectedin and Eribulin: Where Do They Fit in the Management of Soft Tissue Sarcoma?

Opinion Statement

Trabectedin and eribulin are two agents that have been recently approved for the treatment of specific soft tissue sarcoma subtypes. They have proved to be a much-needed line of additional treatment for patients with these rare tumors, but their activity remains admittedly modest in most cases. Further exploitation of these novel agents is likely to require a more granular understanding of the salient mechanisms of action. For example, if as some studies suggest, eribulin derives its benefit from restructuring of tumor vasculature to improve efficacy of subsequent lines of therapy, then patients may benefit from its use earlier in the treatment pathway. The sequencing of trabectedin with other agents is also worth examining. In a disease like myxoid liposarcoma, consideration should be given to using trabectedin before other salvage regimens like gemcitabine and docetaxel, given its tolerability and excellent efficacy against this sarcoma subtype. Also, to be further investigated is the use of trabectedin in sarcoma subtypes which were excluded from the phase III study, but in which activity has been documented in earlier trials and subsequent reports. Combinations of trabectedin with other agents, particularly doxorubicin, have been explored, but the data to date do not support the routine use of these regimens.

http://ift.tt/2rLzFYH

Immune Checkpoint Inhibitor Therapy: What Line of Therapy and How to Choose?

Opinion statement

Immunotherapy is now an established part of the treatment paradigm for advanced non-small cell lung cancer (NSCLC), but the line of therapy and the sequence of agents are still in flux. In this time when much is to be learned, the optimal therapy for most patients in both the first-line and previously treated settings is in the context of a clinical trial. For standard therapy, however, there are good data to support the practice of programmed death-ligand 1 (PD-L1) testing in the front-line advanced setting and to use pembrolizumab as first-line therapy for those with ≥50% PD-L1 expression. In those who have progressed after receiving platinum-based chemotherapy in the first-line, multiple PD-1/PD-L1 agents are available and currently approved, including nivolumab, pembrolizumab, and atezolizumab. There are no data to suggest that one agent is more efficacious than the others, but pembrolizumab should be reserved for patients with PD-L1 expression ≥1%. Prescribers and patients must be cognizant of the toxicity profile of these agents, as severe immune-related adverse events can occur with therapy. At this time, this practice pattern for immunotherapy in the first- and second-line can be considered the standard of care, but new data are likely to impact the role of immunotherapy as monotherapy or in combination in the near future.

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Advancing Immunotherapy in Metastatic Breast Cancer

Opinion statement

Despite many advances in the treatment of breast cancer, the development of metastatic disease remains an incurable and frequent cause of cancer death for women worldwide. An improved understanding of the role of host immunosurveillance in modulating breast cancer disease biology, as well as impressive survival benefits seen to checkpoint blockade in other malignancies have provided great hope for an expanding role of immunotherapies in breast cancer management. While these novel therapies are currently being investigated in clinical trials, signals of efficacy, and tolerability in early phase studies suggest these will eventually make their way into standard practice algorithms. Ongoing research has highlighted a high degree of intertumoural heterogeneity in tumour lymphocytic infiltrates, suggesting some tumours or subtypes are more immunogenic than others. Furthermore, tumour intrinsic mechanisms of immune evasion are beginning to be uncovered, potentially representing key therapeutic targets to use in combination with checkpoint blockade, exemplifying the emerging concept of personalised medicine approaches to immune therapies. Subsequently, different immunotherapeutic strategies may be required based on stratification by these factors—for the minority of tumours with a high level of pre-existing immunity, immune checkpoint blockade monotherapy may be sufficient. However, for the majority of tumours with lower levels of pre-existing immunity, combination approaches will likely be required to achieve maximal therapeutic effect. Results of ongoing clinical trials including combinations with chemotherapy, radiation therapy, and targeted therapies are eagerly awaited.

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Trabectedin and Eribulin: Where Do They Fit in the Management of Soft Tissue Sarcoma?

Opinion Statement

Trabectedin and eribulin are two agents that have been recently approved for the treatment of specific soft tissue sarcoma subtypes. They have proved to be a much-needed line of additional treatment for patients with these rare tumors, but their activity remains admittedly modest in most cases. Further exploitation of these novel agents is likely to require a more granular understanding of the salient mechanisms of action. For example, if as some studies suggest, eribulin derives its benefit from restructuring of tumor vasculature to improve efficacy of subsequent lines of therapy, then patients may benefit from its use earlier in the treatment pathway. The sequencing of trabectedin with other agents is also worth examining. In a disease like myxoid liposarcoma, consideration should be given to using trabectedin before other salvage regimens like gemcitabine and docetaxel, given its tolerability and excellent efficacy against this sarcoma subtype. Also, to be further investigated is the use of trabectedin in sarcoma subtypes which were excluded from the phase III study, but in which activity has been documented in earlier trials and subsequent reports. Combinations of trabectedin with other agents, particularly doxorubicin, have been explored, but the data to date do not support the routine use of these regimens.

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Traumatic phacocele: a rare but unique scenario

Description

The term phacocele is derived from a Greek word, where 'phaco' denotes lens and 'kele' meaning herniation. It is an unusual and very rare clinical condition.1

A 48-year-old male patient presented with sudden-onset diminution of vision, redness, pain in his left eye following blunt trauma 2 days ago. There was no significant ocular or systemic history. Visual acuity was perception of light positive with projection of rays accurate in left eye and 20/20 in right eye. On slit-lamp examination of the affected eye, there was a solid globular mass in the subconjunctival space located in the superonasal quadrant measuring 8x9 mm with smooth surface and rounded margins. There was an area of suspected scleral dehiscence, temporal to the mass lesion with uveal show (figure 1A). There was diffuse corneal oedema with descemet's folds. Anterior chamber detail was not clearly visible because of hyphaema (figure 1B). Intraocular pressure was 4 mm Hg....

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Angioscopy-guided selective aspiration thrombectomy for acute pulmonary thromboembolism

An 83-year-old woman with a history of pulmonary thromboembolism 10 years ago was referred for dyspnea. Anticoagulation therapy was terminated by her family doctor 3 years previously. On admission, D-dimer level was 16.6 µg/mL and arterial blood gas showed 88.1% on room air. Pulmonary arteriography (PAG) revealed some filling defects, mainly in the right interlobar artery (figure 1A). Non-obstructive angioscopy (NOA)1 showed two kinds of thrombi in the pulmonary arteries. At the translucent area, a massive, red, smooth thrombus was seen (figure 1B, video 1). Between the massive thrombus, floating, mobile, white-red, puff-like thrombi were demonstrated (figure 1C, video 2). As the thrombi entered the catheter spontaneously, aspiration was performed using a 20 mL syringe. Thrombi in the guiding catheter were collected by removing the guiding catheter. For the first trial, red thrombi were effectively aspirated (figure...

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Laryngocoele formation after ingestion of fish bone

Description

A 72-year-old man presented to the clinic with a 3-week history of anterior left neck pain. He described constant discomfort since eating fish a few weeks prior. He recalled pain at the time of eating, and felt he had ingested a fish bone.

There was no dysphagia, dyspnoea or haemoptysis on presentation. He had a medical history of type II diabetes mellitus, with no previous Ear, Nose and Throat issues.

Examination of the neck and oropharynx was normal. There were no palpable nodes or masses. Flexible nasendoscopy demonstrated a normal larynx. A lateral X-ray of the neck was arranged and showed no foreign body.

He was treated with simple analgesia and antacid, with a plan to review in 1 week.

He was reviewed and again examination and nasendoscopy were normal. CT scan revealed a traumatic laryngocoele at the left piriform sinus (figures 1 and 2).

...

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Severe medication-induced peripheral neuropathy treated with topical doxepin cream in a paediatric patient with leukaemia

A 17-year-old female with recently relapsed acute lymphoblastic leukaemia and a treatment course complicated by rhinocerebral mucormycosis infection developed severe peripheral neuropathy during the treatment for mucormycosis infection. This was felt to be a medication side effect. Her peripheral neuropathy was refractory to many well-established treatments, but ultimately responded dramatically and consistently to a novel therapy, topical doxepin cream (5%). This case report is the first published report of the application of topical doxepin cream for treatment of peripheral neuropathy in a paediatric patient.

http://ift.tt/2qbySQz

Systemic inflammatory response syndrome (SIRS) and a left bundle branch block (LBBB) due to nitrofurantoin

We present a case of a 74-year-old woman, who was on nitrofurantoin treatment for urinary tract infection (UTI), with fever and chills 7 hours after taking nitrofurantoin. She was hospitalised and evaluated for worsening UTI and sepsis. Initially, it appeared to be secondary to post-UTI sepsis because of possible resistant infection or conditions like pulmonary embolism or acute hepatitis. The patient also developed systemic inflammatory response syndrome, left bundle branch block (LBBB), thrombocytopaenia and transaminitis. Considering the side effects of nitrofurantoin, it was stopped. The patient showed improvement and recovered completely with symptomatic and supportive treatment. During follow-up visits with her primary care physician, thrombocytopaenia, transaminitisandLBBB were found to have been resolved.

http://ift.tt/2rvuNuj

Actinomycosis presenting as an anterior abdominal mass after laparoscopic cholecystectomy

Abdominal actinomycosis is a rare disease caused by different anaerobic Actinomyces species. We report the case of a 55-year-old woman who presented with a painless, slow growing, left upper abdominal mass that developed after a laparoscopic cholecystectomy. A CT scan and MRI of the abdomen revealed a desmoid tumour of the left rectus abdominis muscle.

Surgical excision was performed with an uneventful postoperative course. The histological analysis of the specimen was inconsistent with a desmoid tumour and revealed an infection of Actinomyces israelii in the anterior abdominal wall that was confirmed with a microbiology culture. The surgical treatment was followed by a course of penicillin antibiotic therapy for 6 months. This treatment resulted in full recovery with no further complications. Although it is rare, the patient's history of laparoscopic cholecystectomy was identified as the likely source of infection.

http://ift.tt/2qbEeew

Pathological fracture of the femoral neck following septic coxitis and chronic osteomyelitis: a potential complication of Lemierres syndrome

We portray the case of a 16-year-old girl who was initially admitted to the paediatric emergency department with non-specific symptoms of a severe cold and was first treated symptomatically on an ambulatory basis. Within 6 days she developed the full clinical picture of Lemierre's syndrome with the extraordinary manifestation of involvement of her right hip. Despite an interdisciplinary coordinated treatment as well as surgical therapy, a full-blown sepsis evolved within a short time period and resulted in almost 2 months of intensive care. While the primary focus could be successfully controlled, a progressive avascular necrosis of the right proximal femur developed on the basis of a chronic osteomyelitis. This finally led to a pathological fracture of the femoral neck. After excluding the possibility of an enduring bacterial infection, the fracture was treated with a total hip replacement.

http://ift.tt/2rvijTw

Impella percutaneous left ventricular assist device for severe acute ischaemic mitral regurgitation as a bridge to surgery

Ischaemic papillary muscle rupture causing acute severe mitral regurgitation (MR) has a dramatic presentation and a very high mortality. Emergent surgical repair improves outcomes, which necessitates robust preoperative stabilisation. Here we discuss a patient with cardiogenic shock with an acute severe MR that was deemed very high risk for emergent valve replacement due to haemodynamic instability and respiratory failure. A percutaneous left ventricular assist device Impella 2.5 (Abiomed, Danvers, MA) drastically improved clinical status, and the patient underwent a successful surgical mitral valve replacement soon after placement of the temporary assist device. Our case highlights that percutaneous ventricular assist devices may help to stabilise patients with severe acute ischaemic MR, and it can serve as a bridge to surgery in high risk patients.

http://ift.tt/2qbhoDP

Incidental discovery of a large complicated arteriovenous haemangioma

Arteriovenous haemangiomas within the chest are rare and uncommonly documented. After a 60-year-old woman with a history of smoking underwent a routine chest X-ray revealing a right apical mass, further investigations led to the discovery of a large extrapulmonary arteriovenous haemangioma in the superior mediastinum. Additionally, this case became complicated when the hemangioma was found to not only be compressing adjacent major arteries and veins, but also invading into the spinal canal and displacing the spinal cord. With multidisciplinary planning, the arteriovenous haemangioma was embolised and successfully resected. Thus, we present a case of an arteriovenous haemangioma in the superior mediastinum and discuss the importance of the case.

http://ift.tt/2rvm0IM

Clostridium difficile extraintestinal abscess: a rare complication

Extraintestinal Clostridium difficile is rare. A 74-year-old man with a history of ulcerative colitis presented after a fall. Trauma work-up showed liver cirrhosis. Two days later he developed abdominal pain, distension, diarrhoea and leucocytosis. Stool tested positive for C. difficile. CT abdomen showed pancolitis with toxic megacolon. Total abdominal colectomy and ileostomy with a rectal stump was performed. He was discharged, but was readmitted with sepsis. CT abdomen showed a 10.4x7.2 cm fluid collection in the pelvis. C. difficile stool was negative. CT-guided abscess drainage grew C. difficile. Barium enema was negative for communication from the rectal stump to the abscess. The patient was treated with metronidazole for 2 weeks. In summary, extraintestinal C. difficile can develop from recent antibiotics use, gastrointestinal surgery and microperforations from toxic megacolon. We recommend abscess drainage, concomitant treatment with metronidazole and or vancomycin, and reimaging of abscess location 2–4 weeks after cessation of antibiotics.

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Non-surgical treatment of a relapsed cystic hygroma in an adult

Lymphatic malformations, also known as lymphangiomas or cystic hygromas, are benign masses that typically affect newborns and infants and involve the head and neck regions. They are, however, rare in adults and even rarer in the axillary region. Although surgery is considered to be the treatment of choice, we present a rare case of a recurrent cystic hygroma 32 years after the first surgical operation. Due to the cosmetic concerns and the risks of a surgical approach, non-surgical therapy with percutaneous sclerosants was performed, with a good outcome after a 2-year follow-up period.

http://ift.tt/2rvtfjS

Native valve endocarditis caused by Lactococcus garvieae: an emerging human pathogen

A 57-year-old man presented with native mitral valve endocarditis caused by Lactococcus garvieae, a known animal pathogen that is increasingly being reported as a cause of human infections. The organism was cultured in four sets of blood cultures and identification was initially made by matrix-assisted laser desorption/ionisation—time of flight mass spectrometry and confirmed by 16S rDNA PCR of the blood culture isolate. He was successfully treated with 6 weeks of both amoxicillin and gentamicin and underwent valve replacement surgery after 4 weeks of antimicrobial treatment. The removed valve was sterile but L. garvieae DNA was detected on the valve using 16S rDNA PCR. The cause of the L. garvieae infection could not be ascertained but flexible sigmoidoscopy demonstrated colonic polyps, which have been linked to infection with this organism.

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Safe administration of S-1 after 5-fluorouracil-induced cardiotoxicity in a patient with colorectal cancer

Cardiotoxicity is a rare but challenging complication of 5-fluorouracil (5-FU) therapy. Compared with 5-FU, after application of S-1 lower plasma levels of the cardiotoxic metabolite alpha-fluoro-beta-alanine have been reported. Evidence for safe administration of S-1 following 5-FU cardiotoxicity is limited to a case report in an Asian patient. Herein we report the first case of S-1 application after 5-FU cardiotoxicity in a Caucasian patient.

A 67-year-old man with right-sided metastatic colorectal cancer and history of 5-FU cardiotoxicity had a progressive disease after 8-month therapy with irinotecan and bevacizumab. In consideration of known 5-FU cardiotoxicity, he was referred to our department for therapy counselling. We started a combination therapy with S-1, oxaliplatin and bevacizumab. The treatment was well tolerated without any cardiac problems.

Our report confirms the safety of S-1 in cases of 5-FU cardiotoxicity also in a Caucasian patient.

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Radiation-associated peritoneal angiosarcoma

Angiosarcomas account for only 1–2% of all soft tissue sarcomas, with the most common site of origin being in the head and neck region. Peritoneal angiosarcoma is an extremely rare tumour and few cases have been reported previously. Presentation of peritoneal angiosarcoma can be very variable, hence making diagnosis difficult. Herein, we review the current literature and describe a rare case of a patient who presented with haemorrhagic ascites, 17 years after radiotherapy for endometrial carcinoma and was subsequently diagnosed with peritoneal angiosarcoma. Due to extensive disease, surgery was not a viable option. She was started on palliative chemotherapy, but despite treatment, her condition deteriorated further and she eventually passed away. We highlight the diagnostic challenges and considerations in these patients as well as current treatment and management options available.

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Sesamoid osteonecrosis treated with radial extracorporeal shock wave therapy

Sesamoid osteonecrosis is a disabling condition resulting in severe forefoot pain, for which there are limited treatment options. We present a 52-year-old man with 1-year history of pain, aggravated by walking and playing tennis. On examination, pain was localised to plantar aspect of the first metatarsophalangeal joint. Imaging revealed evolving end-stage avascular necrosis of lateral sesamoid with early secondary degenerative changes. Previous exhaustive conservative treatment had been unsuccessful in alleviating his pain. As an alternative to surgery, radial extracorporeal shock wave therapy (rESWT) was proposed. Treatment protocol was 2000 pulses at frequency of 5 Hz, and pressure was varied from 1.2 to 1.8 bar according to patient tolerance. A total of eight sessions were delivered. At completion of treatment, the patient reported minimal discomfort to no pain and was able to return to playing tennis with no recurrence. We propose rESWT to be an effective novel conservative treatment for sesamoid osteonecrosis.

http://ift.tt/2rvo7wv

Cardiac compression due to gastric volvulus: an unusual cause of chest pain

A 42-year-old man was admitted to coronary care for assessment with severe retrosternal chest pain. Echocardiography showed significant external compression of the left atrium. A subsequent CT scan revealed him to have a large hiatus hernia, with most of his stomach herniating into his thorax causing left atrial compression and gastric volvulus. He subsequently underwent successful emergency decompression of the gastric volvulus and repair of his hiatus hernia.

http://ift.tt/2qbF8HT

A Syrian man with abdominal pain

A 32-year-old man presented with progressive abdominal pain, nausea and vomiting after swallowing a packet of dollar bills, his entire money savings, during his journey to Europe as a refugee. Subsequent imaging confirmed the presence of a foreign body in his stomach, which required surgical intervention to be removed. This is one of many cases that illustrate the hopeless circumstances people in the Middle-Eastern warzone are currently facing.

http://ift.tt/2rvw9FD

'The dark pancreas: classic CT appearance of total pancreatic lipomatosis

Description

A 31-year-old male patient presented with a history of chronic abdominal pain and progressive loss of weight. Patient also had massive steatorrhea and had been a chronic alcoholic. There was no history of diabetes mellitus, tuberculosis or hypertension. Laboratory investigations revealed profound hypoproteinaemia. Patient underwent a contrast-enhanced CT of the abdomen. It demonstrated a striking 'dark' pancreas showing an attenuation of –88 Hounsfield units corresponding to fat (figure 1). No obvious enhancing solid component was seen. Careful review of the multiplanar CT reconstruction images confirmed the presence of dilated pancreatic duct with multiple intraductal calculi (figure 2). The CT findings were diagnostic of total pancreatic lipomatosis secondary to obstructed pancreatic ductal system by calculi/chronic calcific pancreatitis. Patient was managed conservatively using pancreatic enzyme replacement therapy.

Figure 1

Axial contrast-enhanced CT image shows the dark, hypoattenuating pancreatic parenchyma corresponding to fat. Note the...

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Caution advised with dapagliflozin in the setting of male urinary tract outlet obstruction

We describe an adverse outcome in a 70-year-old man with type 2 diabetes mellitus treated with sodium–glucose cotransporter type 2 (SGLT2) inhibitor dapagliflozin. SGLT2 inhibitors act in the proximal tubules to prevent glucose reabsorption and induce urinary glucose excretion, they have been associated with increased risk of urinary tract infection (UTI). Our patient presented to hospital with Escherichia coli septicaemia with positive urine and blood cultures on the background of two previous UTIs occurring post commencement of dapagliflozin in the community. Renal tract ultrasound in hospital revealed incomplete bladder emptying with evidence of urinary stasis, and a postvoid residual volume of 180 mL. His dapagliflozin was ceased, and he has had no further episodes of UTI. This case suggests there may be an increased risk of UTI in patients prescribed SGLT2 inhibitors who also have evidence of bladder outlet obstruction—caution is advised in the prescribing of SGLT2 inhibitors in this setting.

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Back pain and oedematous Schmorl node: a diagnostic dilemma

A 26-year-old female from India presented with progressive, unremitting low back pain for over 1 year. She had been treated unsuccessfully for left-sided sacroiliitis, pelvic floor dysfunction, ankylosing spondylitis and seronegative spondyloarthritis. MRI lumbar spine showed a Schmorl node with surrounding marrow oedema at L4, the relevance of which is not clear in literature. One year after initial presentation, a biopsy of this lesion revealed culture positive diagnosis of spinal tuberculosis. Despite advances in imaging, delayed diagnosis is not uncommon in spinal tuberculosis (TB). In our case, it was also attributed to an unknown early lesion: Schmorl node with surrounding oedema. Any association of this lesion with spinal TB has previously not been reported.

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Racial Differences in 20-Year Cardiovascular Mortality Risk Among Childhood and Young Adult Cancer Survivors

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


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From the Editor-in-Chief's Desk

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


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Risk factors for patient-reported errors during cancer follow-up: Results from a national survey in Denmark

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Anne Hjøllund Christiansen, Henriette Lipczak, Janne Lehmann Knudsen, Anne Mette Tranberg Kejs
Due to an increased cancer survival, more cancer patients are referred to follow-up after primary treatment. Knowledge of patient safety during follow-up is sparse.ObjectiveTo examine patient-reported errors during cancer follow-up and identify factors associated with errors.DesignA national survey on cancer patients' experiences of treatment and aftercare was conducted in 2012, about two years following cancer diagnosis (N=6914). Associations between patient-reported errors during follow-up and covariates were examined using multiple logistic regression. Qualitative responses were analysed using text analysis.ResultsThis study included 3731 patients, representing a response rate of 64%. Overall, 27.6% of patients reported at least one error during cancer follow-up. 11.7% reported that important information was missing at follow-up consultations; 9.8% were not called in for a follow-up as expected; 16.7% reported that the doctor/nurse handling the follow-up consultation were ill-prepared on their course of disease. Other errors were reported by 4.7%. Patients who reported errors in follow-up were more likely to report an error or complication during primary cancer treatment, not having one health professional with oversight and responsibility for their overall follow-up pathway, be younger, have a diagnosis of rare cancer, poorer self-rated health and high usage of healthcare services.ConclusionWorkflows related to handling of test results, referrals, bookings and medical records have to be improved. Introduction of one particular healthcare professional responsible for the patients' follow-up may result in fewer patient-reported errors however interventions are needed to examine this. Patients prone to errors should be subject to particular attention.



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MicroRNA-196b-5p regulates colorectal cancer cell migration and metastases through interaction of HOXB7 and GALNT5

Purpose: MicroRNA-196b-5p (miR-196b-5p) has been previously implicated in malignant transformation, however, its role in colorectal cancer (CRC) has not been fully explored. In the current study, we examine the clinical and biological relevance of miR-196b-5p, and the molecular pathways regulated by miR-196b-5p in CRC. <p>Experimental design: MiR-196b-5p expression was quantitated by qRT-PCR in two independent cohorts comprised of 292 CRC patients in total, to explore its biomarker potential. Transient and stable gain and loss of function experiments were conducted in a panel of CRC cell lines and mice, to evaluate the impact of miR-196b-5p on proliferation, chemo-sensitivity, migration/invasion and metastases formation in vitro and in vivo. The molecular pathways influenced by miR-196b-5p were characterized using whole transcriptome profiling, in-silico target prediction tools, luciferase-interaction assays, and pheno-copy/rescue gene knock-down experiments.</p> <p>Results: Low miR-196b-5p expression was significantly associated with metastases and poor outcomes in two independent CRC patient cohorts (p<0.05, log-rank test). MiR-196b-5p inhibition led to significantly increased CRC cell migration/invasion and metastases formation in mice, whereas ectopic overexpression showed the opposite phenotype. Molecular profiling and target confirmation identified an interaction between miR-196b-5p and HOXB7 and GALNT5, which in turn regulate CRC cell migration.</p> <p>Conclusions: The association of low levels of miR-196b-5p and poor prognosis in CRC patients can be explained by its influence on cancer cell migration and metastases formation. MiR-196b-5p impacts CRC progression pathways through direct interaction with genes involved in cancer cell migration.

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Detecting the Presence and Progression of Premalignant Lung Lesions via Airway Gene Expression

Purpose:  Lung cancer (LC) is the leading cause of cancer death in the US. The molecular events preceding the onset of disease are poorly understood and no effective tools exist to identify smokers with premalignant lesions (PMLs) that will progress to invasive cancer. Prior work identified molecular alterations in the smoke-exposed airway field of injury associated with LC.  Here we focus on an earlier stage in the disease process leveraging the airway field of injury to study PMLs and its utility in LC chemoprevention.<br />Experimental Design: Bronchial epithelial cells from normal appearing bronchial mucosa were profiled by mRNA-Seq from subjects with (n=50) and without (n=25) PMLs. Using surrogate variable and gene set enrichment analysis we identified genes, pathways, and LC-related gene sets differentially expressed between subjects with and without PMLs.  A computational pipeline was developed to build and test a chemoprevention-relevant biomarker.<br />Results:  We identified 280 genes in the airway field associated with the presence of PMLs.  Among the up-regulated genes, oxidative phosphorylation was strongly enriched and immunohistochemistry and bioenergetics studies confirmed pathway findings in PMLs. The relationship to PMLs and squamous cell carcinomas (SCC) was also confirmed using published LC datasets. The biomarker performed well predicting the presence of PMLs (AUC=0.92, n=17), and changes in the biomarker score associated with progression/stability vs. regression of PMLs (AUC=0.75, n=51).<br />Conclusions:  Transcriptomic alterations in the airway field of smokers with PMLs reflect metabolic and early lung SCC alterations and may be leveraged to stratify smokers at high-risk for PML progression and monitor outcome in chemoprevention trials.

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Multi-functional effects of a small-molecule STAT3 inhibitor on NASH and HCC in mice

Purpose: The incidence of hepatocellular carcinoma (HCC) is increasing in the United States and liver cancer is the second leading cause of cancer-related mortality worldwide. Non-alcoholic steatohepatitis (NASH) is becoming an important risk for HCC and most patients with HCC have underlying liver cirrhosis and compromised liver function, which limit treatment options. Thus, novel therapeutic strategies to prevent or treat HCC in the context of NASH and cirrhosis are urgently needed. <br /><br />Experimental Design: Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in HCC tumors. STAT3 signaling plays a pivotal role in HCC survival, growth, angiogenesis and metastasis. We identified C188-9, a novel small-molecule STAT3 inhibitor using computer-aided rational drug design. In this study, we evaluated the therapeutic potential of C188-9 for HCC treatment and prevention. <br /><br />Results: C188-9 showed antitumor activity in vitro in three HCC cell lines. In mice with hepatocyte-specific deletion of Pten (HepPten- mice), C188-9 treatment blocked HCC tumor growth, reduced tumor development, and reduced liver steatosis, inflammation and bile ductular reactions, resulting in improvement of the pathological lesions of NASH. Remarkably, C188-9 also greatly reduced liver injury in these mice as measured by serum AST and ALT levels. Analysis of gene expression showed that C188-9 treatment of HepPten- mice resulted in inhibition of signaling pathways downstream of STAT3, STAT1, TREM-1, and Toll-like receptors. In contrast, C188-9 treatment increased liver specification and differentiation gene pathways. <br /><br />Conclusions: Our results suggest that C188-9 should be evaluated further for the treatment and/or prevention of HCC.

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Fractionated radiation therapy stimulates anti-tumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD1 blockade

Purpose: Radiotherapy (RT) is a highly effective anti-cancer treatment forming part of the standard of care for the majority of patients, but local and distal disease recurrence remains a major cause of mortality. RT is known to enhance tumor immunogenicity; however, the contribution and mechanisms of RT induced immune responses are unknown. <p>Experimental Design: The impact of low-dose fractionated RT (5 x 2 Gy) alone and in combination with αPD-1 mAb on the tumor microenvironment was evaluated by flow cytometry and next-generation sequencing (NGS) of the T-cell receptor (TCR)-repertoire. A dual-tumor model was used, with fractionated RT delivered to a single tumor site to enable evaluation of the local and systemic response to treatment and ability to induce abscopal responses outside the radiation field.</p> <p>Results: We show that fractionated RT leads to T-cell infiltration at the irradiated site; however, the TCR landscape remains dominated by polyclonal expansion of pre-existing T-cell clones. Adaptive resistance via the PD-1/PD-L1 pathway restricts the generation of systemic anti-cancer immunity following RT which can be overcome through combination with αPD-1 mAb leading to improved local and distal tumor control. Moreover, we show that effective clearance of tumor following combination therapy is dependent on both T-cells resident in the tumor at the time of RT and infiltrating T-cells.</p> <p>Conclusions: These data provide evidence that RT can enhance T-cell trafficking to locally-treated tumor sites and augment pre-existing anti-cancer T-cell responses with the capacity to mediate regression of out-of-field tumor lesions when delivered in combination with αPD-1 mAb therapy.

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MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer

Purpose: <br />The phase 2 MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor positive (HR+), HER2- metastatic breast cancer (MBC). <br /><br />Experimental Design: <br />MONARCH 1 was a phase 2 single arm open-label study. Women with HR+/HER2- MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS) and overall survival (OS).<br /><br />Results: <br />Patients (n=132) had a median of 3 (range 1-8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastatic sites. At the 12 month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI: 13.3, 27.5; 15% not excluded); clinical benefit rate (CR+PR+SD≥6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%). <br /><br />Conclusions:<br /> <p>In this poor-prognosis, heavily pre-treated population with refractory HR+/HER2- metastatic breast cancer, continuous dosing of single agent abemaciciclib was well tolerated and exhibited promising clinical activity.

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IGF1R Protein Expression Is Not Associated with Differential Benefit to Concurrent Trastuzumab in Early-Stage HER2+ Breast Cancer from the North Central Cancer Treatment Group (Alliance) Adjuvant Trastuzumab Trial N9831

Background: Preclinical evidence indicates that increased insulin-like growth factor receptor-1 (IGF1R) signaling interferes with the action of trastuzumab suggesting a possible mechanism of trastuzumab resistance. Thus, we evaluated IGF1R prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the prospective phase III HER2⁺ adjuvant N9831 trial.

Methods: IGF1R protein expression was determined in tissue microarray sections (three cores per block; N = 1,197) or in whole tissue sections (WS; N = 537) using IHC (rabbit polyclonal antibody against IGF1R β-subunit). A tumor was considered positive (IGF1R⁺) if any core or WS had ≥1+ membrane staining in >0% invasive cells. Median follow-up was 8.5 years.

Results: Of 1,734 patients, 708 (41%) had IGF1R⁺ breast tumors. IGF1R⁺ was associated with younger age (median 48 vs. 51, P = 0.007), estrogen receptor/progesterone receptor positivity (78% vs. 35%, P < 0.001), nodal positivity (89% vs. 83%, P < 0.001), well/intermediate grade (34% vs. 24%, P < 0.001), tumors ≥2 cm (72% vs. 67%, P = 0.02) but not associated with race or tumor histology. IGF1R did not affect DFS within arms. Between Arms A and C, patients with IGF1R⁺ and IGF1R^– tumors had DFS HRs of 0.48 (P ≤ 0.001) and 0.68 (P = 0.009), respectively (P_interaction = 0.17). Between Arms A and B, patients with IGF1R⁺ and IGF1R^– tumors had DFS HRs of 0.83 (P = 0.25) and 0.69 (P = 0.01), respectively (P_interaction = 0.42).

Conclusions: In contrast to preclinical studies that suggest a decrease in trastuzumab sensitivity in IGF1R⁺ tumors, our adjuvant data show benefit of adding trastuzumab for patients with either IGF1R⁺ and IGF1R^– breast tumors. Clin Cancer Res; 1–9. ©2016 AACR.

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Comparison of particle beam therapy and stereotactic body radiotherapy for early stage non-small cell lung cancer: A systematic review and hypothesis-generating meta-analysis

To assess hypo-fractionated particle beam therapy (PBT)'s efficacy relative to that of photon stereotactic body radiotherapy (SBRT) for early stage (ES) non-small cell lung cancer (NSCLC).

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Irradiation in a flash: Unique sparing of memory in mice after whole brain irradiation with dose rates above 100Gy/s

This study shows for the first time that normal brain tissue toxicities after WBI can be reduced with increased dose rate. Spatial memory is preserved after WBI with mean dose rates above 100Gy/s, whereas 10Gy WBI at a conventional radiotherapy dose rate (0.1Gy/s) totally impairs spatial memory.

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Efficacy of postoperative radiation treatment for bone metastases in the extremities

Impending or pathological fractures due to bone metastases may require surgical fixation. Postoperative radiation is often recommended to reduce local progression and prevent prosthesis displacement, hence reducing the need for second surgery. The objectives of this study were to investigate the need for second surgery, and to report on rates of re-irradiation, tumor progression and prosthesis displacement following postoperative radiation.

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Enzymatic inactivation of endogenous IgG by IdeS enhances therapeutic antibody efficacy

Endogenous plasma IgG sets an immunological threshold that dictates the activity of tumor-directed therapeutic antibodies. Saturation of cellular antibody receptors by endogenous antibody limits antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Here we show how enzymatic cleavage of IgG using the bacterial enzyme IdeS can be utilized to empty both high and low affinity Fc-receptors and clear the entire endogenous antibody pool. Using in vitro models, tumor animal models as well as ex vivo analysis of sera collected during a previous clinical trial with IdeS, we show how clearing of competing plasma antibody levels with IdeS unblocks cellular antibody receptors. We show that therapeutic antibodies against breast cancer (trastuzumab), colon cancer (cetuximab) and lymphomas (rituximab and alemtuzumab) can be potentiated when endogenous IgG is removed. Overall, IdeS is shown to be a potent tool to reboot the human antibody repertoire and to generate a window to preferentially load therapeutic antibodies onto effector cells and thereby create an armada of dedicated tumor seeking immune cells.

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Metformin Inhibits Cellular Proliferation and Bioenergetics in Colorectal Cancer Patient-Derived Xenografts

There is increasing pre-clinical evidence suggesting that metformin, an anti-diabetic drug, has anti-cancer properties against various malignancies including colorectal cancer (CRC). However, majority of evidence which were derived from cancer cell lines and xenografts are likely to overestimate the benefit of metformin since these models are inadequate and require supraphysiological levels of metformin. Here, we generated patient-derived xenografts (PDX) lines from 2 CRC patients to assess the properties of metformin and 5-fluorouracil (5-FU), the first-line drug treatment for CRC. Metformin (150 mg/kg) as a single agent inhibits the growth of both PDX tumours by at least 50% (p < 0.05) when administered orally for 24 days. In one of the PDX models, metformin given concurrently with 5-FU (25 mg/kg) leads to an 85% (p = 0.054) growth inhibition. Ex vivo culture of organoids generated from PDX demonstrate that metformin inhibits growth by executing metabolic changes to decrease oxygen consumption and activating AMPK-mediated pathways. In addition, we also performed genetic characterizations of serial PDX samples with corresponding parental tissues from patients using next generation sequencing (NGS). Our pilot NGS study demonstrates that PDX represent a useful platform for analysis in cancer research since it demonstrates high fidelity with parental tumour. Furthermore, NGS analysis of PDX may be useful to determine genetic identifiers of drug response. This is the first pre-clinical study using PDX and PDX-derived organoids to investigate the efficacy of metformin in colorectal cancer. <br />

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Metformin synergizes with BCL-XL/BCL-2 inhibitor ABT-263 to induce apoptosis specifically in p53-defective cancer cells

p53 deficiency, a frequent event in multiple kinds of malignancies, decreases the sensitivity of diverse targeted chemotherapeutics including the BCL-XL/BCL-2 inhibitor ABT-263. Loss of p53 function can activate mTOR complex 1 (mTORC1), which may make it a vulnerable target. Metformin has shown anti-neoplastic efficiency partially through suppressing mTORC1. However, it remains unknown whether mTORC1 activation confers ABT-263 resistance and whether metformin can overcome it in the p53-defective contexts. In this study, we for the first time demonstrated that metformin and ABT-263 synergistically elicited remarkable apoptosis through orchestrating the pro-apoptotic machineries in various p53-defective cancer cells. Mechanistic studies revealed that metformin sensitized ABT-263 via attenuating mTORC1-mediated cap-dependent translation of MCL-1 and SURVIVIN, and weakening internal ribosome entry site (IRES)-dependent translation of XIAP. Meanwhile, ABT-263 sensitized metformin through disrupting the BCL-XL/BIM complex. However, metformin and ABT-263 had no synergistic killing effect in p53 wild type (p53-WT) cancer cells because the cotreatment dramatically induced the senescence-associated secretory phenotype (SASP) in the presence of wild type p53, and SASP could aberrantly activate the AKT/ERK-mTORC1-4EBP1-MCL-1/SURVIVIN signaling axis. Blocking the axis using corresponding kinase inhibitors or neutralizing antibodies against different SASP components sensitized the cotreatment effect of metformin and ABT-263 in p53-WT cancer cells. The in vivo experiments showed that metformin and ABT-263 synergistically inhibited the growth of p53-defective (but not p53-WT) cancer cells in tumor-xenograft nude mice. These results suggest that the combination of metformin and ABT-263 may be a novel targeted therapeutic strategy for p53-defective cancers.

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Akt signaling is sustained by a CD44 splice isoform-mediated positive feedback loop

Tumor cells nearly invariably evolve sustained PI3K/Akt signaling as an effective means to circumvent apoptosis and maintain survival. However, for those tumor cells that do not acquire PI3K/Akt mutations to achieve this end the underlying mechanisms have remained obscure. Here we describe the discovery of a splice isoform-dependent positive feedback loop that is essential to sustain PI3K/Akt signaling in breast cancer. Splice isoform CD44s promoted expression of the hyaluronan synthase HAS2 by activating the Akt signaling cascade. The HAS2 product hyaluronan (HA) further stimulated CD44s-mediated Akt signaling, creating a feed-forward signaling circuit that promoted tumor cell survival. Mechanistically, we identified FOXO1 as a bona fide transcriptional repressor of HAS2. Akt-mediated phosphorylation of FOXO1 relieved its suppression of HAS2 transcription, with FOXO1 phosphorylation status maintained by operation of the positive feedback loop. In clinical specimens of breast cancer, we established that the expression of CD44s and HAS2 were positively correlated. Our results establish a positive feedback mechanism that sustains PI3K/Akt signaling in tumor cells, further illuminating the nearly universal role of this pathway in cancer cell survival.

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VHL inactivation in precancerous kidney cells induces an inflammatory response via ER stress-activated IRE1{alpha} signaling

Mutations and epigenetic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) are major causes of clear-cell renal cell carcinoma (ccRCC) that may originate from chronic inflammation. However, the role of VHL loss-of-function in the development of ccRCC via inflammation remains poorly understood. VHL mutant cells exhibit metabolic abnormalities that can cause chronic endoplasmic reticulum (ER) stress and unfolded protein response (UPR). We hypothesize that unresolved ER stress induces the inflammatory responses observed in ccRCC. ER stress markers including BiP and XBP1s were significantly increased in cultured and primary VHL loss-of-function kidney cells. In epithelial cells, the kinase activity of IRE1α was required for the induction of NFκB and JNK and for the recruitment of macrophages. IRE1α kinase activity was also important for the development of fibrotic phenotype in conditional Vhlh knockout mice. Our results offer insights into the therapeutic potential against ccRCC development by relieving metabolic stress. Such cancer prevention strategy may be critical for high-risk cohorts such as the familial VHL disease patients.

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Chimeric PD-1:28 receptor upgrades low-avidity T cells and restores effector function of tumor-infiltrating lymphocytes for adoptive cell therapy

Inherent intermediate-to-low affinity T cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity. Upgrading the function of low-avidity T cells without changing the TCR affinity will allow a large arsenal of low-avidity T cells previously thought to be therapeutically inefficient to be considered for ATT. PD-1:28 engineering re-instated Th1 function in tumor-infiltrating lymphocytes (TILs) that had been functionally disabled in the human renal cell carcinoma (RCC) environment without unleashing undesired Th2 cytokines or IL-10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways. In mouse tumor models of ATT, PD-1:28 engineering enabled low-avidity T cells to proliferate stronger and prevented PD-L1 upregulation and Th2 polarization in the tumor milieu. Engineered T cells combined with checkpoint blockade secreted significantly more IFN-γ compared to T cells without PD-1:28, suggesting a beneficial combination with checkpoint blockade therapy or other therapeutic strategies. Altogether, the supportive effects of PD-1:28 engineering on T cell function makes it an attractive tool for ATT.

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Prognostic value of visceral pleural invasion in non-small cell lung cancer: A propensity score matching study based on the SEER registry

Background and Objectives

Visceral pleural invasion (VPI) is considered a poor prognostic factor in non-small cell lung cancer (NSCLC). We aimed to analyze the effect of VPI on cancer-specific survival, using propensity score matching (PSM) based on the Surveillance, Epidemiology, and End Results database.

Methods

We identified 9901 patients with T1-2N0-2M0 who received segmentectomy, lobectomy, or pneumonectomy. Ten covariates were included in PSM. The effect of VPI on survival was assessed, stratified by nodal status and tumor size.

Results

One-thousand and eighty-three pairs of patients were matched with standardized differences of covariates <10% after matching. We found that VPI was associated with a significantly worse survival (3-year survival rate: 84.6% vs. 75.9%, P = 0.005), especially in N0 (P < 0.001), but not in N1 or N2. No significant difference was observed between the extent of VPI. Moreover, VPI conferred a significantly worse survival in tumors >1-2 (P = 0.034) and >2–3 cm (P < 0.001), not ≤1, >3-4, or >4-5 cm in N0.

Conclusions

VPI is a poor prognostic factor; but with increasing tumor size and nodal stage, its negative effect disappears. Our findings support current staging system which assigns higher T-stage for early >1-2 and >2-3 cm tumors.

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The efficacy of systematic lymph node dissection in advanced epithelial ovarian cancer during interval debulking surgery performed after neoadjuvant chemotherapy

Background and Objective

The therapeutic role of systematic lymph node dissection (LND) remains unclear in advanced epithelial ovarian cancer (EOC), especially during interval debulking surgery (IDS) performed after neoadjuvant chemotherapy (NAC). We analyzed the therapeutic and prognostic roles of systematic LND in advanced EOC patients.

Methods

Data from consecutive patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV disease, who underwent optimal IDS (<1cm) after NAC, were obtained via a retrospective chart review. Patients were classified into a lymph node sampling (LNS; node count <20) group and an LND (node count ≥20) group.

Results

Among 133 study patients, 65 and 68 underwent LND and LNS, respectively, during IDS. Overall survival (OS) was significantly better in the LND group than in the LNS group. In subgroup analysis with negative lymphadenopathy on preoperative imaging, progression-free survival (PFS) and OS were significantly better in the LND group than in the LNS group. Follow-up of subsequent recurrences showed significantly lower nodal and peritoneal recurrence rates among patients who underwent LND. Multivariate analysis identified LND as an independent prognostic factor for PFS and OS.

Conclusion

Systematic LND may have therapeutic value in advanced EOC patients treated with NAC and IDS.

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The prognostic importance of scalp location in primary head and neck melanoma

Background and Objectives

For patients with cutaneous melanoma, primary tumors located in the head and neck is associated with poor outcomes. The reason for this difference and whether it is applicable to all locations within the head and neck remains unclear. We hypothesized that scalp melanoma is uniquely distinguished from other anatomic sites and is independently responsible for the poor prognosis of head and neck melanoma.

Methods

Query and analysis of a prospectively maintained melanoma database of all patients treated for primary cutaneous melanoma from 1971 to 2010.

Results

Of 11 384 patients identified, 7% (n = 799) of lesions originated on the scalp. Scalp primaries were more often found in males and were associated with increased Breslow thickness and were more frequently ulcerated compared to all other anatomic sites (P = 0.0001). On multivariate analysis, scalp location was an independent predictor of worse melanoma-specific (HR 1.75; CI 1.50-2.04; P < 0.0001) and overall survival (HR 1.62; CI 1.41-1.86; P < 0.0001).

Conclusions

This, the largest series examining scalp melanoma, confirms that scalp location is independently responsible for the negative prognosis associated with head and neck melanoma. Although the pathophysiology of this difference remains to be determined, these data argue for more rigorous surveillance of this anatomic location.

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Regional immunotherapy for liver and peritoneal metastases

Pancreatic adenocarcinoma is a biologically aggressive disease, with liver and peritoneal metastases being a frequent cause of death. We examine how the pancreatic carcinoma microenvironment and immunosuppressive landscape favor tumor progression. Immunotherapy has shown promise in select solid tumors, yet challenges remain in applying these gains to stage IV pancreatic adenocarcinoma. We discuss how regional therapy strategies may be leveraged to open new avenues for treating pancreatic carcinoma metastases with immunotherapy.

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“Heat shock protein 70 in pancreatic diseases: Friend or foe”

The heat shock response in pancreatitis that is activated via HSP70 protects acinar cells through multiple simultaneous mechanisms. It inhibits trypsinogen activation and modulates NF-κB signaling to limit acinar cell injury. On the other hand, HSP70 is overexpressed in pancreatic cancer and is hijacked by the cellular machinery to inhibit apoptosis. Inhibition of HSP70 in pancreatic cancer by a novel compound, Minnelide, has shown considerable clinical promise.

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Mechanical analysis of the vascularized fibular graft prosthetic composite (VFGPC) for internal hemipelvectomy reconstruction

INTRODUCTION

The vascularized fibular graft prosthetic composite (VFGPC) is used for reconstruction after internal hemipelvectomy. The purpose of this study was to create a mathematical model that calculates the mechanical effects of the vascularized fibular graft on the VFGPC.

METHODS

The effects of the VFG positioning were calculated based on three-dimensional static analyzes to determine the direction, magnitude, and distribution of the forces through the prosthesis and VFG. The shear stress (SS) and cyclic loads to failure (CLF) were calculated. By varying the location of the VFG on the sacrum the zone of acceptable placement was calculated.

RESULTS

Utilization of the VFG decreased the forces through the implant by 15-35% and decreased SS 20-54%, depending on stance. The CLF improved by 94%. The zone of acceptable placement for the VFG was found to be between 0° and 15° of the vertical axis in the sagittal plane and 0° and 30° of the posterior axis in coronal plane.

CONCLUSION

Determining the position of the VFG pre-operatively allows for the creation of a customized cutting jig can be utilized to create graft allowing for accurate fibular osteotomies, minimization of ischemia time, and decreased intra-operative handling of the graft.

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Akt signaling is sustained by a CD44 splice isoform-mediated positive feedback loop

Tumor cells nearly invariably evolve sustained PI3K/Akt signaling as an effective means to circumvent apoptosis and maintain survival. However, for those tumor cells that do not acquire PI3K/Akt mutations to achieve this end the underlying mechanisms have remained obscure. Here we describe the discovery of a splice isoform-dependent positive feedback loop that is essential to sustain PI3K/Akt signaling in breast cancer. Splice isoform CD44s promoted expression of the hyaluronan synthase HAS2 by activating the Akt signaling cascade. The HAS2 product hyaluronan (HA) further stimulated CD44s-mediated Akt signaling, creating a feed-forward signaling circuit that promoted tumor cell survival. Mechanistically, we identified FOXO1 as a bona fide transcriptional repressor of HAS2. Akt-mediated phosphorylation of FOXO1 relieved its suppression of HAS2 transcription, with FOXO1 phosphorylation status maintained by operation of the positive feedback loop. In clinical specimens of breast cancer, we established that the expression of CD44s and HAS2 were positively correlated. Our results establish a positive feedback mechanism that sustains PI3K/Akt signaling in tumor cells, further illuminating the nearly universal role of this pathway in cancer cell survival.

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VHL inactivation in precancerous kidney cells induces an inflammatory response via ER stress-activated IRE1{alpha} signaling

Mutations and epigenetic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) are major causes of clear-cell renal cell carcinoma (ccRCC) that may originate from chronic inflammation. However, the role of VHL loss-of-function in the development of ccRCC via inflammation remains poorly understood. VHL mutant cells exhibit metabolic abnormalities that can cause chronic endoplasmic reticulum (ER) stress and unfolded protein response (UPR). We hypothesize that unresolved ER stress induces the inflammatory responses observed in ccRCC. ER stress markers including BiP and XBP1s were significantly increased in cultured and primary VHL loss-of-function kidney cells. In epithelial cells, the kinase activity of IRE1α was required for the induction of NFκB and JNK and for the recruitment of macrophages. IRE1α kinase activity was also important for the development of fibrotic phenotype in conditional Vhlh knockout mice. Our results offer insights into the therapeutic potential against ccRCC development by relieving metabolic stress. Such cancer prevention strategy may be critical for high-risk cohorts such as the familial VHL disease patients.

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Chimeric PD-1:28 receptor upgrades low-avidity T cells and restores effector function of tumor-infiltrating lymphocytes for adoptive cell therapy

Inherent intermediate-to-low affinity T cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity. Upgrading the function of low-avidity T cells without changing the TCR affinity will allow a large arsenal of low-avidity T cells previously thought to be therapeutically inefficient to be considered for ATT. PD-1:28 engineering re-instated Th1 function in tumor-infiltrating lymphocytes (TILs) that had been functionally disabled in the human renal cell carcinoma (RCC) environment without unleashing undesired Th2 cytokines or IL-10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways. In mouse tumor models of ATT, PD-1:28 engineering enabled low-avidity T cells to proliferate stronger and prevented PD-L1 upregulation and Th2 polarization in the tumor milieu. Engineered T cells combined with checkpoint blockade secreted significantly more IFN-γ compared to T cells without PD-1:28, suggesting a beneficial combination with checkpoint blockade therapy or other therapeutic strategies. Altogether, the supportive effects of PD-1:28 engineering on T cell function makes it an attractive tool for ATT.

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Circulating tumor DNA profiling reveals clonal evolution and real-time disease progression in advanced hepatocellular carcinoma

Abstract

Circulating tumor DNA (ctDNA) provides a potential non-invasive biomarker for cancer diagnosis and prognosis, but whether it could reflect tumor heterogeneity and monitor therapeutic responses in hepatocellular carcinoma (HCC) is unclear. Focusing on 574 cancer genes known to harbor actionable mutations, we identified the mutation repertoire of HCC tissues, and monitored the corresponding ctDNA features in blood samples to evaluate its clinical significance. Analysis of 3 HCC patients' mutation profiles revealed that ctDNA could overcome tumor heterogeneity and provide information of tumor burden and prognosis. Further analysis was conducted on the 4th HCC case with multiple lesion samples and sequential plasma samples. We identified 160 subclonal SNVs in tumor tissues as well as matched peritumor tissues with PBMC as control. 96.9% of this patient's tissue mutations could be also detected in plasma samples. These subclonal SNVs were grouped into 9 clusters according to their trends of cellular prevalence shift in tumor tissues. Two clusters constituted of tumor stem somatic mutations showed circulating levels relating with cancer progression. Analysis of tumor somatic mutations revealed that circulating level of such tumor stem somatic mutations could reflect tumor burden and even predict prognosis earlier than traditional strategies. Furthermore, HCK (p.V174M), identified as a recurrent/metastatic related mutation site, could promote migration and invasion of HCC cells. Taken together, study of mutation profiles in biopsy and plasma samples in HCC patients showed that ctDNA could overcome tumor heterogeneity and real-time track the therapeutic responses in the longitudinal monitoring. This article is protected by copyright. All rights reserved.

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Hepcidin levels and gastric cancer risk in the EPIC-EurGast Study

Abstract

Hepcidin is the main regulator of iron homeostasis and dysregulation of proteins involved in iron metabolism has been associated with tumorogenesis. However, to date, no epidemiological study has researched the association between hepcidin levels and gastric cancer risk. To further investigate the relationship between hepcidin levels and gastric cancer risk, we conducted a nested case-control study (EURGAST) within the multicentric European Prospective Investigation into Cancer and Nutrition (EPIC) study. The study included 456 primary incident gastric adenocarcinoma cases and 900 matched controls that occurred during an average of 11 years of follow-up. We measured serum levels of hepcidin-25, iron, ferritin, transferrin and C-reactive protein. Odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer by hepcidin levels were estimated from multivariable conditional logistic regression models. Mediation effect of the ferritin levels on the hepcidin-gastric cancer pathway was also evaluated.

After adjusting for relevant confounders, we observed a statistically significant inverse association between gastric cancer and hepcidin levels (OR 5ng/l = 0.96, 95% CI = 0.93-0.99). No differences were found by tumor localization or histological type. In mediation analysis, we found that the direct effect of hepcidin only represents a non-significant 38% (95% CI: -69%, 91%). In summary, these data suggest that the inverse association of hepcidin levels and gastric cancer risk was mostly accounted by ferritin levels. Further investigation including repeated measures of hepcidin is needed to clarify their role in gastric carcinogenesis. This article is protected by copyright. All rights reserved.

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Circulating tumor DNA profiling reveals clonal evolution and real-time disease progression in advanced hepatocellular carcinoma

Abstract

Circulating tumor DNA (ctDNA) provides a potential non-invasive biomarker for cancer diagnosis and prognosis, but whether it could reflect tumor heterogeneity and monitor therapeutic responses in hepatocellular carcinoma (HCC) is unclear. Focusing on 574 cancer genes known to harbor actionable mutations, we identified the mutation repertoire of HCC tissues, and monitored the corresponding ctDNA features in blood samples to evaluate its clinical significance. Analysis of 3 HCC patients' mutation profiles revealed that ctDNA could overcome tumor heterogeneity and provide information of tumor burden and prognosis. Further analysis was conducted on the 4th HCC case with multiple lesion samples and sequential plasma samples. We identified 160 subclonal SNVs in tumor tissues as well as matched peritumor tissues with PBMC as control. 96.9% of this patient's tissue mutations could be also detected in plasma samples. These subclonal SNVs were grouped into 9 clusters according to their trends of cellular prevalence shift in tumor tissues. Two clusters constituted of tumor stem somatic mutations showed circulating levels relating with cancer progression. Analysis of tumor somatic mutations revealed that circulating level of such tumor stem somatic mutations could reflect tumor burden and even predict prognosis earlier than traditional strategies. Furthermore, HCK (p.V174M), identified as a recurrent/metastatic related mutation site, could promote migration and invasion of HCC cells. Taken together, study of mutation profiles in biopsy and plasma samples in HCC patients showed that ctDNA could overcome tumor heterogeneity and real-time track the therapeutic responses in the longitudinal monitoring. This article is protected by copyright. All rights reserved.

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Hepcidin levels and gastric cancer risk in the EPIC-EurGast Study

Abstract

Hepcidin is the main regulator of iron homeostasis and dysregulation of proteins involved in iron metabolism has been associated with tumorogenesis. However, to date, no epidemiological study has researched the association between hepcidin levels and gastric cancer risk. To further investigate the relationship between hepcidin levels and gastric cancer risk, we conducted a nested case-control study (EURGAST) within the multicentric European Prospective Investigation into Cancer and Nutrition (EPIC) study. The study included 456 primary incident gastric adenocarcinoma cases and 900 matched controls that occurred during an average of 11 years of follow-up. We measured serum levels of hepcidin-25, iron, ferritin, transferrin and C-reactive protein. Odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer by hepcidin levels were estimated from multivariable conditional logistic regression models. Mediation effect of the ferritin levels on the hepcidin-gastric cancer pathway was also evaluated.

After adjusting for relevant confounders, we observed a statistically significant inverse association between gastric cancer and hepcidin levels (OR 5ng/l = 0.96, 95% CI = 0.93-0.99). No differences were found by tumor localization or histological type. In mediation analysis, we found that the direct effect of hepcidin only represents a non-significant 38% (95% CI: -69%, 91%). In summary, these data suggest that the inverse association of hepcidin levels and gastric cancer risk was mostly accounted by ferritin levels. Further investigation including repeated measures of hepcidin is needed to clarify their role in gastric carcinogenesis. This article is protected by copyright. All rights reserved.

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Prognostic value of visceral pleural invasion in non-small cell lung cancer: A propensity score matching study based on the SEER registry

Background and Objectives

Visceral pleural invasion (VPI) is considered a poor prognostic factor in non-small cell lung cancer (NSCLC). We aimed to analyze the effect of VPI on cancer-specific survival, using propensity score matching (PSM) based on the Surveillance, Epidemiology, and End Results database.

Methods

We identified 9901 patients with T1-2N0-2M0 who received segmentectomy, lobectomy, or pneumonectomy. Ten covariates were included in PSM. The effect of VPI on survival was assessed, stratified by nodal status and tumor size.

Results

One-thousand and eighty-three pairs of patients were matched with standardized differences of covariates <10% after matching. We found that VPI was associated with a significantly worse survival (3-year survival rate: 84.6% vs. 75.9%, P = 0.005), especially in N0 (P < 0.001), but not in N1 or N2. No significant difference was observed between the extent of VPI. Moreover, VPI conferred a significantly worse survival in tumors >1-2 (P = 0.034) and >2–3 cm (P < 0.001), not ≤1, >3-4, or >4-5 cm in N0.

Conclusions

VPI is a poor prognostic factor; but with increasing tumor size and nodal stage, its negative effect disappears. Our findings support current staging system which assigns higher T-stage for early >1-2 and >2-3 cm tumors.

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The efficacy of systematic lymph node dissection in advanced epithelial ovarian cancer during interval debulking surgery performed after neoadjuvant chemotherapy

Background and Objective

The therapeutic role of systematic lymph node dissection (LND) remains unclear in advanced epithelial ovarian cancer (EOC), especially during interval debulking surgery (IDS) performed after neoadjuvant chemotherapy (NAC). We analyzed the therapeutic and prognostic roles of systematic LND in advanced EOC patients.

Methods

Data from consecutive patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV disease, who underwent optimal IDS (<1cm) after NAC, were obtained via a retrospective chart review. Patients were classified into a lymph node sampling (LNS; node count <20) group and an LND (node count ≥20) group.

Results

Among 133 study patients, 65 and 68 underwent LND and LNS, respectively, during IDS. Overall survival (OS) was significantly better in the LND group than in the LNS group. In subgroup analysis with negative lymphadenopathy on preoperative imaging, progression-free survival (PFS) and OS were significantly better in the LND group than in the LNS group. Follow-up of subsequent recurrences showed significantly lower nodal and peritoneal recurrence rates among patients who underwent LND. Multivariate analysis identified LND as an independent prognostic factor for PFS and OS.

Conclusion

Systematic LND may have therapeutic value in advanced EOC patients treated with NAC and IDS.

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The prognostic importance of scalp location in primary head and neck melanoma

Background and Objectives

For patients with cutaneous melanoma, primary tumors located in the head and neck is associated with poor outcomes. The reason for this difference and whether it is applicable to all locations within the head and neck remains unclear. We hypothesized that scalp melanoma is uniquely distinguished from other anatomic sites and is independently responsible for the poor prognosis of head and neck melanoma.

Methods

Query and analysis of a prospectively maintained melanoma database of all patients treated for primary cutaneous melanoma from 1971 to 2010.

Results

Of 11 384 patients identified, 7% (n = 799) of lesions originated on the scalp. Scalp primaries were more often found in males and were associated with increased Breslow thickness and were more frequently ulcerated compared to all other anatomic sites (P = 0.0001). On multivariate analysis, scalp location was an independent predictor of worse melanoma-specific (HR 1.75; CI 1.50-2.04; P < 0.0001) and overall survival (HR 1.62; CI 1.41-1.86; P < 0.0001).

Conclusions

This, the largest series examining scalp melanoma, confirms that scalp location is independently responsible for the negative prognosis associated with head and neck melanoma. Although the pathophysiology of this difference remains to be determined, these data argue for more rigorous surveillance of this anatomic location.

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Regional immunotherapy for liver and peritoneal metastases

Pancreatic adenocarcinoma is a biologically aggressive disease, with liver and peritoneal metastases being a frequent cause of death. We examine how the pancreatic carcinoma microenvironment and immunosuppressive landscape favor tumor progression. Immunotherapy has shown promise in select solid tumors, yet challenges remain in applying these gains to stage IV pancreatic adenocarcinoma. We discuss how regional therapy strategies may be leveraged to open new avenues for treating pancreatic carcinoma metastases with immunotherapy.

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“Heat shock protein 70 in pancreatic diseases: Friend or foe”

The heat shock response in pancreatitis that is activated via HSP70 protects acinar cells through multiple simultaneous mechanisms. It inhibits trypsinogen activation and modulates NF-κB signaling to limit acinar cell injury. On the other hand, HSP70 is overexpressed in pancreatic cancer and is hijacked by the cellular machinery to inhibit apoptosis. Inhibition of HSP70 in pancreatic cancer by a novel compound, Minnelide, has shown considerable clinical promise.

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Mechanical analysis of the vascularized fibular graft prosthetic composite (VFGPC) for internal hemipelvectomy reconstruction

INTRODUCTION

The vascularized fibular graft prosthetic composite (VFGPC) is used for reconstruction after internal hemipelvectomy. The purpose of this study was to create a mathematical model that calculates the mechanical effects of the vascularized fibular graft on the VFGPC.

METHODS

The effects of the VFG positioning were calculated based on three-dimensional static analyzes to determine the direction, magnitude, and distribution of the forces through the prosthesis and VFG. The shear stress (SS) and cyclic loads to failure (CLF) were calculated. By varying the location of the VFG on the sacrum the zone of acceptable placement was calculated.

RESULTS

Utilization of the VFG decreased the forces through the implant by 15-35% and decreased SS 20-54%, depending on stance. The CLF improved by 94%. The zone of acceptable placement for the VFG was found to be between 0° and 15° of the vertical axis in the sagittal plane and 0° and 30° of the posterior axis in coronal plane.

CONCLUSION

Determining the position of the VFG pre-operatively allows for the creation of a customized cutting jig can be utilized to create graft allowing for accurate fibular osteotomies, minimization of ischemia time, and decreased intra-operative handling of the graft.

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Immer wichtiger in Zeiten der Multiresistenz

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 322-322
DOI: 10.1055/s-0042-122774

Georg Thieme Verlag KG Stuttgart · New York

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Wiederaufnahme auf die Intensivstation taugt nicht als Prognosekriterium

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 317-317
DOI: 10.1055/s-0043-109144

Georg Thieme Verlag KG Stuttgart · New York

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Präoperative Vorbereitung: Optimierung pulmonaler Erkrankungen

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 356-366
DOI: 10.1055/s-0042-108926

Lungenerkrankungen wie COPD oder Asthma sind bedeutende Risikofaktoren perioperativer pulmonaler Komplikationen. Die Optimierung dieser Erkrankungen ist deshalb wichtiger Bestandteil des präoperativen Managements. Das Wissen um die Pathophysiologie und medikamentöse Therapie ist dabei essenziell.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Vibrationstraining zur Verbesserung der Critical-Illness-Myopathie?

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 317-318
DOI: 10.1055/s-0043-109145

Georg Thieme Verlag KG Stuttgart · New York

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Präoperative Vorbereitung: Patient Blood Management – Was ist optimal?

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 326-340
DOI: 10.1055/s-0042-108925

Patient Blood Management (PBM) fokussiert auf ein umfassendes Anämiemanagement, die Minimierung (unnötiger) iatrogener Blutverluste und die Ausschöpfung der natürlichen Anämietoleranz mit rationalem Einsatz von Erythrozytenkonzentrat-Transfusionen. Im Mittelpunkt des aktuellen Beitrags stehen die in der präoperativen Phase entscheidenden PBM-Komponenten: Management einer Anämie, prätransfusionelle Vorbereitungen und Management von Antikoagulanzien. Die präoperative Anämie ist ein unabhängiger Risikofaktor für eine erhöhte perioperative Morbidität und Sterblichkeit. Zum frühestmöglichen Zeitpunkt sollte daher vor elektiven Eingriffen die Ursachen der Anämie abgeklärt und bei behandelbaren Ursachen der Anämie eine spezifische Behandlung eingeleitet werden. Die präoperative prätransfusionelle Analytik sollte in Abhängigkeit von der Transfusionswahrscheinlichkeit (und dem Ausgangshämoglobinwert) einem Stufenkonzept folgen und aktuelle hausinterne Daten berücksichtigen. Im Umgang mit (oralen) Antikoagulanzien sollte bereits in der präoperativen Phase eine individuelle Risikostratifizierung erfolgen. Anhand des individuellen Blutungs- und Thromboembolierisikos wird sodann entschieden, ob die Medikation fortgeführt, pausiert oder überbrückt werden muss. Ohne klar definierte Verantwortlichkeiten im präoperativen PBM-Team, Kommunikation und Schulung aller Beteiligten ist langfristig kein Erfolg des präoperativen PBM-Programms zu erwarten.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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ECMO-Therapie: Langzeitüberleben bei respiratorischem Versagen

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 318-319
DOI: 10.1055/s-0043-109143

Georg Thieme Verlag KG Stuttgart · New York

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Kasuistik: ECMO-Einsatz bei hyperkapnischer Hirndruckkrise

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 376-381
DOI: 10.1055/s-0043-103506

Unter der Geburt trübte sich bei einer 29-jährigen Patientin die Vigilanz progredient bis zum Koma. Grund war eine schwere Hirnblutung als Komplikation eines bis dahin nicht erkennbaren HELLP-Syndroms. Nach der zerebralen OP entwickelte die Patientin aggravierend ein schweres ARDS mit Hyperkapnie und kritischem Anstieg des intrakraniellen Druckes. Trotz Kontraindikation war eine ECMO-Therapie für insgesamt 31 Tage letztlich erfolgreich.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Traumapatienten: niedrigere Mortalität unter NOAKs als unter Warfarin

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 319-320
DOI: 10.1055/s-0043-105635

Georg Thieme Verlag KG Stuttgart · New York

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Präoperative Vorbereitung

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 324-325
DOI: 10.1055/s-0043-108751

Georg Thieme Verlag KG Stuttgart · New York

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Infusionsmenge korreliert mit interstitieller Flüssigkeitsansammlung

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 320-321
DOI: 10.1055/s-0043-108530

Georg Thieme Verlag KG Stuttgart · New York

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Präoperative Vorbereitung und Evaluation: der ältere Patient

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 342-355
DOI: 10.1055/s-0042-109286

Aufgrund der steigenden Lebenserwartung müssen sich heutzutage immer mehr ältere und hochbetagte Patienten einer Operation unterziehen – eine Herausforderung für die Chirurgie und insbesondere für die Anästhesiologie. Dieser Beitrag beschreibt, wie altersbedingte Besonderheiten präoperativ erfasst und entsprechende Maßnahmen eingeleitet werden können, um das Risiko der postoperativen Morbidität – oder gar Pflegebedürftigkeit – zu verringern.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Guter Einstieg

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 322-322
DOI: 10.1055/s-0042-108793

Georg Thieme Verlag KG Stuttgart · New York

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Akutschmerztherapie bei Appendektomie

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 367-374
DOI: 10.1055/s-0043-104599

Schmerztherapie spielt in der Chirurgie eine zentrale Rolle. Eine strukturierte Akutschmerztherapie verbessert unmittelbar die Lebensqualität, senkt mittelfristig die Morbidität und verhindert langfristig eine Schmerzchronifizierung – bei deutlichen ökonomischen Vorteilen wie reduzierter Krankenhausverweildauer und kürzerem Krankenstand. Diese 4 Aspekte werden oft und gerade bei scheinbar „kleinen Operationen" stiefmütterlich behandelt.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Pssst … AINS-Secrets: Heute aus der Traumatologie und Orthopädie

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 382-386
DOI: 10.1055/s-0042-101659

Georg Thieme Verlag KG Stuttgart · New York

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Masterplan Medizinstudium 2020

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 313-313
DOI: 10.1055/s-0043-109409

Georg Thieme Verlag KG Stuttgart · New York

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Overdiagnostic uncertainty

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Overdiagnostic uncertainty

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Overdiagnostic uncertainty

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Power of pedigree likelihood analysis in extended pedigrees to classify rare variants of uncertain significance in cancer risk genes

Abstract

Rare and private variants of uncertain significance (VUS) are routinely identified in clinical panel, exome, and genome sequencing. We investigated the power of single family co-segregation analysis to aid classification of VUS. We simulated thousands of pedigrees using demographics in China and the United States, segregating benign and pathogenic variants. Genotypes and phenotypes were simulated using penetrance models for Lynch syndrome and breast/ovarian cancer. We calculated LOD scores adjusted for proband ascertainment (LODadj), to determine power to yield quantitative evidence for, or against, pathogenicity of the VUS. Power to classify VUS was higher for Chinese than United States pedigrees. The number of affected individuals explained the most variation in LODadj (21–38%). The distance to the furthest affected relative (FAR) from the proband explained 1–7% of the variation for the benign VUS and Lynch associated cancers. Minimum age of onset (MAO) explained 5–13% of the variation in families with pathogenic breast/ovarian cancer variants. Random removal of 50% of the phenotype/genotype data reduced power and the variation in LODadj was best explained by FAR followed by the number of affected individuals and MAO when the founder was only two generations from the proband. Power to classify benign variants was ~2x power to classify pathogenic variants. Affecteds-only analysis resulted in virtually no power to correctly classify benign variants and reduced power to classify pathogenic variants. These results can be used to guide recruitment efforts to classify rare and private VUS.

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Detection of IKKε by immunohistochemistry in primary breast cancer: association with EGFR expression and absence of lymph node metastasis

Abstract

Background

IKKε is an oncogenic kinase that was found amplified and overexpressed in a substantial percentage of human breast cancer cell lines and primary tumors using genomic and gene expression analyses. Molecular studies have provided the rational for a key implication of IKKε in breast cancer cells proliferation and invasiveness through the phosphorylation of several substrates.

Methods

Here, we performed immunohistochemical detection of IKKε expression on tissue microarrays constituted of 154 characterized human breast cancer tumors. We further determined the association with multiple clinicopathological parameters and 5-years overall, disease-free and distant disease free survival.

Results

We observed expression of IKKε in 60.4% of the breast cancer tumors. IKKε expression status showed no association with a panel of markers used for molecular classification of the tumors, including ER/PR/HER2 status, or with the molecular subtypes. However, IKKε expression was inversely associated with lymph node metastasis status (p = 0.0032). Additionally, we identified a novel association between IKKε and EGFR expression (p = 0.0011).

Conclusions

The unexpected observation of an inverse association between IKKε and lymph node metastasis advocates for larger scale immunohistochemical profiling of primary breast tumors to clarify the role of IKKε in metastasis. This study suggests that breast cancer tumors expressing EGFR and IKKε may be potential targets for drugs aiming at inhibiting IKKε activity or expression.

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Use of the QIAGEN GeneReader NGS system for detection of KRAS mutations, validated by the QIAGEN Therascreen PCR kit and alternative NGS platform

Abstract

Background

The detection of somatic mutations in primary tumors is critical for the understanding of cancer evolution and targeting therapy. Multiple technologies have been developed to enable the detection of such mutations. Next generation sequencing (NGS) is a new platform that is gradually becoming the technology of choice for genotyping cancer samples, owing to its ability to simultaneously interrogate many genomic loci at massively high efficiency and increasingly lower cost. However, multiple barriers still exist for its broader adoption in clinical research practice, such as fragmented workflow and complex bioinformatics analysis and interpretation.

Methods

We performed validation of the QIAGEN GeneReader NGS System using the QIAact Actionable Insights Tumor Panel, focusing on clinically meaningful mutations by using DNA extracted from formalin-fixed paraffin-embedded (FFPE) colorectal tissue with known KRAS mutations. The performance of the GeneReader was evaluated and compared to data generated from alternative technologies (PCR and pyrosequencing) as well as an alternative NGS platform. The results were further confirmed with Sanger sequencing.

Results

The data generated from the GeneReader achieved 100% concordance with reference technologies. Furthermore, the GeneReader workflow provides a truly integrated workflow, eliminating artifacts resulting from routine sample preparation; and providing up-to-date interpretation of test results.

Conclusion

The GeneReader NGS system offers an effective and efficient method to identify somatic (KRAS) cancer mutations.

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Power of PgR expression as a prognostic factor for ER-positive/HER2-negative breast cancer patients at intermediate risk classified by the Ki67 labeling index

Abstract

Background

The Ki67 labeling index (LI) is regarded as a significant prognostic marker in ER-positive/HER2-negative breast cancer patients. The expression of PgR has recently been identified as another prognostic marker. In the present study, we investigated the prognostic utilities and most suitable cut-off values for Ki67 and PgR, and evaluated the relationship between Ki67 LI and PgR expression in ER-positive/HER2-negative breast cancer.

Patients and methods

In the present study, 177 consecutive Japanese women with ER-positive/HER2-negative invasive carcinoma of no special type who were treated between 2000 and 2001 were enrolled. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were analyzed according to Ki67 LI and PgR expression, and significant cut-off values for selecting patients with a poor prognosis were evaluated.

Results

The cut-off values for Ki67 LI as a prognostic marker plotted against P values showed bimodal peaks at 10% and 30%. Among the cut-off points examined for the PgR status, 20% PgR positivity was the most significant for predicting survival differences (RFS: P = 0.0003; CSS: P < 0.0001). A multivariate analysis showed that PgR (≥20%) was an independent prognostic marker (RFS: P = 0.0092; CSS: P = 0.00014). Furthermore, in the intermediate risk group with Ki67 LI of 10–30%, the low PgR <20% group had a markedly poorer prognosis for RFS and CSS (RFS: P < 0.0001; CSS: P < 0.0001).

Conclusions

The expression of PgR is a potent prognostic indicator for evaluating the long-term prognosis of ER-positive/HER2-negative breast cancer, and the most suitable cut-off value was found to be 20%. Furthermore, the PgR status is a powerful method for selecting patients with a poor prognosis among ER-positive/HER2-negative patients at intermediate risk, as assessed using Ki67 LI.

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