Burnout and resilience in anaesthesia and intensive care medicine

1H022H013J02

http://ift.tt/2rHDJvV

Management of elective laryngectomy

1CO12A013A02

http://ift.tt/2rcldbt

A Case Report Demonstrating the Potential Clinical Benefit of Exhaustive Molecular Profiling in an Aggressive Muscle-Invasive High-Grade Metastatic Urothelial Carcinoma

We present a muscle-invasive high-grade metastatic urothelial carcinoma patient, aged 71 years, with rapid progression from the diagnosis and a poor prognosis after 3 lines of treatment. A clinical exhaustive genomic profile was performed with the goal of finding potential actionable molecular alterations. The patient showed significant symptomatic and laboratory improvement with a nonstandard chemotherapy combination treatment identified by the molecular profiling, which would otherwise not have been considered. This approach illustrates the clinical benefit of a comprehensive genomic analysis in an aggressive and refractory urothelial carcinoma.
Case Rep Oncol 2017;10:493–500

http://ift.tt/2r8pMII

Small Cell Cancer of the Genitourinary Tract: A Case Report and Review of the Literature

Small cell carcinoma of the urinary tract is an extremely rare disease with very few cases reported in the literature. Its clinical course is aggressive, and the prognosis is poor. Here, we present a case of metastatic extrapulmonary small cell carcinoma of the upper urinary tract in a 74-year-old African-American male. He initially presented with gross hematuria, 20-pound weight loss, and abdominal pain for 2 months. CT imaging showed a 14.0 × 7.0 × 16.0 cm retroperitoneal mass within the left renal fossa; biopsy revealed a carcinoma which was positive for synaptophysin and chromogranin. The patient also had detectable neuroendocrine cells in his urine cytology, confirming the diagnosis of small cell carcinoma. He was treated with carboplatin and etoposide as extrapolated from the treatment of its pulmonary counterpart. Due to the rarity of urinary tract small cell carcinoma, no randomized studies exist to guide therapy or management.
Case Rep Oncol 2017;10:489–492

http://ift.tt/2rSzTPg

Dermoscopic images of malignant and benign skin lesions

http://sfaki.blogspot.com/2017/06/using-watson-to-diagnose-skin-cancer.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Tilt-induced cardio-inhibitory reflex syncope (BIOSync trial) : 12-item questionnaire to distinguish between complete transient loss of consciousness (i.e., syncope) and pre-syncope or other minor symptoms and, additionally, to provide a standardized categorical description of the clinical presentation of syncope including duration, reproducibility with previous episodes, presence of prodromes, presence of witnesses, context, and consequences of the episode.

http://sfaki.blogspot.com/2017/06/12-item-questionnaire-to-distinguish.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Monoclonal antibodies against IL-5 or IL-5 receptor alpha (mepolizumab, reslizumab, benralizumab), IL-13 (lebrikizumab, tralokinumab), IL-4 receptor alpha (dupilumab), Immune globuline E (IgE) (omalizumab), anti-Thymic Stromal Lymphopoitin (TSLP) (tezepelumab) and small molecule therapies such as prostaglandin D2 blockers (fevipiprant, timapiprant). New Anti-Eosinophil Drugs for asthma and COPD

http://sfaki.blogspot.com/2017/06/monoclonal-antibodies-against-il-5-or.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Planning strategies for inter-fractional robustness in pancreatic patients treated with scanned carbon therapy

Managing inter-fractional anatomy changes is a challenging task in radiotherapy of pancreatic tumors, especially in scanned carbon-ion delivery. This treatment planning study aims to focus on clinically feasib...

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Planning strategies for inter-fractional robustness in pancreatic patients treated with scanned carbon therapy

Managing inter-fractional anatomy changes is a challenging task in radiotherapy of pancreatic tumors, especially in scanned carbon-ion delivery. This treatment planning study aims to focus on clinically feasib...

http://ift.tt/2r7meXv

High expression of COX5B is associated with poor prognosis in breast cancer

Future Oncology Ahead of Print.


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High expression of COX5B is associated with poor prognosis in breast cancer

Future Oncology Ahead of Print.


http://ift.tt/2rHhDKd

High expression of COX5B is associated with poor prognosis in breast cancer

Future Oncology Ahead of Print.


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Clinical outcomes of female breast cancer according to BRCA mutation status

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Deirdre P. Cronin-Fenton, Anders Kjærsgaard, Mette Nørgaard, Inge Søkilde Pedersen, Mads Thomassen, James A. Kaye, Lia Gutierrez, Claire Telford, Jan Lewis, Jerzy E. Tyczynski, Henrik Toft Sørensen
BackgroundTo investigate breast cancer prognosis (disease-free (DFS) and overall survival (OS)) among carriers of germline BRCA mutations (BRCAm) in Denmark.MethodsWe identified all women in Central and Northern Denmark diagnosed with breast cancer during 2004–2011. We retrieved information on germline BRCAm testing from Clinical Genetics departments and clinical/treatment characteristics from population-based medical registries. Follow-up for recurrence, new primary cancer, and mortality extended from 180days after diagnosis until 31/12/2012. We estimated median DFS and OS and five-year cumulative incidence and incidence rates (IR/1000 person-years), and 95% confidence intervals (95% CI), for each outcome.ResultsAmong 9874 patients, 523 (5%) underwent BRCA testing—90 were BRCAm carriers, 433 were BRCA wildtype (BRCAwt). Compared with BRCAwt women, BRCAm carriers were younger, had lower stage, and ER- and HER2- tumors. Median time from diagnosis to BRCA testing was 0.91 years and 1.3 years in BRCAm and BRCAwt women; median follow-up to first event was 3.9 and 3.4 years, respectively. Five-year DFS and OS were higher in BRCAm than BRCAwt women: 88% (95%CI=78.3–93.5) vs. 75.3% (95%CI=70.2–79.6) and 97.8% (95%CI=91.4–99.4) vs 92.2% (95%CI=88.5–94.7), respectively. Five-year IRs of recurrence were 36.7/1000 person-years (95%CI=15.8–72.2) in the BRCAm cohort vs. 58.4 (95%CI=42.9–77.6) in the BRCAwt cohort.ConclusionsBRCAm carriers may have a better prognosis than BRCAwt women. However, limited testing conducted mainly during follow-up, yielded low numbers for precise estimations, and may be attributable to selection bias.



http://ift.tt/2sJeyrw

Erratum to: Sarcopenic overweight is associated with early acute limiting toxicity of anti-PD1 checkpoint inhibitors in melanoma patients

http://ift.tt/2s9oAF2

Outcomes and prognostic factors for relapsed or refractory lymphoma patients in phase I clinical trials

Summary

Background Although safety and prognostic factors for overall survival (OS) have been extensively studied in Phase I clinical trials on patients with solid tumours, data on lymphoma trials are scarce. Here, we investigated safety, outcomes and prognostic factors in relapsed or refractory lymphoma patients included in a series of Phase I trials. Method and patients All consecutive adult patients with recurrent/refractory lymphoma enrolled in 26 Phase I trials at a single cancer centre in France between January 2008 and June 2016 were retrospectively assessed. Results 133 patients (males: 65%) were included in the analysis. The median (range) age was 65 (23–86). Aggressive non-Hodgkin, indolent non-Hodgkin and Hodgkin types accounted for 64%, 25% and 11% of the patients, respectively. The patients had received a median (range) of 3 (1–13) lines of treatment prior to trial entry. The median [95% confidence interval] progression-free survival and OS times were 3.0 [1.8–3.6] and 17.8 [12.7–30.4] months, respectively. High-grade toxicity (grade 3 or higher, according to the National Cancer Institute's Common Terminology Criteria for Adverse Events classification) was experienced by 56 of the 133 patients (42%) and was related to the investigational drug in 44 of these cases (79%). No toxicity-related deaths occurred. Dose-limiting toxicity (DLT) was encountered in 11 (9%) of the 116 evaluable patients. High-grade toxicity occurred during the DLT period for 34 of the 56 patients (61%) and after the DLT period in the remaining 22 (39%). The main prognostic factors for poor OS were the histological type (i.e. tumour aggressiveness), an elevated serum LDH level, and a low serum albumin level. Early withdrawal from a trial was correlated with the performance status score, the histological type and the serum LDH level. The overall objective response and disease control rates were 24% and 57%, respectively. Conclusion Performance status, LDH, albumin and histological type (tumour aggressiveness) appear to be the most relevant prognostic factors for enrolling Phase I participants with relapsed or refractory lymphoma. 39% of the patients experienced a first high-grade toxic event after the dose-limiting toxicity period, suggesting that the conventional concept of dose-limiting toxicity (designed for chemotherapy) should be redefined in the era of modern cancer therapies.

http://ift.tt/2rc0bKf

Clinical outcomes of female breast cancer according to BRCA mutation status

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Deirdre P. Cronin-Fenton, Anders Kjærsgaard, Mette Nørgaard, Inge Søkilde Pedersen, Mads Thomassen, James A. Kaye, Lia Gutierrez, Claire Telford, Jan Lewis, Jerzy E. Tyczynski, Henrik Toft Sørensen
BackgroundTo investigate breast cancer prognosis (disease-free (DFS) and overall survival (OS)) among carriers of germline BRCA mutations (BRCAm) in Denmark.MethodsWe identified all women in Central and Northern Denmark diagnosed with breast cancer during 2004–2011. We retrieved information on germline BRCAm testing from Clinical Genetics departments and clinical/treatment characteristics from population-based medical registries. Follow-up for recurrence, new primary cancer, and mortality extended from 180days after diagnosis until 31/12/2012. We estimated median DFS and OS and five-year cumulative incidence and incidence rates (IR/1000 person-years), and 95% confidence intervals (95% CI), for each outcome.ResultsAmong 9874 patients, 523 (5%) underwent BRCA testing—90 were BRCAm carriers, 433 were BRCA wildtype (BRCAwt). Compared with BRCAwt women, BRCAm carriers were younger, had lower stage, and ER- and HER2- tumors. Median time from diagnosis to BRCA testing was 0.91 years and 1.3 years in BRCAm and BRCAwt women; median follow-up to first event was 3.9 and 3.4 years, respectively. Five-year DFS and OS were higher in BRCAm than BRCAwt women: 88% (95%CI=78.3–93.5) vs. 75.3% (95%CI=70.2–79.6) and 97.8% (95%CI=91.4–99.4) vs 92.2% (95%CI=88.5–94.7), respectively. Five-year IRs of recurrence were 36.7/1000 person-years (95%CI=15.8–72.2) in the BRCAm cohort vs. 58.4 (95%CI=42.9–77.6) in the BRCAwt cohort.ConclusionsBRCAm carriers may have a better prognosis than BRCAwt women. However, limited testing conducted mainly during follow-up, yielded low numbers for precise estimations, and may be attributable to selection bias.



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Erratum to: Sarcopenic overweight is associated with early acute limiting toxicity of anti-PD1 checkpoint inhibitors in melanoma patients

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Outcomes and prognostic factors for relapsed or refractory lymphoma patients in phase I clinical trials

Summary

Background Although safety and prognostic factors for overall survival (OS) have been extensively studied in Phase I clinical trials on patients with solid tumours, data on lymphoma trials are scarce. Here, we investigated safety, outcomes and prognostic factors in relapsed or refractory lymphoma patients included in a series of Phase I trials. Method and patients All consecutive adult patients with recurrent/refractory lymphoma enrolled in 26 Phase I trials at a single cancer centre in France between January 2008 and June 2016 were retrospectively assessed. Results 133 patients (males: 65%) were included in the analysis. The median (range) age was 65 (23–86). Aggressive non-Hodgkin, indolent non-Hodgkin and Hodgkin types accounted for 64%, 25% and 11% of the patients, respectively. The patients had received a median (range) of 3 (1–13) lines of treatment prior to trial entry. The median [95% confidence interval] progression-free survival and OS times were 3.0 [1.8–3.6] and 17.8 [12.7–30.4] months, respectively. High-grade toxicity (grade 3 or higher, according to the National Cancer Institute's Common Terminology Criteria for Adverse Events classification) was experienced by 56 of the 133 patients (42%) and was related to the investigational drug in 44 of these cases (79%). No toxicity-related deaths occurred. Dose-limiting toxicity (DLT) was encountered in 11 (9%) of the 116 evaluable patients. High-grade toxicity occurred during the DLT period for 34 of the 56 patients (61%) and after the DLT period in the remaining 22 (39%). The main prognostic factors for poor OS were the histological type (i.e. tumour aggressiveness), an elevated serum LDH level, and a low serum albumin level. Early withdrawal from a trial was correlated with the performance status score, the histological type and the serum LDH level. The overall objective response and disease control rates were 24% and 57%, respectively. Conclusion Performance status, LDH, albumin and histological type (tumour aggressiveness) appear to be the most relevant prognostic factors for enrolling Phase I participants with relapsed or refractory lymphoma. 39% of the patients experienced a first high-grade toxic event after the dose-limiting toxicity period, suggesting that the conventional concept of dose-limiting toxicity (designed for chemotherapy) should be redefined in the era of modern cancer therapies.

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Human Papillomavirus Vaccine Is Crucial for Adolescent and Young Adult Cancer Survivors

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


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“From Snail Mode to Rocket Ship Mode”: Adolescents and Young Adults' Experiences of Returning to Work and School After Hematopoietic Cell Transplantation

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


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Human Papillomavirus Vaccine Is Crucial for Adolescent and Young Adult Cancer Survivors

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


http://ift.tt/2s9wYEH

“From Snail Mode to Rocket Ship Mode”: Adolescents and Young Adults' Experiences of Returning to Work and School After Hematopoietic Cell Transplantation

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


http://ift.tt/2sJaLKA

Corrigendum to “Risk stratification and pattern of cardiotoxicity in pediatric Ewing sarcoma” [J. Egypt Natl. Cancer Instit. 29 (2017) 53–56]

Publication date: Available online 7 June 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Emad Moussa, Manal Zamzam, Ahmed Kamel, Zeinab Salah, Iman Attia, Lina Gaber, Ranin Soliman, Sameera Ezzat




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Corrigendum to “Risk stratification and pattern of cardiotoxicity in pediatric Ewing sarcoma” [J. Egypt Natl. Cancer Instit. 29 (2017) 53–56]

Publication date: Available online 7 June 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Emad Moussa, Manal Zamzam, Ahmed Kamel, Zeinab Salah, Iman Attia, Lina Gaber, Ranin Soliman, Sameera Ezzat




http://ift.tt/2rH5zbI

Treatment of retroperitoneal sarcoma: current standards and new developments

Purpose of review: Retroperitoneal sarcomas are rare tumors and with complex treatment. In this manuscript we give an overview of current standards in treatment of this disease and discuss new developments. Recent findings: Surgery with complete resection of the primary tumor is still the only curative modality. The role of preoperative radiotherapy is not clear and is currently being investigated in a clinical trial. Neo-adjuvant chemotherapy is not the standard of care but can be considered occasionally when complete resection is uncertain. Local and distant recurrent disease carries a dismal prognosis, although long-term survival can be achieved. Liposarcomas tend to recur locally, whereas distant recurrences are more often seen in leiomyosarcoma and other subtypes. Outcome improves when patients are treated in high volume sarcoma centers. In the metastatic setting, newer systemic agents have recently been approved. Summary: Treatment of retroperitoneal sarcomas is complex and all patients should be treated in a multidisciplinary sarcoma centers. Increasing international collaboration of expert centers in sharing expertise and performing clinical trials might lead to better treatment and improved survival.

http://ift.tt/2s95oY4

Advances in management of hepatocellular carcinoma

Purpose of review: Hepatocellular carcinoma (HCC) is one of the leading causes of death by cancer worldwide due to a dismal prognosis. The aim of this review is to summarize the main advances in the pathophysiology and management of HCC. Recent findings: Genomic analysis has recently delineated the key signaling pathways aberrantly deregulated in HCC (telomere maintenance, cell cycle gene, Wnt/β-catenin, epigenetic modifier, oxidative stress etc.). Major advances in the clinical care of patients with HCC are helping to refine the diagnosis algorithm and tumor staging. Extension of criteria for liver transplantation, but also for liver resection and percutaneous ablation, aims to increase the number of patients being treated in a curative attempt. Moreover, radioembolization is a competitor for transarterial chemoembolization in Barcelona clinic liver cancer B patients, and sorafenib in Barcelona clinic liver cancer C with tumor portal thrombosis. In advanced HCC, sorafenib is the standard of first-line care and regorafenib as a second line. Summary: New concepts on liver resection, percutaneous ablation or liver transplantation aim to extend the numbers of patients treated for HCC in curative attempts. Moreover, immunotherapy (anti death protein 1) and biotherapy adapted to tumor biology seem promising and are currently being tested in advanced stages.

http://ift.tt/2s9rZ79

Long-term survival after cancer: at what cost?

No abstract available

http://ift.tt/2sICjzU

Preclinical models for translational sarcoma research

Purpose of review: Sarcoma is a basket term for mesenchymal tumors for which more than 75 genetically and histologically distinct subtypes are recognized. Therapeutic progress has largely been achieved with classical chemotherapeutic drugs that were tested in empirical clinical trials. However, outcome in metastatic patients remains poor and with few exceptions numerous trials have failed or only provided limited improvement in recent years. Recent findings: Given the genomic heterogeneity, preclinical model systems will be indispensable to identify new molecular targets and to prioritize drugs and drug combinations. Cell culture is still widely used in preclinical sarcoma research to identify potential novel therapeutic approaches and resistance mechanisms. New and improved techniques in genome-wide and proteome-wide screens enable a better characterization. In addition to cell line xenograft mouse models, patient-derived xenografts crucially broadened and improved preclinical studies using primary human samples. Finally, novel strategies for genome editing, like CRISPR/Cas and sleeping beauty transposon, lead to development of novel genetically engineered cell lines and mouse models. Summary: The present review gives a non-comprehensive overview on current model systems used in sarcoma research and discusses their translational relevance. Those include cell lines, subtype-specific patient-derived cell lines and xenografts as well as developments in genome editing and genetically engineered cell lines and mouse models.

http://ift.tt/2sIwwu2

Physical long-term side-effects in young adult cancer survivors: germ cell tumors model

Purpose of review: After the important advances in the treatment of germ cell tumors (GCTs) leading to high cure rates, physical long-term side-effects represent an important cause of death in these young adult survivors. Highlighting these physical long-term side-effects, their monitoring and their prevention modalities is necessary for a better management of these cancer survivors. Recent findings: Impaired fertility, increased risk of developing a second cancer, cardiac, pulmonary, renal and neural toxicity, hearing and vision impairment are the major physical side-effects in young adult cancer survivors. Long-term cardiac toxicity, next to second malignancies, represents life-threatening conditions in testicular cancer survivors. The long-term nephrotoxity in testicular GCTs survivors is most frequently associated to the treatment either in those treated with cisplatin-based chemotherapy, mainly Bleomycine, Etoposide, Cisplatin, or those receiving infradiaphragmatic radiation therapy, whereas pulmonary toxicity is mainly attributed to bleomycin related toxicities. Summary: There are no clear and comprehensive data concerning the monitoring and prevention of long-term side-effects in testicular cancer survivors. Physical activity and interventions in modifiable cardiovascular risk factors and lifestyles may reduce the incidence of long-term side-effects in these cancer survivors.

http://ift.tt/2sICXNC

Editorial introductions

No abstract available

http://ift.tt/2sIP2CE

Integrative medicine in cancer survivors

Purpose of review: Due to medical advances and an aging population, the number of cancer survivors continues to rise. Survivors often experience late and long-term sequelae of cancer and its treatment (e.g., fatigue, pain, fear of recurrence, and stress). As a result, some patients have utilized or expressed interest in integrative medicine (IM) modalities for prevention of recurrence, optimizing health, enhancing quality of life, and managing symptoms. The purpose of this review is to focus on research published during the past year that informs our understanding of the utility of IM for cancer survivors. Recent findings: Physical activity, diet, dietary supplements, mind–body modalities, acupuncture, and massage therapy all may play a role in the management of the physical (e.g., fatigue and pain) and emotional (e.g., anxiety and fear) issues faced by cancer survivors. Summary: IM therapies are appealing to and utilized by many cancer survivors and may reduce symptom burden. Clinicians who provide cancer survivorship care may improve patient care by understanding the evidence for and against their use.

http://ift.tt/2sIzcYy

Adult desmoid tumors: biology, management and ongoing trials

Purpose of review: To summarize the current knowledge about the biology and clinical management of adult desmoid tumors. Recent findings: In the past decade, we have learned that desmoid tumors are driven by alterations of the Wnt/APC/β-catenin pathway, sporadic desmoid tumors are associated with somatic mutations of CTNNB1, and germline mutations of APC and somatic mutations of CTNNB1 are probably mutually exclusive. One-third of desmoid tumors are misdiagnosed; a second pathological opinion is therefore of major importance for desmoid tumor. Surgery is no longer regarded as the cornerstone of desmoid tumors; several retrospective studies have demonstrated the safety of a 'wait and see' policy in sporadic abdominal wall desmoid tumor. Desmoid tumors is no longer regarded as an absolute contraindication for pregnancy. At least two new investigational drugs targeting the Wnt/APC/β-catenin pathway are currently being developed. Summary: The management of desmoid tumors requires multidisciplinary expertise by an experienced team. We must fully understand the physiopathology of the disease (factors influencing the natural history of the disease) and learn how to avoid desmoid tumors occurrence in patients with APC germline mutations, identify reliable prognostic/predictive factors and better assess the efficacy of systemic treatment.

http://ift.tt/2sIllBN

Controversies about fertility and pregnancy issues in young breast cancer patients: current state of the art

Purpose of review: For trying to help physicians in counseling their young patients with breast cancer interested in fertility preservation and future reproductive plans, this manuscript aims to perform an overview of the main available data on 10 controversies in this field. Recent findings: Thanks to the improvement in patients' prognosis, a growing attention towards fertility and pregnancy issues has been given over the past years and is currently provided to young breast cancer patients. However, several grey zones persist in many domains of this field and some physicians are still uncomfortable to deal with these issues. Summary: Despite the great number of breast cancer patients experiencing fertility and pregnancy concerns at the time of diagnosis, the pursuit of fertility preserving strategies is realized only for a small proportion of them. The lack of adequate oncofertility counseling at the time of anticancer treatment decisions and the high costs of fertility preserving procedures can be considered the main explanations for these findings. The several ongoing registries and prospective studies investigating fertility and pregnancy issues in young breast cancer patients are crucial to acquire more robust data and try to address and solve the still unmet controversies in this field.

http://ift.tt/2sICX04

The meaningness of colon cancer sidedness

No abstract available

http://ift.tt/2s9dvEf

Neoadjuvant treatment: a novel standard?

Purpose of review: The aim of this study was to summarize developments in the adjuvant/neoadjuvant chemotherapy of high-risk adult-type soft tissue sarcomas (STS). Recent findings: The role of adjuvant/neaodjuvant chemotherapy in these patients is controversial, with a meta-analysis suggesting a 10% survival benefit. Recently, a randomized controlled trial in high-risk STS of extremities and trunk wall showed a 20% improvement in progression-free and overall survival after three preoperative cycles of epirubicin along with ifosfamide compared with a histology-tailored chemotherapy. This study has major strengths, including the selected high-risk population and the full-dose chemotherapy regimen. However, this was an interim analysis with a short follow-up in a trial originally planned to test the superiority of a histology-driven chemotherapy. As to high-risk patient selection, the new AJCC TNM staging system adds primary tumour site as a stratifying factor, while available prognostic nomograms account for additional criteria. Summary: A recent trial strengthens perioperative chemotherapy as an option for high-risk STS patients within a shared decision-making process. If the final analysis of this trial confirms the currently observed progression-free and overall survival benefits, perioperative chemotherapy may become a standard. Also, new staging tools may refine our ability to select patients with a risk high enough as to deserve chemotherapy.

http://ift.tt/2s9aK5P

Tackling immunomonitoring in gastrointestinal cancer

Purpose of review: The growing awareness that the immune system is a key player in the antitumoral response and the excellent clinical results achieved in some settings with anti-programmed cell death 1 (PD1)/programmed death ligand 1 (PDL1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) drugs has led to the rise of immunotherapy as a supplement or an alternative to conventional cancer treatment. The high costs associated with these therapies, their significant toxicity and the need to understand and circumvent immune escape mechanisms raise the urgent need for immunological assessment of therapy response. The study of the immunological parameters before, during and after treatment is referred to as immunomonitoring. This review discusses the current knowledge of immunomonitoring markers in gastrointestinal cancers. Recent findings: The last decade has seen a collaborative effort to standardize the assays performed in clinical trials to assess response to immunotherapy. Since then, multiple studies have been conducted on blood samples, biopsies and surgical specimens to determine their immunological profiles leading to the identification of several immunological markers possessing a predictive value of response to treatment. Summary: Future research will focus on detangling the predictive value of immune markers in different therapeutic models, and also to develop new noninvasive means to monitor the immune response of patients. Video abstract: http://ift.tt/2rlA6sx .

http://ift.tt/2sIoph7

Thrombotic Thrombocytopenic Purpura Associated With Pegylated Interferon Alfa-2a Use in a Patient With Polycythemia Vera

Pegylated interferon alfa-2a (pegIFNa) is being increasingly used for treatment of myeloproliferative neoplasms; however, its side effects, including autoimmune complications, are not unusual. We report on a 47-year-old woman with polycythemia vera (PV) treated with pegIFNa and in complete hematologic remission who developed thrombotic thrombocytopenic purpura (TTP). To our knowledge, thrombotic microangiopathy has been reported as a side effect of interferon (IFN) use in patients with hepatitis and chronic myeloid leukemia, but not in those with PV. Our patient had a low ADAMTS13 level due to an inhibitor, which normalized after withholding pegIFNa and initiating treatment for TTP with therapeutic plasma exchange and corticosteroids. She experienced refractory TTP, necessitating treatment with rituximab and splenectomy. Postsplenectomy, she developed a high platelet count, warranting the need to restart treatment for PV. However, JAK2^V617F allelic burden by real-time PCR was 0.7%, indicating that the increased platelet count was likely secondary to splenectomy. Therefore, we elected to monitor her counts and JAK2^V617F allelic burden closely. With this case report, we hope to alert treating physicians that TTP should be considered as a complication of pegIFNa therapy in PV and that prompt discontinuation of the drug with necessary treatment should be instituted to prevent fatal complications.

http://ift.tt/2rb6EVH

Oncology Research Program

http://ift.tt/2raJnU0

Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non–clear cell renal carcinoma. These guidelines are developed by a multidisciplinary panel of leading experts from NCCN Member Institutions consisting of medical oncologists, hematologists and hematologic oncologists, radiation oncologists, urologists, and pathologists. The NCCN Guidelines are in continuous evolution and are updated annually or sometimes more often, if new high-quality clinical data become available in the interim.

http://ift.tt/2rGcP7M

NCCN News

http://ift.tt/2raTQ1w

Morphologic and Molecular Characteristics of De Novo AML With JAK2 V617F Mutation

Background: JAK2 V617F mutation (mut) in acute myeloid leukemia (AML) is rare. We describe the clinicopathologic findings of a single-institution series of 11 de novo AML cases with JAK2 V617. Methods: We identified cases of de novo AML with JAK2 V617F over a 10-year period. We reviewed diagnostic peripheral blood and bone marrow (BM) morphologic, cytogenetic, and molecular studies, including next-generation sequencing. The control group consisted of 12 patients with JAK2 wild-type (wt) AML matched for age, sex, and diagnosis. Results: We identified 11 patients (0.5%) with JAK2 V617F, with a median age at diagnosis of 72.5 years (range, 36–90 years). Ten neoplasms were classified as AML with myelodysplasia-related changes and 1 as AML with t(8;21)(q22;q22). All JAK2mut AML cases showed at least bilineage dysplasia, 7 of 11 showed fibrosis, 8 of 11 had an abnormal karyotype, and 5 had deletions or monosomy of chromosomes 5 and 7. Using the European LeukemiaNet (ELN) classification, 9 patients (82%) with JAK2mut AML were intermediate-2 and adverse risk. Cases of JAK2mut AML did not have mutations in other activating signaling pathways (P=.013); 7 (64%) showed additional mutations in at least one gene involving DNA methylation and/or epigenetic modification. Patients with JAK2mut AML had a significantly higher median BM granulocyte percentage (12% vs 3.5%; P=.006) and a higher frequency of ELN intermediate-2 and adverse risk cytogenetics (P=.04) compared with those with JAK2wt AML. JAK2mut AML showed higher circulating blasts, but this difference was not significant (17% vs 5.5%; P=not significant). No difference was seen in the median overall survival rate of patients with JAK2mut AML versus those with JAK2wt AML (14 vs 13.5 months, respectively). Conclusions: De novo JAK2mut AML is rare and frequently found in patients with dysplasia, BM fibrosis, and abnormal karyotype with intermediate- or high-risk features; gene mutations in DNA methylation and epigenetic-modifying pathways; and absence of gene mutations in activating signaling pathways.

http://ift.tt/2rGjaQv

Getting Practical About Recertification

http://ift.tt/2raUXOH

Oncology Research Program

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Integrating Immunotherapy Into the Management of Renal Cell Carcinoma

Before 2005, systemic treatment of metastatic renal cell carcinoma (RCC) was limited to a few minimally effective options. Since then, new agents have emerged targeting the vascular endothelial growth factor and mTOR pathways, which has improved outcomes for patients. Options increased even further beginning in 2015 with 3 new agents, including the addition of nivolumab, the first immune checkpoint inhibitor to demonstrate improved survival in RCC. RCC has long been considered a malignancy with immunogenic potential, and nivolumab offers the potential for durable responses in some patients with a generally tolerable toxicity profile. With so many drugs available to clinicians and patients, properly integrating immune checkpoint blockade (ICB) into the treatment paradigm is challenging. Additionally, emerging research with other ICB agents, as well as ongoing trials of combination strategies, is likely to further impact clinical decision-making. This article attempts to provide some context to inform systemic treatment decisions in the current landscape, with a particular emphasis on the role of immunotherapy, outlines the ongoing immunotherapy research in RCC, and discusses how treatment may evolve.

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Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non–clear cell renal carcinoma. These guidelines are developed by a multidisciplinary panel of leading experts from NCCN Member Institutions consisting of medical oncologists, hematologists and hematologic oncologists, radiation oncologists, urologists, and pathologists. The NCCN Guidelines are in continuous evolution and are updated annually or sometimes more often, if new high-quality clinical data become available in the interim.

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Keeping Up in the Community

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NCCN News

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Overuse of Chest CT in Patients With Stage I and II Breast Cancer: An Opportunity to Increase Guidelines Compliance at an NCCN Member Institution

Background: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommend that patients with clinical stage I/II breast cancer undergo advanced imaging for staging only when symptomatic. Regardless, many asymptomatic patients undergo chest CT. The goal of this study was to assess the use and results of chest CT in these patients at an NCCN Member Institution. Methods: Patients with breast cancer diagnosed between 1998 and 2012 were identified in a prospectively maintained database. All patients with clinical stage I/II disease who did not receive neoadjuvant chemotherapy were included. Data collected included demographics, tumor size, node status, chest CT within 6 months of diagnosis, imaging findings, need for additional workup, and identification of metastatic disease. Appropriate statistical tests were used for analysis. Results: From 1998 to 2012, 3,321 patients were diagnosed with early-stage breast cancer. Of these, 2,062 (62.1%) had clinical stage I breast cancer at diagnosis and 1,259 (37.9%) had stage II; 227 patients (11%) with stage I and 456 (36.2%) with stage II breast cancer received staging chest CT. Of patients undergoing CT, 184 (26.9%) were found to have pulmonary nodules, which measured ≤5 mm for 128 patients (69.6%), 5 to 10 mm for 46 patients (25.0%), 11 to 20 mm for 6 patients (3.2%), and ≥20 mm for 4 patients (2.2%). Patients undergoing chest CT for staging subsequently underwent a mean of 2.34 (range, 0–16) additional CTs in follow-up. Of all patients undergoing chest CT for staging, only 9 (1.3%) were ultimately diagnosed with pulmonary metastases at an average of 25 months (range, 0–97) after initial staging chest CT. Conclusions: A significant percentage of patients with stage I/II breast cancer underwent unnecessary chest CT as part of their initial workup. Nearly one-third of these patients were found to have pulmonary nodules, but only 1.3% were ever diagnosed with pulmonary metastases. Adherence to NCCN Guidelines will reduce the excessive use of CT chest imaging.

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Morphologic and Molecular Characteristics of De Novo AML With JAK2 V617F Mutation

Background: JAK2 V617F mutation (mut) in acute myeloid leukemia (AML) is rare. We describe the clinicopathologic findings of a single-institution series of 11 de novo AML cases with JAK2 V617. Methods: We identified cases of de novo AML with JAK2 V617F over a 10-year period. We reviewed diagnostic peripheral blood and bone marrow (BM) morphologic, cytogenetic, and molecular studies, including next-generation sequencing. The control group consisted of 12 patients with JAK2 wild-type (wt) AML matched for age, sex, and diagnosis. Results: We identified 11 patients (0.5%) with JAK2 V617F, with a median age at diagnosis of 72.5 years (range, 36–90 years). Ten neoplasms were classified as AML with myelodysplasia-related changes and 1 as AML with t(8;21)(q22;q22). All JAK2mut AML cases showed at least bilineage dysplasia, 7 of 11 showed fibrosis, 8 of 11 had an abnormal karyotype, and 5 had deletions or monosomy of chromosomes 5 and 7. Using the European LeukemiaNet (ELN) classification, 9 patients (82%) with JAK2mut AML were intermediate-2 and adverse risk. Cases of JAK2mut AML did not have mutations in other activating signaling pathways (P=.013); 7 (64%) showed additional mutations in at least one gene involving DNA methylation and/or epigenetic modification. Patients with JAK2mut AML had a significantly higher median BM granulocyte percentage (12% vs 3.5%; P=.006) and a higher frequency of ELN intermediate-2 and adverse risk cytogenetics (P=.04) compared with those with JAK2wt AML. JAK2mut AML showed higher circulating blasts, but this difference was not significant (17% vs 5.5%; P=not significant). No difference was seen in the median overall survival rate of patients with JAK2mut AML versus those with JAK2wt AML (14 vs 13.5 months, respectively). Conclusions: De novo JAK2mut AML is rare and frequently found in patients with dysplasia, BM fibrosis, and abnormal karyotype with intermediate- or high-risk features; gene mutations in DNA methylation and epigenetic-modifying pathways; and absence of gene mutations in activating signaling pathways.

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Evaluating the NCCN Clinical Criteria for Recommending BRCA1 and BRCA2 Genetic Testing in Patients With Breast Cancer

Background: Mutations in the BRCA1 and BRCA2 genes predispose individuals to a significantly elevated risk for breast and ovarian cancers. Identification of these individuals allows for proper screening, management, and testing of at-risk relatives. NCCN has established clinical criteria for recommending BRCA1/2 testing. Patients and Methods: A retrospective chart review of 1,123 patients with breast cancer was performed to evaluate the positive predictive values (PPVs) of 14 individual criteria for predicting BRCA1/2 mutations. Results: Two criteria had PPVs significantly below 10%. Only 2 of 115 patients who were recommended for testing based solely on the criterion of "diagnosed with breast cancer at ≤45 years of age" had pathogenic mutations at a PPV of 1.6% (95% CI, 0.2%–6.0%). Additionally, 0 of 37 individuals who underwent testing based on the criterion, "diagnosed with breast cancer at any age with ≥2 close blood relatives with breast cancer at any age" tested positive (95% CI, 0%–9%). Overall, meeting >1 criterion has a PPV of 12%, whereas meeting only 1 criterion has a PPV of 3.2% (95% CI, 1.6%–5.7%), significantly below 10% (P<.0001) for predicting BRCA1/2 positivity. Conclusions: Patients with breast cancer meeting >1 criterion constitute a population significantly enriched for BRCA1/2 mutations, whereas those meeting only 1 criterion test positive at a rate similar to unselected patients with breast cancer. These data will inform ongoing discussions regarding how to best implement BRCA1/2 genetic testing.

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Getting Practical About Recertification

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NCCN Guidelines Insights: Head and Neck Cancers, Version 2.2017

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus–associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.

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Integrating Immunotherapy Into the Management of Renal Cell Carcinoma

Before 2005, systemic treatment of metastatic renal cell carcinoma (RCC) was limited to a few minimally effective options. Since then, new agents have emerged targeting the vascular endothelial growth factor and mTOR pathways, which has improved outcomes for patients. Options increased even further beginning in 2015 with 3 new agents, including the addition of nivolumab, the first immune checkpoint inhibitor to demonstrate improved survival in RCC. RCC has long been considered a malignancy with immunogenic potential, and nivolumab offers the potential for durable responses in some patients with a generally tolerable toxicity profile. With so many drugs available to clinicians and patients, properly integrating immune checkpoint blockade (ICB) into the treatment paradigm is challenging. Additionally, emerging research with other ICB agents, as well as ongoing trials of combination strategies, is likely to further impact clinical decision-making. This article attempts to provide some context to inform systemic treatment decisions in the current landscape, with a particular emphasis on the role of immunotherapy, outlines the ongoing immunotherapy research in RCC, and discusses how treatment may evolve.

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Optimal Surveillance Strategies After Surgery for Renal Cell Carcinoma

One in 5 patients who undergo surgical resection for clinically localized renal cell carcinoma (RCC) develop local and/or distant recurrences which, when detected early, may be amenable to salvage local and systemic therapies. When considering that approximately half of these recurrences will occur during the first 2 years, a clear rationale exists for optimizing surveillance strategies after surgery. Although there is a notable dearth of high-quality data on this subject, clinical principles can guide clinicians as they attempt to balance the burden of surveillance strategies with potential clinical benefit. The objective of this review is to summarize the evidence regarding optimal surveillance protocols after surgery for RCC. We provide an overview of the rationale supporting surveillance after surgery, a summary of the American Urological Association and NCCN guidelines, reasons against routine long-term surveillance, surveillance costs, and ancillary issues, such as the utility of bone scan, PET/CT scan, and surveillance after thermoablation.

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Keeping Up in the Community

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Developments in Molecular Testing and Biosimilars

Molecular testing and biosimilars offer the potential for increased access to targeted treatment options and reduction in healthcare costs, but come with significant challenges in ensuring patient access to innovation in cancer care while maintaining safe, effective, ethical, and affordable treatment options. As providers, payers, patients, and the larger healthcare systems become inundated with a wide variety of molecular diagnostics and an increased number of biosimilars coming to market, it will be important to understand regulatory guidance and policy implications relating to the appropriateness of molecular testing and the clinical use of biosimilars in cancer care. In September 2016, NCCN hosted the Molecular Testing and Biosimilars Policy Summit to address the challenges, issues, and opportunities in both the molecular testing and biosimilar landscapes. Keynote presentations and panelists further discussed the status and future of molecular testing and biosimilars within the oncology space, as well as patient access and education needs moving forward.

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Overuse of Chest CT in Patients With Stage I and II Breast Cancer: An Opportunity to Increase Guidelines Compliance at an NCCN Member Institution

Background: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommend that patients with clinical stage I/II breast cancer undergo advanced imaging for staging only when symptomatic. Regardless, many asymptomatic patients undergo chest CT. The goal of this study was to assess the use and results of chest CT in these patients at an NCCN Member Institution. Methods: Patients with breast cancer diagnosed between 1998 and 2012 were identified in a prospectively maintained database. All patients with clinical stage I/II disease who did not receive neoadjuvant chemotherapy were included. Data collected included demographics, tumor size, node status, chest CT within 6 months of diagnosis, imaging findings, need for additional workup, and identification of metastatic disease. Appropriate statistical tests were used for analysis. Results: From 1998 to 2012, 3,321 patients were diagnosed with early-stage breast cancer. Of these, 2,062 (62.1%) had clinical stage I breast cancer at diagnosis and 1,259 (37.9%) had stage II; 227 patients (11%) with stage I and 456 (36.2%) with stage II breast cancer received staging chest CT. Of patients undergoing CT, 184 (26.9%) were found to have pulmonary nodules, which measured ≤5 mm for 128 patients (69.6%), 5 to 10 mm for 46 patients (25.0%), 11 to 20 mm for 6 patients (3.2%), and ≥20 mm for 4 patients (2.2%). Patients undergoing chest CT for staging subsequently underwent a mean of 2.34 (range, 0–16) additional CTs in follow-up. Of all patients undergoing chest CT for staging, only 9 (1.3%) were ultimately diagnosed with pulmonary metastases at an average of 25 months (range, 0–97) after initial staging chest CT. Conclusions: A significant percentage of patients with stage I/II breast cancer underwent unnecessary chest CT as part of their initial workup. Nearly one-third of these patients were found to have pulmonary nodules, but only 1.3% were ever diagnosed with pulmonary metastases. Adherence to NCCN Guidelines will reduce the excessive use of CT chest imaging.

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Evidence-Based Guidelines: Optimizing Imaging in Cancer Care

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Thrombotic Thrombocytopenic Purpura Associated With Pegylated Interferon Alfa-2a Use in a Patient With Polycythemia Vera

Pegylated interferon alfa-2a (pegIFNa) is being increasingly used for treatment of myeloproliferative neoplasms; however, its side effects, including autoimmune complications, are not unusual. We report on a 47-year-old woman with polycythemia vera (PV) treated with pegIFNa and in complete hematologic remission who developed thrombotic thrombocytopenic purpura (TTP). To our knowledge, thrombotic microangiopathy has been reported as a side effect of interferon (IFN) use in patients with hepatitis and chronic myeloid leukemia, but not in those with PV. Our patient had a low ADAMTS13 level due to an inhibitor, which normalized after withholding pegIFNa and initiating treatment for TTP with therapeutic plasma exchange and corticosteroids. She experienced refractory TTP, necessitating treatment with rituximab and splenectomy. Postsplenectomy, she developed a high platelet count, warranting the need to restart treatment for PV. However, JAK2^V617F allelic burden by real-time PCR was 0.7%, indicating that the increased platelet count was likely secondary to splenectomy. Therefore, we elected to monitor her counts and JAK2^V617F allelic burden closely. With this case report, we hope to alert treating physicians that TTP should be considered as a complication of pegIFNa therapy in PV and that prompt discontinuation of the drug with necessary treatment should be instituted to prevent fatal complications.

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Evaluating the NCCN Clinical Criteria for Recommending BRCA1 and BRCA2 Genetic Testing in Patients With Breast Cancer

Background: Mutations in the BRCA1 and BRCA2 genes predispose individuals to a significantly elevated risk for breast and ovarian cancers. Identification of these individuals allows for proper screening, management, and testing of at-risk relatives. NCCN has established clinical criteria for recommending BRCA1/2 testing. Patients and Methods: A retrospective chart review of 1,123 patients with breast cancer was performed to evaluate the positive predictive values (PPVs) of 14 individual criteria for predicting BRCA1/2 mutations. Results: Two criteria had PPVs significantly below 10%. Only 2 of 115 patients who were recommended for testing based solely on the criterion of "diagnosed with breast cancer at ≤45 years of age" had pathogenic mutations at a PPV of 1.6% (95% CI, 0.2%–6.0%). Additionally, 0 of 37 individuals who underwent testing based on the criterion, "diagnosed with breast cancer at any age with ≥2 close blood relatives with breast cancer at any age" tested positive (95% CI, 0%–9%). Overall, meeting >1 criterion has a PPV of 12%, whereas meeting only 1 criterion has a PPV of 3.2% (95% CI, 1.6%–5.7%), significantly below 10% (P<.0001) for predicting BRCA1/2 positivity. Conclusions: Patients with breast cancer meeting >1 criterion constitute a population significantly enriched for BRCA1/2 mutations, whereas those meeting only 1 criterion test positive at a rate similar to unselected patients with breast cancer. These data will inform ongoing discussions regarding how to best implement BRCA1/2 genetic testing.

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NCCN Guidelines Insights: Head and Neck Cancers, Version 2.2017

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus–associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.

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Optimal Surveillance Strategies After Surgery for Renal Cell Carcinoma

One in 5 patients who undergo surgical resection for clinically localized renal cell carcinoma (RCC) develop local and/or distant recurrences which, when detected early, may be amenable to salvage local and systemic therapies. When considering that approximately half of these recurrences will occur during the first 2 years, a clear rationale exists for optimizing surveillance strategies after surgery. Although there is a notable dearth of high-quality data on this subject, clinical principles can guide clinicians as they attempt to balance the burden of surveillance strategies with potential clinical benefit. The objective of this review is to summarize the evidence regarding optimal surveillance protocols after surgery for RCC. We provide an overview of the rationale supporting surveillance after surgery, a summary of the American Urological Association and NCCN guidelines, reasons against routine long-term surveillance, surveillance costs, and ancillary issues, such as the utility of bone scan, PET/CT scan, and surveillance after thermoablation.

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Developments in Molecular Testing and Biosimilars

Molecular testing and biosimilars offer the potential for increased access to targeted treatment options and reduction in healthcare costs, but come with significant challenges in ensuring patient access to innovation in cancer care while maintaining safe, effective, ethical, and affordable treatment options. As providers, payers, patients, and the larger healthcare systems become inundated with a wide variety of molecular diagnostics and an increased number of biosimilars coming to market, it will be important to understand regulatory guidance and policy implications relating to the appropriateness of molecular testing and the clinical use of biosimilars in cancer care. In September 2016, NCCN hosted the Molecular Testing and Biosimilars Policy Summit to address the challenges, issues, and opportunities in both the molecular testing and biosimilar landscapes. Keynote presentations and panelists further discussed the status and future of molecular testing and biosimilars within the oncology space, as well as patient access and education needs moving forward.

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Evidence-Based Guidelines: Optimizing Imaging in Cancer Care

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Prognostic factors in patients with advanced biliary tract cancer treated with first-line gemcitabine plus cisplatin: retrospective analysis of 740 patients

Abstract

Purpose

Biliary tract cancer (BTC) is a heterogeneous group of diseases comprising intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer. Although gemcitabine plus cisplatin (GEMCIS) was established as the standard first-line chemotherapy based on the ABC-02 trial, more data are needed to define the clinical course of BTC and its prognostic factors with the standard GEMCIS treatment.

Methods

Between April 2010 and June 2016, 740 patients with histologically documented cholangiocarcinoma and gallbladder cancer were treated with first-line GEMCIS in Asan Medical Center, Seoul, Korea.

Results

In 389 patients with measurable disease (53%), the objective response rate was 13% (n = 50) and there was no significant difference between primary tumor sites (p = 0.45). With a median follow-up duration of 27.3 months (95% CI 24.2–30.5), the median PFS and OS were 5.2 months (95% CI 4.7–5.6) and 10.4 months (95% CI 9.6–11.2), respectively. In multivariate analysis, male gender (female versus male, hazard ratio [HR] 0.83), baseline CA 19-9 level (elevated versus normal, HR 1.31), initially metastatic disease (versus locally advanced disease, HR 1.92), poor performance status (2 versus 0–1, HR 1.45), and measurable disease by RECIST criteria (versus non-measurable, HR 1.40) were significantly associated with a poorer OS (all p < 0.05).

Conclusions

Our retrospective analysis of a large number of patients in a real-world setting found comparable efficacy outcomes to the ABC-02 trial. The prognostic factors identified here may help to predict clinical outcomes and design future clinical trials for advanced BTC.

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Prognostic factors in patients with advanced biliary tract cancer treated with first-line gemcitabine plus cisplatin: retrospective analysis of 740 patients

Abstract

Purpose

Biliary tract cancer (BTC) is a heterogeneous group of diseases comprising intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer. Although gemcitabine plus cisplatin (GEMCIS) was established as the standard first-line chemotherapy based on the ABC-02 trial, more data are needed to define the clinical course of BTC and its prognostic factors with the standard GEMCIS treatment.

Methods

Between April 2010 and June 2016, 740 patients with histologically documented cholangiocarcinoma and gallbladder cancer were treated with first-line GEMCIS in Asan Medical Center, Seoul, Korea.

Results

In 389 patients with measurable disease (53%), the objective response rate was 13% (n = 50) and there was no significant difference between primary tumor sites (p = 0.45). With a median follow-up duration of 27.3 months (95% CI 24.2–30.5), the median PFS and OS were 5.2 months (95% CI 4.7–5.6) and 10.4 months (95% CI 9.6–11.2), respectively. In multivariate analysis, male gender (female versus male, hazard ratio [HR] 0.83), baseline CA 19-9 level (elevated versus normal, HR 1.31), initially metastatic disease (versus locally advanced disease, HR 1.92), poor performance status (2 versus 0–1, HR 1.45), and measurable disease by RECIST criteria (versus non-measurable, HR 1.40) were significantly associated with a poorer OS (all p < 0.05).

Conclusions

Our retrospective analysis of a large number of patients in a real-world setting found comparable efficacy outcomes to the ABC-02 trial. The prognostic factors identified here may help to predict clinical outcomes and design future clinical trials for advanced BTC.

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Prognostic factors in patients with advanced biliary tract cancer treated with first-line gemcitabine plus cisplatin: retrospective analysis of 740 patients

Abstract

Purpose

Biliary tract cancer (BTC) is a heterogeneous group of diseases comprising intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer. Although gemcitabine plus cisplatin (GEMCIS) was established as the standard first-line chemotherapy based on the ABC-02 trial, more data are needed to define the clinical course of BTC and its prognostic factors with the standard GEMCIS treatment.

Methods

Between April 2010 and June 2016, 740 patients with histologically documented cholangiocarcinoma and gallbladder cancer were treated with first-line GEMCIS in Asan Medical Center, Seoul, Korea.

Results

In 389 patients with measurable disease (53%), the objective response rate was 13% (n = 50) and there was no significant difference between primary tumor sites (p = 0.45). With a median follow-up duration of 27.3 months (95% CI 24.2–30.5), the median PFS and OS were 5.2 months (95% CI 4.7–5.6) and 10.4 months (95% CI 9.6–11.2), respectively. In multivariate analysis, male gender (female versus male, hazard ratio [HR] 0.83), baseline CA 19-9 level (elevated versus normal, HR 1.31), initially metastatic disease (versus locally advanced disease, HR 1.92), poor performance status (2 versus 0–1, HR 1.45), and measurable disease by RECIST criteria (versus non-measurable, HR 1.40) were significantly associated with a poorer OS (all p < 0.05).

Conclusions

Our retrospective analysis of a large number of patients in a real-world setting found comparable efficacy outcomes to the ABC-02 trial. The prognostic factors identified here may help to predict clinical outcomes and design future clinical trials for advanced BTC.

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Phase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers

Abstract

Background

Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers.

Methods

Eligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m²) and carboplatin (area under the curve [AUC] 5–6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated.

Results

Thirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1–5 and 8–12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1–12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles.

Conclusions

Treatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1–5 and 8–12) plus day 1 paclitaxel (175 mg/m²) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle.

Trial registration

ClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).

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Phase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers

Abstract

Background

Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers.

Methods

Eligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m²) and carboplatin (area under the curve [AUC] 5–6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated.

Results

Thirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1–5 and 8–12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1–12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles.

Conclusions

Treatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1–5 and 8–12) plus day 1 paclitaxel (175 mg/m²) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle.

Trial registration

ClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).

http://ift.tt/2siMTAo

Malignant hypertension as a rare cause of thrombotic microangiopathy

Malignant hypertension can occasionally be associated with microangiopathic haemolytic anaemia. A 38-year-old male presented with nausea, vomiting, loss of appetite and oliguria for 2 weeks. He was diagnosed with hypertensive emergency with cardiac and renal dysfunction. Interestingly, further workup was diagnostic for the presence of thrombotic microangiopathy (TMA): haemoglobin =12.7 g/dL, indirect bilirubin =2.0 mg/dL, haptoglobin ≤6 mg/dL, platelet count =121 000/μL and schistocytes on peripheral smear. At the outset, the cause of TMA was unclear. Patient denied having diarrhoea, making haemolytic uremic syndrome less likely. A normal ADAMTS13 activity test ruled out thrombotic thrombocytopaenic purpura. Malignant hypertension induced TMA was highest on the differential and plasma exchange was deferred. Renal biopsy revealed features of TMA and malignant nephrosclerosis. Patient eventually became dialysis dependent. Aggressive blood pressure control was obtained with multiple medications.

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Intrahepatic fetus: unusual image of an intratumoural haemorrhage

Description

A 65-year-old man presented to our institution with acute onset, right upper quadrant pain, on a background of rheumatoid arthritis and asthma. He was a lifelong non-smoker, with minimal alcohol consumption and no intravenous drug use. CT and MRI demonstrated a large tumour involving the entire segment IV of the liver positioned between the middle and the left hepatic veins. A T1-weighted axial MRI at the level of right hepatic vein demonstrated an odd, fetus-like lesion within the mass (figure 1). Junior medical staff questioned whether this could be a primary hepatic pregnancy. However, they were reassured that this image portrayed an intraparenchymal bleed, consistent with hepatocellular carcinoma (HCC). A diagnosis of HCC was confirmed by non-invasive criteria for diagnosing HCC recommended by both the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver consensus statement.

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Mediastinal seminoma presenting with superior vena cava syndrome

We present a rare cause of superior vena cava syndrome (SVC) in a previously healthy male aged 31 years. Malignancy was suspected due to unintentional weight loss and childhood exposure to radioactive fallout from a nuclear facility accident. A very large anterior mediastinal mass was identified and demonstrated to be an extragonadal seminoma. Extragonadal germ cell tumours are rare tumours with a high potential for cardiovascular, pulmonary and vascular sequelae. Studies have documented an increased risk of developing seminoma in patients with radioactive exposure. Chemotherapy was initiated, during which the patient experienced progressive and new symptoms, found to be due to extensive thromboembolic disease, which responded well to anticoagulation. Seventy-two months after completing chemotherapy, without need for surgical management, he remains free of the disease.

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Pituitary abscess

Pituitary abscess is an uncommon pituitary lesion. Its clinical diagnosis can be difficult to distinguish from other pituitary lesions. This pathology is characterised by vague symptoms of headaches, generalised tiredness and hypopituitarism manifestations. A history of recent meningitis, paranasal sinusitis or head surgery can be a suggestive of the source of infection.

A 20-year-old man was admitted to neurosurgery department with complain of headache, fatigue, polyuria, polydipsia, blurred vision and sexual dysfunction. MRI of the head revealed a suprasellar mass that was centrally hyperintense lesion on T2-weighted images with peripheral hypointensity and isointense centrally on T1 images with peripheral hyperintensity images. Treatment of this lesion pituitary abscess was surgical drainage of the pituitary area through a trans-sphenoidal approach and broad spectrum antibiotic therapy with ceftriaxone, metronidazole and vancomycin for 6 weeks. The patient continues to have pituitary insufficiency and treated with oral hydrocortisone.

Although pituitary abscess is a rare condition, it should always be kept in mind when evaluating a patient with hypopituitarism. After the diagnosis, the surgery and antibiotics should be commenced rapidly. The outcome is usually good with proper treatment.

http://ift.tt/2r6cDjA

A case of a chronic salmonella infection following Roux-en-Y gastric bypass surgery, treated successfully by a laparoscopic cholecystectomy

We report a case of chronic infection caused by Salmonella and cured by a laparoscopic cholecystectomy after Roux-en-Y gastric bypass (RYGB) surgery for obesity. This patient presented with a 2-year history of chronic abdominal pain, loose stools and excessive weight loss. Her stool and urine cultures were positive for Salmonella. Despite multiple courses of antibiotics, she remained positive.

After undergoing a laparoscopic cholecystectomy, the patient became asymptomatic and stools remained negative. In chronic carriers for Salmonella, the gall bladder is the common reservoir for the bacteria and removing it is usually curative.

The possibility that the source of the may be in the biliary limb of her bariatric procedure and not in the gall bladder remained a concern.

In patients who have had a RYGB, cholecystectomy is an effective treatment.

All patients presenting with abdominal symptoms following RYGB should have stool and urine cultures taken as part of their work up.

http://ift.tt/2rQ6eGa

Surgical management of isolated mesenteric autoimmune disease: addressing the spectrum of IgG4-related disease and sclerosing mesenteritis

IgG₄-related disease (IgG₄-RD) is a rare form of autoimmune sclerosing disease, characterised by elevated serum IgG₄ and tissue IgG₄ levels, specific histopathological findings, multiorgan involvement and adequate response to glucocorticoid treatment. The low incidence and the heterogeneous nature of the disease has made consensus on diagnostic criteria for IgG₄-RD difficult. Whether sclerosing mesenteritis (SM) is considered a manifestation of IgG₄-RD is strongly debated. We present the case of a patient with a history of rheumatoid arthritis who presented with a calcified abdominal mass. She was found to have an isolated, pedunculated mesenteric mass positive for IgG₄ and concurrently elevated serum IgG₄ levels. Clinical features did not classify her disease as either SM or IgG₄-RD as currently described in consensus statements. Concurrent diagnoses of IgG₄-RD, SM and other autoimmune disorders, as well as postoperative recommendations for resected isolated IgG₄-positive masses, are discussed.

http://ift.tt/2rPXMqm

Isolated gastric sarcoidosis: a rare entity

We present a case of isolated granulomatous gastritis in a 21-year-old woman. Initial symptoms included nausea, vomiting and inability to tolerate oral intake. An upper oesophagogastroduodenoscopy revealed nodular and thickened mucosa with histological findings of granulomatous gastritis. Infectious, inflammatory and malignant causes were excluded prior to making a diagnosis of gastric sarcoidosis.

http://ift.tt/2r6cCw2

Congenital prepubic sinus (an epispadiac variant of dorsal urethral duplication) with dorsal penile curvature in an adult man: a rare association

Urethral duplication is among a very rare congenital disorder with multiple anatomical variants reported. Urethral duplication of complete type is usually diagnosed during childhood with urinary incontinence or double urinary stream as common presentation. However, patients with incomplete urethral duplication usually present with intermittent mucous discharge from the accessory urethral opening. A 20-year-old man presented to us with intermittent mucous discharge from the accessory opening along with dorsal penile curvature making sexual intercourse very difficult. The epispadiac urethral tract with proximal fibrous tract was excised, and the dorsal penile curvature was corrected by ventral plication, implicating that the fibrous cord may be the causative factor for the development of dorsal curvature.

http://ift.tt/2rPRsiP

Persistent lesion hyperintensity on brain diffusion-weighted MRI is an early sign of intravascular lymphoma

A 63-year-old man presented with right-sided hemianopia and unsteady gait. Brain MRI revealed multiple hyperintense infarct-like lesions on diffusion-weighted images (DWI). Hyperintensity persisted in some of these lesions even after 6 weeks, although his symptoms were ameliorated then. The patient developed episodic dizziness and a transient event of apraxia at 18 weeks after the first episode. Brain MRI revealed additional hyperintense lesions on DWI, which persisted even after 7 weeks. Eventually, the patient manifested cauda equina syndrome 39 weeks after the first episode. Brain MRI showed the presence of new lesions in addition to the persistent hyperintense lesions on DWI over 21 weeks in the right frontal lobe. Based on laboratory findings and the pathological assessment of bone marrow and random skin biopsies, the patient was diagnosed with intravascular lymphoma (IVL). Persistent hyperintense lesions on DWI of brain MRI may precede the clinical exacerbation of IVL.

http://ift.tt/2r5PCgx

Delayed progression of bulls eye maculopathy

Chloroquine-induced maculopathy may progress years after drug cessation and an apparent period of visual stability. Both doctor and patients should be fully aware of the risks of retinal toxicity, including delayed onset and progression. It is therefore crucial that regular monitoring continues in affected patients, long after the initial diagnosis of maculopathy.

http://ift.tt/2rQ6Iwa

Primary myeloid sarcoma of small bowel

Description

A 45-year-old woman presented with severe lower abdominal pain and vomiting. On physical examination, she was found to have tenderness in the suprapubic region and right iliac fossa. An ultrasound abdomen performed to rule out acute appendicitis and pelvic inflammatory disease was not contributory. Blood parameters were within normal limits. As the patient continued to be symptomatic, a contrast-enhanced CT of the abdomen was performed. It revealed eccentric focal bowel wall thickening involving the ileum measuring 3.3x2.4 cm, with homogeneous enhancement on postcontrast images causing mild luminal compromise (figures 1, figure 2). Oral contrast was noted to pass distally with no proximal hold-up. Mild dilatation of proximal ileal loops with diffuse wall thickening was noted (figure 3). No perifocal mesenteric fat infiltration was identified. Few discrete enlarged perifocal lymph nodes were noted (figure 4). There was no retroperitoneal lymphadenopathy. In view of...

http://ift.tt/2r5T6zL

Cisplatin induces expression of drug resistance-related genes through c-jun N-terminal kinase pathway in human lung cancer cells

Abstract

Purpose

Change of multidrug resistance-related genes (e.g., lung resistance protein, LRP) and overexpression of anti-apoptotic genes (Bcl-2, Bcl-Xl, XIAP, Survivin) are responsible for cisplatin resistance. In our study, we investigated the mechanism by which cisplatin induces LRP, Bcl-2, Bcl-xL, XIAP, and Survivin expression in human lung adenocarcinoma A549 cells and human H446 small cell lung cancer cells at mRNA and protein levels.

Methods

In our study, cell proliferation was assessed with CCK-8 assays, and cell apoptosis was assessed with flow cytometric analysis and Annexin-V/PI staining. qPCR was used to complete RNA experiments. Protein expression was assessed with Western blotting.

Results

Cisplatin increased Bcl-2, LRP, and Survivin expression, but decreased Bcl-xL and XIAP expression in a dose-dependent manner. Preincubation with JNK-specific inhibitor, SP600125, significantly inhibited these genes' expression at mRNA and protein levels, enhanced chemosensitivity of lung cancer cells to cisplatin, and promoted cisplatin-induced apoptosis.

Conclusion

Our data suggest that the JNK signaling pathway plays an important role in cisplatin resistance. Lung resistance protein (LRP) and anti-apoptotic genes (Bcl-2, Bcl-Xl, XIAP, Survivin) are involved in the process. The results reminded us of a novel therapy target for lung cancer treatment.

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Efficacy and safety of postoperative bio-chemoradiotherapy using cetuximab and docetaxel for high-risk head and neck cancer patients in Japan

Abstract

Purpose

To confirm the efficacy and safety of cetuximab and docetaxel in postoperative radiotherapy for high-risk head and neck cancer patients who cannot to be administered high-dose cisplatin.

Patients and methods

The eligibility criteria required stage III–IVB head and neck cancer patients who had undergone total resection, and for whom pathological evaluation revealed positive or close margins in the primary site and/or extracapsular nodal extension and/or two or more nodal metastases. In each case, the patients general condition prevented the use of high-dose cisplatin. Instead, they received cetuximab and docetaxel every week during a 66.6 Gy course of postoperative radiotherapy.

Results

Eleven patients were enrolled; the median follow-up period was 22 months, and the 1- and 2-year disease free survival rates were 91 and 55%, respectively. Grade 3 adverse events included oral mucositis, radiation dermatitis, reduced white blood cell and neutrophil counts, lung infection, aspiration, and hyponatremia; however, no grade 4 adverse events were observed.

Conclusion

Administration of cetuximab and docetaxel during postoperative radiotherapy for high-risk poor condition head and neck cancer patients in poor general condition was both feasible and tolerable. With the safety of this treatment confirmed, we propose a phase trail to further clarify the efficacy of cetuximab and docetaxel use for high-risk cisplatin-intolerant patients.

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Phase II study of induction gemcitabine and S-1 followed by chemoradiotherapy and systemic chemotherapy using S-1 for locally advanced pancreatic cancer

Abstract

Purpose

S-1 has systemic activity for locally advanced pancreatic cancer (LAPC). Here, the efficacy and safety of induction gemcitabine (GEM) and S-1 (GS) followed by chemoradiotherapy (CRT) and systemic chemotherapy using S-1 for LAPC were assessed.

Methods

The treatment consisted of four cycles of induction GS (S-1 60, 80, or 100 mg/day based on body surface area for 14 days every 3 weeks plus GEM 1000 mg/m² on days 8 and 15), followed by S-1 (80, 100, or 120 mg/day based on body surface area on days 1–14 and 22–35) and concurrent radiotherapy (50.4 Gy in 28 fractions). Maintenance chemotherapy with S-1 was started 1–4 weeks after CRT until disease progression or unacceptable toxicity was observed. The primary endpoint was 1-year survival.

Results

A total of 30 patients with LAPC were enrolled. The median survival and progression-free survival were 21.3 and 12.7 months, respectively. Overall survival rates at 1, 2, 3, and 4 years were 73.3, 36.7, 23.3, and 16.7%, respectively. The median survival of 23 patients who received CRT was 22.9 months, with a 3-year survival rate of 30.4%. The two most common grade 3 or 4 adverse events during induction GS were neutropenia (63.3%) and biliary tract infection (20%). Toxicities during CRT or maintenance chemotherapy were generally mild.

Conclusions

This regimen was feasible and highly active resulting in encouraging survival in patients with LAPC. Further investigations are warranted to elucidate the effectiveness of this treatment strategy in future studies.

Clinical trials information: UMIN000006332.

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Port site recurrence after laparoscopic radical nephrectomy: a case report

Due to the recent development of laparoscopic devices, laparoscopic radical nephrectomy is the standard procedure for localized renal cell carcinoma. However, some studies have reported postoperative port site...

http://ift.tt/2sH1oeq

Cisplatin induces expression of drug resistance-related genes through c-jun N-terminal kinase pathway in human lung cancer cells

Abstract

Purpose

Change of multidrug resistance-related genes (e.g., lung resistance protein, LRP) and overexpression of anti-apoptotic genes (Bcl-2, Bcl-Xl, XIAP, Survivin) are responsible for cisplatin resistance. In our study, we investigated the mechanism by which cisplatin induces LRP, Bcl-2, Bcl-xL, XIAP, and Survivin expression in human lung adenocarcinoma A549 cells and human H446 small cell lung cancer cells at mRNA and protein levels.

Methods

In our study, cell proliferation was assessed with CCK-8 assays, and cell apoptosis was assessed with flow cytometric analysis and Annexin-V/PI staining. qPCR was used to complete RNA experiments. Protein expression was assessed with Western blotting.

Results

Cisplatin increased Bcl-2, LRP, and Survivin expression, but decreased Bcl-xL and XIAP expression in a dose-dependent manner. Preincubation with JNK-specific inhibitor, SP600125, significantly inhibited these genes' expression at mRNA and protein levels, enhanced chemosensitivity of lung cancer cells to cisplatin, and promoted cisplatin-induced apoptosis.

Conclusion

Our data suggest that the JNK signaling pathway plays an important role in cisplatin resistance. Lung resistance protein (LRP) and anti-apoptotic genes (Bcl-2, Bcl-Xl, XIAP, Survivin) are involved in the process. The results reminded us of a novel therapy target for lung cancer treatment.

http://ift.tt/2sGSWMh

The cardiac glycoside oleandrin induces apoptosis in human colon cancer cells via the mitochondrial pathway

Abstract

Purpose

Evidence indicates that the cardiac glycoside oleandrin exhibits cytotoxic activity against several different types of cancer. However, the specific mechanisms underlying oleandrin-induced anti-tumor effects remain largely unknown. The present study examined the anti-cancer effect and underlying mechanism of oleandrin on human colon cancer cells.

Methods

The cytotoxicity and IC50 of five small molecule compounds (oleandrin, neriifolin, strophanthidin, gitoxigenin, and convallatoxin) in human colon cancer cell line SW480 cells and normal human colon cell line NCM460 cells were determined by cell counting and MTT assays, respectively. Apoptosis was determined by staining cells with annexin V-FITC and propidium iodide, followed by flow cytometry. Intracellular Ca²⁺ was determined using Fluo-3 AM,glutathione (GSH) levels were measured using a GSH detection kit,and the activity of caspase-3, -9 was measured using a peptide substrate. BAX, pro-caspase-3, -9, cytochrome C and BCL-2 expression were determined by Western blotting.

Results

Oleandrin significantly decreased cell viabilities in SW480, HCT116 and RKO cells. The IC50 for SW480 cells was 0.02 µM, whereas for NCM460 cells 0.56 µM. More interestingly, the results of flow cytometry showed that oleandrin potently induced apoptosis in SW480 and RKO cells. Oleandrin downregulated protein expression of pro-caspase-3, -9, but enhanced caspase-3, -9 activities. These effects were accompanied by upregulation of protein expression of cytochrome C and BAX, and downregulation of BCL-2 protein expression in a concentration-dependent manner. Furthermore, oleandrin increased intracellular Ca²⁺ concentration, but decreased GSH concentration in the cells.

Conclusions

The present results suggest that oleandrin induces apoptosis in human colorectal cancer cells via the mitochondrial pathway. Our findings provide new insight into the mechanism of anti-cancer property of oleandrin.

http://ift.tt/2rFcOB1

Clinical significance of systemic chemotherapy after curative resection of metachronous pulmonary metastases from colorectal cancer

Abstract

Purpose

The use of systemic chemotherapy after resection remains controversial in patients with resectable metachronous pulmonary metastases from colorectal cancer (CRC). This retrospective study compared systemic chemotherapy with observation alone after resection of pulmonary metastases from CRC.

Methods

Between 2001 and 2015, 91 patients with metachronous pulmonary metastases underwent curative surgical resection at five centers. Patients with stage IV at diagnosis were excluded. Overall survival (OS) was defined as the time from pulmonary resection until death. The disease-free interval (DFI) was defined as the time from pulmonary resection until recurrence or death.

Results

Among the 91 patients, 63 were in the chemotherapy group, while 28 were in the observation alone group. The characteristics were similar between the two groups, except for the carcinoembryonic antigen level after pulmonary metastases and the use of adjuvant treatment after resection of the primary tumor. With a median follow-up duration of 46 months (11–126), the estimated 5-year DFI and OS rates were 32.8 and 61.4%, respectively. The chemotherapy following pulmonary resection was not significantly associated with the DFI (p = 0.416) and OS (p = 0.119).

Conclusion

Systemic chemotherapy after pulmonary resection was not found to have a significant effect on survival.

http://ift.tt/2rZzMTP

Efficacy and safety of postoperative bio-chemoradiotherapy using cetuximab and docetaxel for high-risk head and neck cancer patients in Japan

Abstract

Purpose

To confirm the efficacy and safety of cetuximab and docetaxel in postoperative radiotherapy for high-risk head and neck cancer patients who cannot to be administered high-dose cisplatin.

Patients and methods

The eligibility criteria required stage III–IVB head and neck cancer patients who had undergone total resection, and for whom pathological evaluation revealed positive or close margins in the primary site and/or extracapsular nodal extension and/or two or more nodal metastases. In each case, the patients general condition prevented the use of high-dose cisplatin. Instead, they received cetuximab and docetaxel every week during a 66.6 Gy course of postoperative radiotherapy.

Results

Eleven patients were enrolled; the median follow-up period was 22 months, and the 1- and 2-year disease free survival rates were 91 and 55%, respectively. Grade 3 adverse events included oral mucositis, radiation dermatitis, reduced white blood cell and neutrophil counts, lung infection, aspiration, and hyponatremia; however, no grade 4 adverse events were observed.

Conclusion

Administration of cetuximab and docetaxel during postoperative radiotherapy for high-risk poor condition head and neck cancer patients in poor general condition was both feasible and tolerable. With the safety of this treatment confirmed, we propose a phase trail to further clarify the efficacy of cetuximab and docetaxel use for high-risk cisplatin-intolerant patients.

http://ift.tt/2s7FPqx

Phase II study of induction gemcitabine and S-1 followed by chemoradiotherapy and systemic chemotherapy using S-1 for locally advanced pancreatic cancer

Abstract

Purpose

S-1 has systemic activity for locally advanced pancreatic cancer (LAPC). Here, the efficacy and safety of induction gemcitabine (GEM) and S-1 (GS) followed by chemoradiotherapy (CRT) and systemic chemotherapy using S-1 for LAPC were assessed.

Methods

The treatment consisted of four cycles of induction GS (S-1 60, 80, or 100 mg/day based on body surface area for 14 days every 3 weeks plus GEM 1000 mg/m² on days 8 and 15), followed by S-1 (80, 100, or 120 mg/day based on body surface area on days 1–14 and 22–35) and concurrent radiotherapy (50.4 Gy in 28 fractions). Maintenance chemotherapy with S-1 was started 1–4 weeks after CRT until disease progression or unacceptable toxicity was observed. The primary endpoint was 1-year survival.

Results

A total of 30 patients with LAPC were enrolled. The median survival and progression-free survival were 21.3 and 12.7 months, respectively. Overall survival rates at 1, 2, 3, and 4 years were 73.3, 36.7, 23.3, and 16.7%, respectively. The median survival of 23 patients who received CRT was 22.9 months, with a 3-year survival rate of 30.4%. The two most common grade 3 or 4 adverse events during induction GS were neutropenia (63.3%) and biliary tract infection (20%). Toxicities during CRT or maintenance chemotherapy were generally mild.

Conclusions

This regimen was feasible and highly active resulting in encouraging survival in patients with LAPC. Further investigations are warranted to elucidate the effectiveness of this treatment strategy in future studies.

Clinical trials information: UMIN000006332.

http://ift.tt/2sH2wPl

Cisplatin induces expression of drug resistance-related genes through c-jun N-terminal kinase pathway in human lung cancer cells

Abstract

Purpose

Change of multidrug resistance-related genes (e.g., lung resistance protein, LRP) and overexpression of anti-apoptotic genes (Bcl-2, Bcl-Xl, XIAP, Survivin) are responsible for cisplatin resistance. In our study, we investigated the mechanism by which cisplatin induces LRP, Bcl-2, Bcl-xL, XIAP, and Survivin expression in human lung adenocarcinoma A549 cells and human H446 small cell lung cancer cells at mRNA and protein levels.

Methods

In our study, cell proliferation was assessed with CCK-8 assays, and cell apoptosis was assessed with flow cytometric analysis and Annexin-V/PI staining. qPCR was used to complete RNA experiments. Protein expression was assessed with Western blotting.

Results

Cisplatin increased Bcl-2, LRP, and Survivin expression, but decreased Bcl-xL and XIAP expression in a dose-dependent manner. Preincubation with JNK-specific inhibitor, SP600125, significantly inhibited these genes' expression at mRNA and protein levels, enhanced chemosensitivity of lung cancer cells to cisplatin, and promoted cisplatin-induced apoptosis.

Conclusion

Our data suggest that the JNK signaling pathway plays an important role in cisplatin resistance. Lung resistance protein (LRP) and anti-apoptotic genes (Bcl-2, Bcl-Xl, XIAP, Survivin) are involved in the process. The results reminded us of a novel therapy target for lung cancer treatment.

from Cancer via ola Kala on Inoreader http://ift.tt/2sGSWMh
via IFTTT

The cardiac glycoside oleandrin induces apoptosis in human colon cancer cells via the mitochondrial pathway

Abstract

Purpose

Evidence indicates that the cardiac glycoside oleandrin exhibits cytotoxic activity against several different types of cancer. However, the specific mechanisms underlying oleandrin-induced anti-tumor effects remain largely unknown. The present study examined the anti-cancer effect and underlying mechanism of oleandrin on human colon cancer cells.

Methods

The cytotoxicity and IC50 of five small molecule compounds (oleandrin, neriifolin, strophanthidin, gitoxigenin, and convallatoxin) in human colon cancer cell line SW480 cells and normal human colon cell line NCM460 cells were determined by cell counting and MTT assays, respectively. Apoptosis was determined by staining cells with annexin V-FITC and propidium iodide, followed by flow cytometry. Intracellular Ca²⁺ was determined using Fluo-3 AM,glutathione (GSH) levels were measured using a GSH detection kit,and the activity of caspase-3, -9 was measured using a peptide substrate. BAX, pro-caspase-3, -9, cytochrome C and BCL-2 expression were determined by Western blotting.

Results

Oleandrin significantly decreased cell viabilities in SW480, HCT116 and RKO cells. The IC50 for SW480 cells was 0.02 µM, whereas for NCM460 cells 0.56 µM. More interestingly, the results of flow cytometry showed that oleandrin potently induced apoptosis in SW480 and RKO cells. Oleandrin downregulated protein expression of pro-caspase-3, -9, but enhanced caspase-3, -9 activities. These effects were accompanied by upregulation of protein expression of cytochrome C and BAX, and downregulation of BCL-2 protein expression in a concentration-dependent manner. Furthermore, oleandrin increased intracellular Ca²⁺ concentration, but decreased GSH concentration in the cells.

Conclusions

The present results suggest that oleandrin induces apoptosis in human colorectal cancer cells via the mitochondrial pathway. Our findings provide new insight into the mechanism of anti-cancer property of oleandrin.

from Cancer via ola Kala on Inoreader http://ift.tt/2rFcOB1
via IFTTT

Clinical significance of systemic chemotherapy after curative resection of metachronous pulmonary metastases from colorectal cancer

Abstract

Purpose

The use of systemic chemotherapy after resection remains controversial in patients with resectable metachronous pulmonary metastases from colorectal cancer (CRC). This retrospective study compared systemic chemotherapy with observation alone after resection of pulmonary metastases from CRC.

Methods

Between 2001 and 2015, 91 patients with metachronous pulmonary metastases underwent curative surgical resection at five centers. Patients with stage IV at diagnosis were excluded. Overall survival (OS) was defined as the time from pulmonary resection until death. The disease-free interval (DFI) was defined as the time from pulmonary resection until recurrence or death.

Results

Among the 91 patients, 63 were in the chemotherapy group, while 28 were in the observation alone group. The characteristics were similar between the two groups, except for the carcinoembryonic antigen level after pulmonary metastases and the use of adjuvant treatment after resection of the primary tumor. With a median follow-up duration of 46 months (11–126), the estimated 5-year DFI and OS rates were 32.8 and 61.4%, respectively. The chemotherapy following pulmonary resection was not significantly associated with the DFI (p = 0.416) and OS (p = 0.119).

Conclusion

Systemic chemotherapy after pulmonary resection was not found to have a significant effect on survival.

from Cancer via ola Kala on Inoreader http://ift.tt/2rZzMTP
via IFTTT

Efficacy and safety of postoperative bio-chemoradiotherapy using cetuximab and docetaxel for high-risk head and neck cancer patients in Japan

Abstract

Purpose

To confirm the efficacy and safety of cetuximab and docetaxel in postoperative radiotherapy for high-risk head and neck cancer patients who cannot to be administered high-dose cisplatin.

Patients and methods

The eligibility criteria required stage III–IVB head and neck cancer patients who had undergone total resection, and for whom pathological evaluation revealed positive or close margins in the primary site and/or extracapsular nodal extension and/or two or more nodal metastases. In each case, the patients general condition prevented the use of high-dose cisplatin. Instead, they received cetuximab and docetaxel every week during a 66.6 Gy course of postoperative radiotherapy.

Results

Eleven patients were enrolled; the median follow-up period was 22 months, and the 1- and 2-year disease free survival rates were 91 and 55%, respectively. Grade 3 adverse events included oral mucositis, radiation dermatitis, reduced white blood cell and neutrophil counts, lung infection, aspiration, and hyponatremia; however, no grade 4 adverse events were observed.

Conclusion

Administration of cetuximab and docetaxel during postoperative radiotherapy for high-risk poor condition head and neck cancer patients in poor general condition was both feasible and tolerable. With the safety of this treatment confirmed, we propose a phase trail to further clarify the efficacy of cetuximab and docetaxel use for high-risk cisplatin-intolerant patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2s7FPqx
via IFTTT

Phase II study of induction gemcitabine and S-1 followed by chemoradiotherapy and systemic chemotherapy using S-1 for locally advanced pancreatic cancer

Abstract

Purpose

S-1 has systemic activity for locally advanced pancreatic cancer (LAPC). Here, the efficacy and safety of induction gemcitabine (GEM) and S-1 (GS) followed by chemoradiotherapy (CRT) and systemic chemotherapy using S-1 for LAPC were assessed.

Methods

The treatment consisted of four cycles of induction GS (S-1 60, 80, or 100 mg/day based on body surface area for 14 days every 3 weeks plus GEM 1000 mg/m² on days 8 and 15), followed by S-1 (80, 100, or 120 mg/day based on body surface area on days 1–14 and 22–35) and concurrent radiotherapy (50.4 Gy in 28 fractions). Maintenance chemotherapy with S-1 was started 1–4 weeks after CRT until disease progression or unacceptable toxicity was observed. The primary endpoint was 1-year survival.

Results

A total of 30 patients with LAPC were enrolled. The median survival and progression-free survival were 21.3 and 12.7 months, respectively. Overall survival rates at 1, 2, 3, and 4 years were 73.3, 36.7, 23.3, and 16.7%, respectively. The median survival of 23 patients who received CRT was 22.9 months, with a 3-year survival rate of 30.4%. The two most common grade 3 or 4 adverse events during induction GS were neutropenia (63.3%) and biliary tract infection (20%). Toxicities during CRT or maintenance chemotherapy were generally mild.

Conclusions

This regimen was feasible and highly active resulting in encouraging survival in patients with LAPC. Further investigations are warranted to elucidate the effectiveness of this treatment strategy in future studies.

Clinical trials information: UMIN000006332.

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via IFTTT

Body Mass Index and Risk of Gastric Cancer: A 30-year Follow-up Study in the Linxian General Population Trial Cohort

Abstract

Although a number of previous studies have noted either positive or no association for body mass index (BMI) and gastric cancers risk, little evidence exists in the Chinese population. We prospectively examined the associations of BMI with risk of gastric cancers in the Linxian General Population Trial cohort, with 29,584 healthy adults enrolled in 1985 and followed through the end of 2014. Body weight and height were measured during physical examination at baseline and BMI was calculated as weight in kilograms divided by height in meters squared. BMI from 138 subjects was missing, and a total of 29,446 participants were included in the final analysis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs). During 30-year of follow-up, we confirmed newly-diagnosed 1,716 gastric cardia adenocarcinoma (GCA) cases and 626 new gastric non-cardia adenocarcinoma (GNCA) cases.Overall, compared to the lowest quartile (BMI less than 20.32 kg/m²), subjects in the fourth quartile (BMI ≥ 23.31 kg/m²) subjects had lower risk of developing GNCA(HR=0.65;95%CI: 0.51-0.83). Age- and sex-specific analyses showed that this protective effect was only observed in men and older (52+ yrs) persons. No associations were observed for BMI with GCA incidence. Higher BMI was associated with decreased risk of GNCA in this population, particularly in men and older persons. Future studies are needed to confirm these findings.

This article is protected by copyright. All rights reserved.

http://ift.tt/2rF77TJ