Cancer by Sfakianakis Alexandros: 09/20/17

Τετάρτη 20 Σεπτεμβρίου 2017

CDK4/6 inhibition in early and metastatic breast cancer: a review

Publication date: Available online 20 September 2017
Source:Cancer Treatment Reviews
Author(s): A.F. de Groot, C.J. Kuijpers, J.R. Kroep
Breast cancer (BC) is responsible for 14% of cancer-related deaths in women. [1] Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of selective drugs, offering an effective and tolerable treatment. CDK 4/6 inhibitors induce cell cycle arrest in the G1 phase, and may thereby prevent tumour progression. Three CDK 4/6 inhibitors have been tested in clinical BC trials: palbociclib, ribociclib, and abemaciclib. The Food and Drug Administration (FDA) and European Commission (EMA) have approved palbociclib for the treatment of patients HR+ HER2- locally advanced or metastatic BC (aBC) in combination with an aromatase inhibitor as initial therapy in postmenopausal women or in combination with fulvestrant in women who have received prior endocrine therapy. Ribociclib has been approved by the FDA in combination with an aromatase inhibitor as initial therapy for postmenopausal women with HR+ HER2- aBC. Moreover, CDK 4/6 inhibitors have shown promising results in the (neo)adjuvant setting. In this review, the principal completed and ongoing clinical trials in aBC are reviewed for both the metastatic as (neo)adjuvant setting. Tables will provide a complete overview of the ongoing clinical trials. At last, the future perspectives of these CDK4/6 inhibitors are discussed.

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Induction of reactive oxygen species: an emerging approach for cancer therapy

Abstract

Reactive oxygen species (ROS), a group of ions and molecules, include hydroxyl radicals (·OH), alkoxyl radicals, superoxide anion (O₂·−), singlet oxygen (¹O₂) and hydrogen peroxide (H₂O₂). Hydroxyl radicals and alkoxyl radicals are extremely and highly reactive species respectively. Endogenous ROS are mainly formed in mitochondrial respiratory chain. Low levels of ROS play important roles in regulating biological functions in mammalian cells. However, excess production of ROS can induce cell death by oxidative damaging effects to intracellular biomacromolecules. Cancer cell death types induced by ROS include apoptotic, autophagic, ferroptotic and necrotic cell death. Since abnormal metabolism in cancer cells, they have higher ROS content compared to normal cells. The higher endogenous ROS levels in cancer cells endow them more susceptible to the ROS-induction treatment. Indeed, some anticancer drugs currently used in clinic, such as molecular targeted drugs and chemotherapeutic agents, effectively kill cancer cells by inducing ROS generation. In addition, photodynamic therapy (PDT) is mainly based on induction of ROS burst to kill cancer cells. The mechanism of cell death induced by radiotherapy using ionizing radiation also refers to ROS production. Moreover, ROS play an important role in tumor immune therapy. Altogether, combining above traditional treatments with ROS-induced agents will be considered as a promising strategy in cancer therapy. In this review, we focus on our current understanding of the anticancer effects of ROS.

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Presence of periaortic gas in Clostridium septicum-infected aortic aneurysm aids in early diagnosis: a case report and systematic review of the literature

Clostridium septicum-infected aortic aneurysm is a fatal and rare disease. We present a fatal case of C. septicum-infected aortic aneurysm and a pertinent literature review with treatm...

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Anesthesia and Perioperative Care for Organ Transplantation.

No abstract available

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Acute Lung Injury and Repair: Scientific Fundamentals and Methods.

No abstract available

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Factors Influencing the Choice of Anesthesia as a Career by Undergraduates of the University of Rwanda.

No abstract available

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Administration of Hypertonic Solutions for Hemorrhagic Shock: A Systematic Review and Meta-analysis of Clinical Trials.

BACKGROUND: Several clinical trials on hypertonic fluid administration have been completed, but the results have been inconclusive. The objective of this study is to summarize current evidence for treating hypovolemic patients with hypertonic solutions by performing a systematic review and meta-analysis. METHODS: Major electronic databases were searched from inception through June 2014. We included only randomized controlled trials involving hemorrhagic shock patients treated with hypertonic solutions. After screening 570 trials, 12 were eligible for the final analysis. Pooled effect estimates were calculated with a random effect model. RESULTS: The 12 studies included 6 trials comparing 7.5% hypertonic saline (HS) with 0.9% saline or Ringer's lactate solution and 11 trials comparing 7.5% hypertonic saline with dextran (HSD) with isotonic saline or Ringer's lactate. Overall, there were no statistically significant survival benefits for patients treated with HS (relative risk [RR], 0.96; 95% confidence interval [CI], 0.82-1.12) or HSD (RR, 0.92; 95% CI, 0.80-1.06). Treatment with hypertonic solutions was also not associated with increased complications (RR, 1.03; 95% CI, 0.78-1.36). Subgroup analysis on trauma patients in the prehospital or emergency department settings did not change these conclusions. There was no evidence of significant publication bias. Metaregression analysis did not find any significant sources of heterogeneity. CONCLUSIONS: Current evidence does not reveal increased mortality when the administration of isotonic solutions is compared to HS or HSD in trauma patients with hemorrhagic shock. HS or HSD may be a viable alternative resuscitation fluid in the prehospital setting. Further studies are needed to determine the optimum volume and regimen of intravenous fluids for the treatment of trauma patients. (C) 2017 International Anesthesia Research Society

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The Little ICU Book, 2nd ed.

No abstract available

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Preventing Mistransfusions: An Evaluation of Institutional Knowledge and a Response.

BACKGROUND: Blood product mistransfusions occur when a process error causes transfusion of incompatible blood products. These events are known sources of negative patient outcomes. One such event demonstrated an institutional knowledge gap and an opportunity to reduce this source of transfusion errors. The focus of this study was to evaluate the application of point of care cognitive aids to bridge potentially lethal knowledge gaps in blood product to patient compatibility. METHODS: A patient-donor ABO antigen compatibility grid for red blood cells (RBC) and fresh frozen plasma (FFP) was developed for creation of a cognitive aid and a blood product safety quiz. Participants included 117 registered nurses and postgraduate medical interns who were given 2 minutes to complete the quiz for establishing institutional controls. A separate group of 111 registered nurses and interns were given the same timed quiz twice, without and then with a blood product compatibility cognitive aid. An analysis of covariance was used to evaluate without cognitive aid versus with cognitive aid quiz results while taking the specialty (nurse versus interns) and baseline score into consideration. The blood bank adopted the grid as a forcing function to be completed before release of blood products. RESULTS: The correct RBC answer percentage increased from 84.7% to 98.3% without and with cognitive aid (average improvement 13.6%, standard deviation [SD] = 18.3%, 95% confidence interval, 10.1%-17.1%, P

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The Relationship Between Women's Intention to Request a Labor Epidural Analgesia, Actually Delivering With Labor Epidural Analgesia, and Postpartum Depression at 6 Weeks: A Prospective Observational Study.

BACKGROUND: Postpartum depression (PPD) is associated with pain during and after delivery, with studies showing reduced rates among women delivering with labor epidural analgesia (LEA). We hypothesized that women who intend to deliver with LEA but do not receive it are at higher risk for PPD at 6 weeks due to the combined experience of untreated labor pain and unmatched expectations during labor, and evaluated the interaction between labor plans related to LEA, satisfaction with pain control when actually delivering with LEA, and PPD at 6 weeks after delivery. METHODS: A total of 1497 women with a vaginal delivery were enrolled into this prospective longitudinal study. Women's initial intention to deliver with or without LEA, how they subsequently delivered, and satisfaction with pain relief were recorded on postpartum day 1. Primary aim was selected as PPD at 6 weeks among women intending to deliver with but subsequently delivering without LEA compared with the rest of the cohort. Primary outcome was PPD at 6 weeks using the Edinburgh Postnatal Depression Scale; PPD was defined with a score >=10 (scale from 0 to 30). Demographic and obstetric data were recorded. Fisher exact test was used for comparisons between groups. The interaction between intention and actual delivery with regard to LEA and PPD was tested. RESULTS: Overall, 87 of 1326 women completing the study at 6 weeks had PPD (6.6%). For the primary aim, 439 (29.3%) delivered without LEA, of which 193 (12.9%) had intended to deliver with LEA; the PPD rate among these women was 8.1%, which was not statistically different from the rest of the cohort (6.3%; odds ratio [OR], 1.30; 95% confidence interval [CI], 0.72-2.38; P = .41). A total of 1058 women (70.7%) delivered with LEA and 439 (29.3%) delivered without; therefore, 1169 (78.1%) delivered as intended and 328 (21.9%) did not (unmatched expectations). Evaluating the interaction between effects, there was a strong negative additive interaction between intending to deliver without LEA and actually delivering with LEA (risk difference = -8.6%, 95% CI, 16.2%-1.6%; P = .014) suggesting that unmatched intention effect is significantly associated with negative outcome. In multiple regression analysis, while intending to deliver with LEA (OR, 1.06; 95% CI, 1.01-1.11; P = .029) and actually delivering with LEA (OR, 1.07; 95% CI, 1.01-1.13; P = .018) both increased the odds for PPD, the multiplicative interaction was protective (OR, 0.92; 95% CI, 0.86-0.99; P = .022), after adjusting for cofactors. CONCLUSIONS: Our study results did not demonstrate a significant increase in the odds for PPD at 6 weeks among women who intended to deliver with LEA but subsequently delivered without. However, we identified a protective interaction between intended LEA use and actual use on the incidence of PPD. Our data suggest an increased risk when women do not deliver as intended, particularly when not initially intending to deliver with LEA. The relationship between unplanned LEA and PPD may be mediated by a physically difficult delivery rather than or in addition to negative emotions related to unmet expectations or a sense of personal failure; therefore, counseling women after delivery to address any negative perceptions may be useful. (C) 2017 International Anesthesia Research Society

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Other Specialties Might Have a GPS.

No abstract available

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Melanoma Drugs Effective as Adjuvants [News in Brief]

Targeted and immune therapies delay recurrence after surgery.

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Gemtuzumab Ozogamicin Makes a Comeback [News in Brief]

CD33-targeting agent reapproved at a lower dose for AML after studies show benefit outweighs risk.

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Are You What You Eat or What Your Mother Ate or Both?

A high-fat high-sugar (HF-HS) diet promotes cancer development and progression. However, does the timing of diet matter? This is an important question with profound public health relevance. By exposing mice to a HF-HS diet either through feeding to a pregnant mother or nursing mother or after weaning and then chemically inducing breast cancer, the authors found the most crucial time for breast cancer risk was after weaning, while a HF-HS in utero diet actually slowed tumor development. Understanding early-life events provides valuable insight for later life events and proves it is never too early to start preventing disease. Cancer Prev Res; 10(10); 1–2. ©2017 AACR.

See related article by Lambertz, p. 553-62.

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A novel oncoplastic technique for breast cancer localized in the lower pole of the breast

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Incidence and predictors of postoperative delirium after cytoreduction surgery-hyperthermic intraperitoneal chemotherapy

Background

Incidence of, and baseline characteristics associated with delirium in patients after cytoreduction surgery-hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), were subject of investigation.

Methods

The study was conducted among a consecutive series of prospectively included patients who underwent CRS-HIPEC at the University Medical Center Groningen, Groningen, the Netherlands, between February 2006 and January 2015. A chart-based instrument for delirium during hospitalization was used to identify patients with symptoms of delirium who were not diagnosed by a psychiatrist during admission. Uni- and multivariate logistic regression analyses were performed.

Results

Data of 136 patients were included in the analysis. Median age was 60 years (range: 18-76) and 50 (37%) patients were male. During hospitalization, 38 (28%) patients were diagnosed with delirium. Factors that differed significantly between the patients with and without delirium by univariate analysis were included in multivariate analysis. Multivariate analysis showed that after adjustment for age and complications other than delirium, having three or more organs resected and the CRP serum levels were independent predictors for delirium (OR: 3.97; 95% 1.24-12.76; OR: 1.01; 95% 1-1.01, respectively).

Conclusions

This report shows an incidence of 28% of delirium, occurring after CRS-HIPEC and suggests a role for systemic inflammation in the development of postoperative delirium.

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Timing of disease occurrence and hepatic resection on long-term outcome of patients with neuroendocrine liver metastasis

Background and Objectives

The objective of the study was to evaluate the impact of timing of disease occurrence and hepatic resection on long-term outcome of neuroendocrine liver metastasis (NELM).

Methods

A total of 420 patients undergoing curative-intent resection for NELM were identified from a multi-institutional database. Date of primary resection, NELM detection and resection, intraoperative details, disease-specific (DSS), and recurrence-free survival (RFS) were obtained.

Results

A total of 243 (57.9%) patients had synchronous NELM, while 177 (42.1%) developed metachronous NELM. On propensity score matching (PSM), patients with synchronous versus metachronous NELM had comparable DSS (10-year DSS, 76.2% vs 85.9%, P = 0.105), yet a worse RFS (10-year RFS, 34.1% vs 59.8%, P = 0.008). DSS and RFS were comparable regardless of operative approach (simultaneous vs staged, both P > 0.1). Among patients who developed metachronous NELM, no difference in long-term outcomes were identified between early (≤2 years, n = 102, 57.6%) and late (>2 years, n = 68, 42.4%) disease on PSM (both P > 0.1).

Conclusions

Patients with synchronous NELM had a higher risk of tumor recurrence after hepatic resection versus patients with metachronous disease. The time to development of metachronous NELM did not affect long-term outcome. Curative-intent hepatic resection should be considered for patients who develop NELM regardless of the timing of disease presentation.

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Frequent BRAF mutations suggest a novel oncogenic driver in colonic neuroendocrine carcinoma

Background and Objectives: The World Health Organization (WHO) 2010 has classified GI neuroendocrine neoplasms into neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). The genetic underpinnings of NEC are poorly understood. The aim of the study was to perform genomic profiling of NEC to better characterize this aggressive disease.

Methods: We identified nine patients with colonic NEC between January 1, 2005 and June 30, 2013. Whole exome sequencing (WES) was performed on tumor DNA from two patients with ≥80% tumor cellularity and matched normal tissue available. Focused BRAF mutational analysis was performed on an additional seven patients via sanger sequencing of BRAF exons 11 and 15.

Results: We identified BRAF exon 15 mutations (c.A1781G: p.D594G and c.T1799A: p.V600E) by WES in two patients. Upon additional screening of seven colonic NECs for BRAF exon 11 and 15 mutations, we identified BRAF V600E mutations in two of seven specimens (29%). Overall, BRAF exon 15 mutations were present in four of nine colonic NECs.

Conclusion: Colonic NEC is a rare but aggressive tumor with high frequency (44%) of BRAF mutations. Further investigation is warranted to ascertain the incidence of BRAF mutations in a larger population as BRAF inhibition may be a potential avenue of targeted treatment for these patients.

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Emerging role of multimodality treatment in gall bladder cancer: Outcomes following 510 consecutive resections in a tertiary referral center

Background and Objectives

Gall bladder cancer (GBC) is a disease with high incidence in India. We analyzed the outcomes of patients with suspected GBC who underwent surgical exploration.

Methods

Analysis of a prospectively maintained database of patients undergoing surgical exploration for clinic-radiologically suspected GBC from January 2010 to August 2015. Outcomes as well as factors influencing survival were analyzed.

Results

Five hundred and ten patients underwent surgery for suspected GBC. Of these 400 had histologically proven malignancy. Eighty patients were deemed inoperable. Radical cholecystectomy was performed in 153 patients, revision surgery for incidental GBC in 160 and port site excision in seven patients. A total of 112 received peri-operative chemotherapy or chemoradiation. Majority were stage III (36%, n = 144) and stage II (31.8% n = 127). At a median follow up of 28.4 months, the median overall survival (OS) was not yet reached. Median disease free survival (DFS) was 33.4 months. Lymph node involvement, stage of the disease and resection status were the main factors influencing outcomes (P = 0.0001).

Conclusion

Surgery alone is curative only for early GBC (Stage I). Combination of surgery and peri-operative systemic therapy results in favorable outcomes even in stage II/III disease. Potentially, multimodality treatment may add meaningful survival for this disease with inherently aggressive tumor biology.

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The role of pre-operative imaging and double balloon enteroscopy in the surgical management of small bowel neuroendocrine tumors: Is it necessary?

Background and Objectives

Pre-operative localization of small bowel neuroendocrine tumors (SBNET) is important for operative planning. The aim was to determine the effectiveness of pre-operative imaging and double-balloon enteroscopy (DBE) in identifying extent of disease.

Methods

Database review identified 85 patients with primary SBNET between 2006 and 2013. Analysis included patients who underwent imaging, endoscopy, and surgery at our institution.

Results

Average age was 60.7 years. Sixty-six (77.1%) patients had a primary NET in the ileum. Seventy-two patients (67.3%) underwent CT, 47 (46.7%) had MRI, 44 (46.7%) had somatostatin receptor imaging (SRI), and 41 (39.3%) underwent DBE. The sensitivity of each in identifying the NET was 59.7% for CT, 54% for MRI, 56% for SRI, and 88.1% for DBE. Eighteen (21.2%) patients had primary tumors not identified on imaging. Of these 18, 13 underwent DBE, and 12 of 13 (92.3%) DBEs identified the primary lesion. DBE was significantly better at identifying the primary NET than CT, MRI or SRI (P = 0.004, 0.007, and 0.012).

Conclusions

Most SBNETs are identified with a combination of imaging modalities. In those with unidentified primary tumors after imaging, DBE should be considered as it may provide valuable information as to the location of the primary tumor.

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The impact of perioperative CA19-9 change on the survival and recurrence patterns after adjuvant chemoradiotherapy in resectable extrahepatic cholangiocarcinoma

Backgrounds

Perioperative CA19-9 value in pancreato-biliary cancers has been recognized as a prognostic factor. Herein, we investigated survival differences and recurrence patterns after adjuvant chemoradiotherapy by perioperative CA19-9 change in surgically resected extrahepatic cholangiocarcinoma.

Methods

Patients were divided into those with preoperative normal CA19-9 (Group 1, n = 52), those with high preoperative and normalized postoperative CA19-9 (Group 2, n = 80), and those with both high pre- and postoperative CA19-9 (Group 3, n = 21).

Results

Depending on the group defined above, the 5-year overall survival (OS) (59.6%, 38.7%, and 9.5%, P < 0.001) and disease-free survival (55.8%, 31.2%, and 9.5%, P < 0.001) between the three groups differed. On multivariable analysis in patients other than group 1, poor prognosticators for OS were high postoperative CA19-9 (HR 2.26, P = 0.008) and N1 disease (HR 2.33, P = 0.001). Group 3, compared with group 2, showed higher distant metastasis rate, shorter disease-free interval, and higher CA19-9 at the time of recurrence.

Conclusions

Survival and recurrence patterns after adjuvant chemoradiotherapy are significantly affected by perioperative CA19-9 change. This may have important implications in patient selection for adjuvant chemoradiotherapy and clinical trial design.

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Systematic assessment of clinical outcomes and toxicities of proton radiotherapy for reirradiation

Reirradiation (reRT) for locoregional recurrences poses unique challenges and risks; re-treatment using proton beam radiotherapy (PBT) could prove advantageous. Assessing clinical outcomes and toxicity profiles, this systematic review comprehensively evaluated available evidence regarding PBT reRT. Fourteen original investigations across central nervous system (CNS) (n=6), head/neck (H&N) (n=4), lung (n=2), and gastrointestinal (n=2) malignancies were analyzed. PBT for recurrent uveal melanoma achieved 5-year eye retention of 55%; for chordomas, reRT afforded a 2-year local control and overall survival (OS) of 85% and 80%, respectively.

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Corrigendum to “Niemann-Pick Disease Type C Presenting as a Developmental Coordination Disorder with Bullying by Peers in a School-Age Child”

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Colorectal cancer: Epigenetic alterations and their clinical implications

Publication date: Available online 20 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Alberto Puccini, Martin D. Berger, Madiha Naseem, Ryuma Tokunaga, Francesca Battaglin, Shu Cao, Diana L. Hanna, Michelle McSkane, Shivani Soni, Wu Zhang, Heinz-Josef Lenz
Colorectal cancer (CRC) is a heterogeneous disease with distinct molecular and clinical features, which reflects the wide range of prognostic outcomes and treatment responses observed among CRC patients worldwide. Our understanding of the CRC epigenome has been largely developed over the last decade and it is now believed that among thousands of epigenetic alterations present in each tumor, a small subgroup of these may be considered as a CRC driver event. DNA methylation profiles have been the most widely studied in CRC, which includes a subset of patients with distinct molecular and clinical features now categorized as CpG island methylator phenotype (CIMP). Major advances have been made in our capacity to detect epigenetic alterations, providing us with new potential biomarkers for diagnostic, prognostic and therapeutic purposes. This review aims to summarize our current knowledge about epigenetic alterations occurring in CRC, underlying their potential future clinical implications in terms of diagnosis, prognosis and therapeutic strategies for CRC patients.

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Overcoming the Challenges of Metastatic Cancer: An Interview with Dr. Rosandra Kaplan

NCI's Dr. Rosandra Kaplan discusses important trends in metastatic cancer research and new ideas for treating and preventing metastatic cancer.

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Overcoming the Challenges of Metastatic Cancer: An Interview with Dr. Rosandra Kaplan

NCI's Dr. Rosandra Kaplan discusses important trends in metastatic cancer research and new ideas for treating and preventing metastatic cancer.

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Cell free nucleic acids as diagnostic and prognostic marker in leukemia

Summary

Nucleic acids in circulation, called cell free DNA (cfDNA) and cell free RNA (cfRNA), have recently been analyzed as suitable diagnostic and prognostic markers in cancer. There have also been several reports about the role of this type of marker in leukemia. The relevant literature was identified by a PubMed search (2000–2017) of English-language literature using the terms "cell free DNA", "Leukemia" and Micro-RNA. Many quantitative and qualitative cfDNA biomarkers including copy number alteration, mutation, LOH and micro-RNA deregulated expression have been investigated in different studies, indicating promising results to distinguish patients from healthy individuals. The findings of this study indicate that nucleic acids in circulation have a high diagnostic and prognostic value in leukemic patients and, thus, have the potential to be used alongside the usual methods in the management of this disease.

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Cell free nucleic acids as diagnostic and prognostic marker in leukemia

Summary

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Use of Telemedicine to Deliver Global Medical Care

By Nathan Douthit

Telemedicine is an important developing field for global health. Its use has been endorsed by the World Health Organization (WHO), Medecins Sans Frontieres and multiple other national health services and Non-Governmental Organizations (NGOs). Telemedicine has multiple definitions, but the one endorsed by the WHO is:

"The delivery of health care services, where distance is a critical factor, by all health care profes- sionals using information and communication technologies for the exchange of valid information for diagnosis, treatment and prevention of disease and injuries, research and evaluation, and for the continuing education of health care providers, all in the interests of advancing the health of individuals and their communities". ¹

One of the earliest recorded instances of telemedicine was the transmission of an electrocardiograph in 1906. However, recent applications include sharing of data for specialist assistance in diagnosis and management, education of healthcare professionals and patients, research on difficult to reach populations and even screening services for health monitoring and maintenance. Telemedicine certainly has applications in the developed world and in urban centres. However, the effective delivery of telemedicine can make an unprecedented impact in developing countries and rural areas.

In the case report, "Remote care of a patient with stroke in rural Trinidad: use of telemedicine to optimize global neurological care," Reyes and Ramcharan describe "The use of… [telemedicine] for low-income countries to provide support for high-risk patients." Their case specifically focuses on the application of teleneurology, or remote access to specialists in neurology. The patient described was seen in hospital by a neurologist, but on discharge home it was noted that the "patient's home was located in a low income village 60 km away from the GP[general practitioner's] office." In order to continue monitoring the patient for improvement, the patient's 24 hour caregiver

"[W]as initially trained by the GP to collect, process and transmit the patient's data by the use of a smart phone and a laptop with internet access. The GP and the neurologist also used similar technology."

This allowed medical care to be provided to the patient in a timely fashion. The caregiver was educated to recognize seizures, falls, neurogenic bladder, and dysphasia.

"Once the event was recognised, the caregiver called on the GP assistance over a phone call and/or via email. The GP instructed the caregiver on first aid actions for the… event in order to prevent further complication… [and, if necessary, arranged] transportation of the patient to the nearest health facility available. Concurrently, the GP called on the senior neurologist for remote assistance…. The GP coordinated initial management of the complicated patient with the caregiver, paramedics and other doctors remotely…. The GP saw the patient directly to verify all instructions were carried out correctly, but there was no need for the neurologist to examine the patient for those reasons."

The authors conclude that this treatment model, "[S]uggest[s] that improved access to primary, secondary and tertiary levels of neurological care in remote and underserved regions of the world is a feasible way forward." They also correctly remind us that, "This is a global issue that requires urgent consensus and actions by stakeholders."

In light of this, BMJ Case Reports invites authors to publish cases regarding the trials and successes of telemedicine in delivering medicine in difficult to reach areas. Global health case reports can emphasize:

-successful models of management, such as the one above

-difficulties in implementing telemedicine due to cultural, geographical or technical constraints

-innovative uses of telemedicine

-the use of telemedicine across linguistic, cultural, ethnic and geopolitical barriers

Manuscripts may be submitted by students, physicians, nurses or other medical professionals to BMJ Case Reports. For more information, review the blog on how to write a global health case report.

Household material hardship in families of children post-chemotherapy

Abstract

Poverty is an important patient-reported outcome of therapy and a potential predictor of outcome disparities in pediatric cancer. We previously identified that nearly 30% of pediatric cancer families experience household material hardship (HMH), a concrete measure of poverty including food, energy, or housing insecurity, during the first 6 months of chemotherapy. We conducted a follow-up survey in a subcohort of these families at least 1 year off-therapy and found that 32% reported HMH in early survivorship. Persistently high concrete resource needs off-therapy may have significance for child health and quality of life, and thus represent targets for future investigation.

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Household material hardship in families of children post-chemotherapy

Abstract

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Primary Hepatic Angiosarcoma: A Case Report with 10-Year Patient Medical Data

In the current study, we report a case of a 46-year-old man who presented with sudden abdominal pain and was diagnosed with rupture of hepatic angiosarcoma (HAS). He underwent surgery, but died 13 days after the onset of the abdominal pain. Chronic exposure to carcinogens, such as thorium dioxide, arsenic, vinyl chloride, and radium, is associated with HAS. However, our patient had not been exposed to such carcinogens. He had submitted himself for annual medical checkups since he was employed. His liver was cirrhotic, and medical history data showed that he had had fatty liver for at least 10 years before HAS onset. Although liver cirrhosis may play a role in the occurrence of HAS, the connection of chronic fatty liver in the tumorigenesis remains unclear. Case reports regarding HAS with fatty liver are few. To the best of our knowledge, this is the first case of HAS occurring in a cirrhotic liver that advanced from persistent fatty stage. Given that HAS is a rare tumor, data collection is important for investigating its pathophysiology. Case presentations considering health conditions before HAS onset are limited; therefore, we present a case of HAS with annual health checkup data before disease onset.
Case Rep Oncol 2017;10:851–856

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Burned-Out Testicular Cancer: Really a Different History?

Two or more histological types characterize more than 60% of testicular germ cell tumors (GCTs). Burned-out testicular tumor refers to partial or complete histological regression of the primary testicular lesions. The most frequent GCT type involved in this kind of histological regression is choriocarcinoma, followed by embryonal carcinoma. To our knowledge, there are no cases of the burned-out phenomenon in teratoma. We report a case of a 19-year-old man presenting to our institute with a right testicular lesion, evidence of mediastinal and abdominal lymph node metastasis, and high levels of GCT serum biomarkers. After orchiectomy, the histopathological examination showed a mixed GCT: mature teratoma, immature teratoma, and histological features of testicular cancer regression (burned-out phenomenon). The patient underwent first-line chemotherapy (BEP regimen) which resulted in a complete instrumental and biochemical response after 4 cycles. Teratoma is considered a less aggressive type of GCT. In this particular case, metastatic disease seems to result from non-germ cell components which underwent early spontaneous regression.
Case Rep Oncol 2017;10:846–850

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Treatment of Leptomeningeal Metastases in a Patient with Non-Small Cell Lung Cancer Harboring EGFR T790M Mutation

Background: Leptomeningeal metastasis (LM) is an uncommon complication in patients with solid tumors, associated with poor survival. However, LM appears to be more frequent in lung cancer patients with EGFR mutations, posing a unique clinical challenge to treating physicians. Case Presentation: We report the case of a 68-year-old Asian man with metastatic lung adenocarcinoma harboring an EGFR L858R mutation, which was initially treated with gefitinib. He developed disease progression 1 year later. Re-biopsy of the right lower lobe primary lesion revealed only an EGFR L858R mutation in the absence of a T790M mutation. The patient also experienced persistent confusion and generalized fatigue, and magnetic resonance imaging (MRI) of the brain demonstrated extensive LM. At this time, a liquid biopsy revealed an EGFR T790M mutation. Following initiation of treatment with osimertinib, the patient exhibited a rapid response with MRI of the brain showing substantial improvement of the LM after 6 months. Unfortunately, the LM recurred after 1 year at which time the patient declined further systemic chemotherapy. Conclusion: To our knowledge, this is the second reported case of LM in a patient with lung cancer harboring an EGFR T790M mutation that was successfully treated with osimertinib.
Case Rep Oncol 2017;10:840–845

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Does intensity-modulated radiation therapy (IMRT) alter prostate size? Magnetic resonance imaging evaluation of patients undergoing IMRT alone

Publication date: November–December 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 6
Author(s): Hidekazu Tanaka, Takahiro Yamaguchi, Kae Hachiya, Masahide Hayashi, Shinichi Ogawa, Hironori Nishibori, Shingo Kamei, Satoshi Ishihara, Masayuki Matsuo
AimTo assess the changes in prostate size in patients with prostate cancer undergoing intensity-modulated radiation therapy (IMRT).BackgroundThe effect of size change produced by IMRT is not well known.Materials and methodsWe enrolled 72 patients who received IMRT alone without androgen-deprivation therapy and underwent magnetic resonance imaging (MRI) examination before and after IMRT. The diameter of the entire prostate in the anterior–posterior (P-AP) and left–right (P-LR) directions was measured. The transitional zone diameter in the anterior–posterior (T-AP) and left–right (T-LR) directions was also measured.ResultsThe average relative P-AP values at 3, 6, 12, 24, and 36 months after IMRT compared to the pre-IMRT value were 0.94, 0.90, 0.89, 0.89, and 0.90, respectively; the average relative P-LR values were 0.93, 0.92, 0.91, 0.91, and 0.90, respectively. The average P-AP and P-LR decreased by approximately 10% during the 12 months post-IMRT, and remained unchanged thereafter. The average relative T-AP values at 3, 6, 12, 24, and 36 months after IMRT compared to the pre-IMRT value were 0.93, 0.88, 0.91, 0.87, and 0.89, respectively; the average relative T-LR values were 0.96, 0.90, 0.91, 0.87, and 0.88, respectively. The average T-AP and T-LR also decreased by approximately 10% during the 12 months post-IMRT, and remained unchanged thereafter. At 12 months after IMRT, the average relative T-AP was significantly lower in patients with recurrence than in those without recurrence.ConclusionsThe average prostate diameter decreased by approximately 10% during the 12 months after IMRT; thereafter remained unchanged.

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Adaptive radiotherapy in a case of adenoid cystic carcinoma of bronchus and its favourable impact on treatment outcome: A case report

Publication date: November–December 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 6
Author(s): Suman Das, Yogaraja Dorairaja, Anandakrishnan Kuppusamy
Adenoid cystic carcinoma is a very rare malignancy commonly originating from the salivary glands of the head and neck. It is again very scantily seen in sites like the bronchus. Surgical resection is the mainstay of treatment but many a times the tumour site and size preclude a favourable outcome of surgery and the patient is advised for other forms of local treatment like Radiotherapy. Here, we present a case report of a young female with primary adenoid cystic carcinoma of the bronchus. The tumour was located in the carina and the left bronchus which was obstructing the airway resulting in collapse of the left lung, this resulted in shifting the mediastinum and abdominal structures in to the thorax. The tumour was inoperable and was advised for radiotherapy. The adenoid cystic carcinoma of the bronchus with such presentation and mediastinal shift is a rare and special situation. During radiotherapy the collapsed lung was inflated which resulted in the shifting of the tumour and other normal structures. The use of adaptive radiotherapy in such situation helped us to achieve improved dose delivery to the tumour and this resulted in an improved survival for the patient as compared to the available literature.

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Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): Implications for the risk of malignancy (ROM) in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC)

BACKGROUND

The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) mostly in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories. In this multi-institutional, retrospective study, the authors investigated variations in the impact of an NIFTP diagnosis on the associated ROM for each TBSRTC category with an emphasis on the influence of pathologist and institutional diagnostic thresholds on the ROM.

METHODS

Baseline data on cytology and histology diagnostic categories were collected over a 3-year period at 3 academic center hospitals (institutions A, B, and C). Histology slides for all cases diagnosed as follicular variant of papillary thyroid carcinoma (FVPTC) were re-reviewed at each institution, and those that qualifying as NIFTP were separated from other PTCs.

RESULTS

The collective case cohort from the 3 institutions included 15,973 thyroid fine-needle aspiration cytology (FNAC) specimens and 5090 thyroid surgical resection specimens. Significant differences in baseline cytology and histology data were noted among the 3 institutions. The number of cases classified as NIFTP compared with FVPTC was highly variable (institution A, 14%; institution B, 39%; and institution C, 12%). For 3250 resected thyroid nodules with a previous FNAC diagnosis, the average decrease in ROM after the exclusion of NIFTP for all TBSRTC categories was as follows: institution A, 9.8%; institution B, 3.9%; and institution C, 1.3%.

CONCLUSIONS

The institutional frequency of NIFTP histopathology diagnosis and cytology baseline data will impact the ROM associated with specific FNAC diagnoses, especially among the indeterminate TBSRTC categories. The range of ROM for each TBSRTC diagnostic category is reflective of the inherent diagnostic thresholds and interobserver and interinstitutional variability in the diagnosis of thyroid lesions. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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Preparing our next generation of pathologists: The criticality of critical reading

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Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): Implications for the risk of malignancy (ROM) in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC)

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

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Preparing our next generation of pathologists: The criticality of critical reading

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[ 18 F]Fluoromisonidazole PET in rectal cancer

Abstract

Background

There is an increasing interest in developing predictive biomarkers of tissue hypoxia using functional imaging for personalised radiotherapy in patients with rectal cancer that are considered for neoadjuvant chemoradiotherapy (CRT). The study explores [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) positron emission tomography (PET) scans for predicting clinical response in rectal cancer patients receiving neoadjuvant CRT.

Methods

Patients with biopsy-proven rectal adenocarcinoma were imaged at 0–45 min, 2 and 4 h, at baseline and after 8–10 fractions of CRT (week 2). The first 6 patients did not receive an enema (the non-enema group) and the last 4 patients received an enema before PET-CT scan (the enema group). [¹⁸F]FMISO production failed on 2 occasions. Static PET images at 4 h were analysed using tumour-to-muscle (T:M) SUVmax and tumour-to-blood (T:B) SUVmax. The 0–45 min dynamic PET scans were analysed using Casciari model to report hypoxia and perfusion. Akaike information criteria (AIC) were used to compare data fittings for different pharmacokinetic models. Pathological tumour regression grade was scored using American Joint Committee on Cancer (AJCC) 7.0. Shapiro-Wilk test was used to evaluate the normality of the data.

Results

Five out of eleven (5/11) patients were classed as good responders (AJCC 0/1 or good clinical response) and 6/11 as poor responders (AJCC 2/3 or poor clinical response). The median T:M SUVmax was 2.14 (IQR 0.58) at baseline and 1.30 (IQR 0.19) at week 2, and the corresponding median tumour hypoxia volume was 1.08 (IQR 1.31) cm³ and 0 (IQR 0.15) cm³, respectively. The median T:B SUVmax was 2.46 (IQR 1.50) at baseline and 1.61 (IQR 0.14) at week 2, and the corresponding median tumour hypoxia volume was 5.68 (IQR 5.86) cm³ and 0.76 (IQR 0.78) cm³, respectively. For 0–45 min tumour modelling, the median hypoxia was 0.92 (IQR 0.41) min⁻¹ at baseline and 0.70 (IQR 0.10) min⁻¹ at week 2. The median perfusion was 4.10 (IQR 1.71) ml g⁻¹ min⁻¹ at baseline and 2.48 (IQR 3.62) ml g⁻¹ min⁻¹ at week 2. In 9/11 patients with both PET scans, tumour perfusion decreased in non-responders and increased in responders except in one patient. None of the changes in other PET parameters showed any clear trend with clinical outcome.

Conclusions

This pilot study with small number of datasets revealed significant challenges in delivery and interpretation of [¹⁸F]FMISO PET scans of rectal cancer. There are two principal problems namely spill-in from non-tumour tracer activity from rectal and bladder contents. Emphasis should be made on reducing spill-in effects from the bladder to improve data quality. This preliminary study has shown fundamental difficulties in the interpretation of [¹⁸F]FMISO PET scans for rectal cancer, limiting its clinical applicability.

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[ 18 F]Fluoromisonidazole PET in rectal cancer

Abstract

Background

Methods

Results

Conclusions

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Evaluating a preoperative protocol that includes magnetic resonance imaging for lymph node metastasis in the Cholangiocarcinoma Screening and Care Program (CASCAP) in Thailand

Abstract

Background

Treatment planning especially liver resection in cholangiocarcinoma (CCA) depends on the extension of tumor and lymph node metastasis which is included as a key criterion for operability. Magnetic resonance imaging (MRI) offers a rapid and powerful tool for the detection of lymph node metastasis (LNM) and in the current manuscript is assessed as a critical tool in the preoperative protocol for liver resection for treatment of CCA. However, the accuracy of MRI to detect LNM from CCA had yet to be comprehensively evaluated.

Methods

The accuracy of MRI to detect LNM was assessed in a cohort of individuals with CCA from the Cholangiocarcinoma Screening and Care Program (CASCAP), a screening program designed to reduce CCA in Northeastern Thailand by community-based ultrasound (US) for CCA. CCA-positive individuals are referred to one of the nine tertiary centers in the study to undergo a preoperative protocol that included enhanced imaging by MRI. Additionally, these individuals also underwent lymph node biopsies for histological confirmation of LNM (the "gold standard") to determine the accuracy of the MRI results.

Results

MRI accurately detected the presence or absence of LNM in only 29 out of the 51 CCA cases (56.9%, 95% CI 42.2–70.7), resulting in a sensitivity of 57.1% (95% CI 34.0–78.2) and specificity of 56.7% (95% CI 37.4–74.5), with positive and negative predictive values of 48.0% (95% CI 27.8–68.7) and 65.4% (95% CI 44.3–82.8), respectively. The positive likelihood ratio was 1.32 (95% CI 0.76–2.29), and the negative likelihood ratio was 0.76 (95% CI 0.42–1.36).

Conclusions

MRI showed limited sensitivity and a poor positive predictive value for the diagnosis of LNM for CCA, which is of particular concern in this resource-limited setting, where simpler detection methods could be utilized that are more cost-effective in this region of Thailand. Therefore, the inclusion of MRI, a costly imaging method, should be reconsidered as part of protocol for treatment planning of CCA, given the number of false positives, especially as it is critical in determining the operability for CCA subjects.

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Evaluating a preoperative protocol that includes magnetic resonance imaging for lymph node metastasis in the Cholangiocarcinoma Screening and Care Program (CASCAP) in Thailand

Abstract

Background

Methods

Results

Conclusions

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Erratum to: Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology

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Erratum to: Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology

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Randomized trial of Tibetan yoga in patients with breast cancer undergoing chemotherapy

BACKGROUND

The current randomized trial examined the effects of a Tibetan yoga program (TYP) versus a stretching program (STP) and usual care (UC) on sleep and fatigue in women with breast cancer who were undergoing chemotherapy.

METHODS

Women with stage (American Joint Committee on Cancer (AJCC) TNM) I to III breast cancer who were undergoing chemotherapy were randomized to TYP (74 women), STP (68 women), or UC (85 women). Participants in the TYP and STP groups participated in 4 sessions during chemotherapy, followed by 3 booster sessions over the subsequent 6 months, and were encouraged to practice at home. Self-report measures of sleep disturbances (Pittsburgh Sleep Quality Index), fatigue (Brief Fatigue Inventory), and actigraphy were collected at baseline; 1 week after treatment; and at 3, 6, and 12 months.

RESULTS

There were no group differences noted in total sleep disturbances or fatigue levels over time. However, patients in the TYP group reported fewer daily disturbances 1 week after treatment compared with those in the STP (difference, -0.43; 95% confidence interval [95% CI], -0.82 to -0.04 [P = .03]) and UC (difference, -0.41; 95% CI, -0.77 to -0.05 [P = .02]) groups. Group differences at the other time points were maintained for TYP versus STP. Actigraphy data revealed greater minutes awake after sleep onset for patients in the STP group 1 week after treatment versus those in the TYP (difference, 15.36; 95% CI, 7.25-23.48 [P = .0003]) and UC (difference, 14.48; 95% CI, 7.09-21.87 [P = .0002]) groups. Patients in the TYP group who practiced at least 2 times a week during follow-up reported better Pittsburgh Sleep Quality Index and actigraphy outcomes at 3 months and 6 months after treatment compared with those who did not and better outcomes compared with those in the UC group.

CONCLUSIONS

Participating in TYP during chemotherapy resulted in modest short-term benefits in sleep quality, with long-term benefits emerging over time for those who practiced TYP at least 2 times a week. Cancer 2017. © 2017 American Cancer Society.

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Probability of cancer in high-risk patients predicted by the protein-based lung cancer biomarker panel in China: LCBP study

BACKGROUND

The authors built a model for lung cancer diagnosis previously based on the blood biomarkers progastrin-releasing peptide (ProGRP), carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), and cytokeratin 19 fragment (CYFRA21-1). In the current study, they examined whether modification of the model to include relevant clinical information, risk factors, and low-dose chest computed tomography screening would improve the performance of the biomarker panel in large cohorts of Chinese adults.

METHODS

The current study was a large-scale multicenter study (ClinicalTrials.gov identifier NCT01928836) performed in a Chinese population. A total of 715 participants were enrolled from 5 regional centers in Beijing, Henan, Nanjing, Shanghai, and Chongqing between October 2012 and February 2014. Serum biomarkers ProGRP, CEA, SCC, and CYFRA21-1 were analyzed on the ARCHITECT i2000SR. Relevant clinical information was collected and used to develop a patient risk model and a nodule risk model.

RESULTS

The resulting patient risk model had an area under the receiver operating characteristic (ROC) curve of 0.7037 in the training data set and 0.7190 in the validation data set. The resulting nodule risk model had an area under the ROC curve of 0.9151 in the training data set and 0.5836 in the validation data set. Moreover, the nodule risk model had a relatively higher area under the ROC curve (0.9151 vs 0.8360; P = 0.001) compared with the American College of Chest Physician model in patients with lung nodules.

CONCLUSIONS

Both the patient risk model and the nodule risk model, developed for the early diagnosis of lung cancer, demonstrated excellent discrimination, allowing for the stratification of patients with different levels of lung cancer risk. These new models are applicable in high-risk Chinese populations. Cancer 2017. © 2017 American Cancer Society.

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Randomized trial of Tibetan yoga in patients with breast cancer undergoing chemotherapy

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

http://ift.tt/2xRIO9u

Probability of cancer in high-risk patients predicted by the protein-based lung cancer biomarker panel in China: LCBP study

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

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Cancers, Vol. 9, Pages 127: Liver Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

Cancers, Vol. 9, Pages 127: Liver Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

Cancers doi: 10.3390/cancers9090127

Authors: Germana Castelli Elvira Pelosi Ugo Testa

Liver cancer is the second most common cause of cancer-related death. The major forms of primary liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Both these tumors develop against a background of cirrhotic liver, non-alcoholic fatty liver disease, chronic liver damage and fibrosis. HCC is a heterogeneous disease which usually develops within liver cirrhosis related to various etiologies: hepatitis B virus (HBV) infection (frequent in Asia and Africa), hepatitis C virus (HCV), chronic alcohol abuse, or metabolic syndrome (frequent in Western countries). In cirrhosis, hepatocarcinogenesis is a multi-step process where pre-cancerous dysplastic macronodules transform progressively into HCC. The patterns of genomic alterations observed in these tumors were recently identified and were instrumental for the identification of potential targeted therapies that could improve patient care. Liver cancer stem cells are a small subset of undifferentiated liver tumor cells, responsible for cancer initiation, metastasis, relapse and chemoresistance, enriched and isolated according to immunophenotypic and functional properties: cell surface proteins (CD133, CD90, CD44, EpCAM, OV-6, CD13, CD24, DLK1, α2δ1, ICAM-1 and CD47); the functional markers corresponding to side population, high aldehyde dehydrogenase (ALDH) activity and autofluorescence. The identification and definition of liver cancer stem cells requires both immunophenotypic and functional properties.

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Cancers, Vol. 9, Pages 127: Liver Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

Cancers, Vol. 9, Pages 127: Liver Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

Cancers doi: 10.3390/cancers9090127

Authors: Germana Castelli Elvira Pelosi Ugo Testa

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Diagnostic and prognostic value of carcinoembryonic antigen in pancreatic cancer: a systematic review and meta-analysis

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Profile of trifluridine/tipiracil hydrochloride in the treatment of metastatic colorectal cancer: efficacy, safety, and place in therapy

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Transient Ischemic Attack and Ischemic Stroke in Danon Disease with Formation of Left Ventricular Apical Thrombus despite Normal Systolic Function

Danon disease is a rare X-linked dominant skeletal and cardiac muscle disorder presenting with hypertrophic cardiomyopathy, Wolf-Parkinson-White syndrome, skeletal myopathy, and mild intellectual disability. Early morbidity and mortality due to heart failure or sudden death are known in Danon disease, more in males than in females. Here, we present a 17-year-old female adolescent with Danon disease and severe concentric hypertrophy with normal left ventricular (LV) systolic function, who has been complaining of intermittent headache and weakness for about 3 years, initially diagnosed with hemiplegic migraine. Subsequently, her neurological manifestation progressed to transient ischemic attack (TIA) and eventually to ischemic stroke confirmed by CT scan with 1-day history of expressive aphasia followed by persistent left side weakness and numbness. Detailed echocardiogram for the first time revealed a small LV apical thrombus with unchanged severe biventricular hypertrophy and normal systolic function. This unexpected LV apical thrombus may be associated with a wide spectrum of neurological deficits ranging from TIA to ischemic stroke in Danon disease. Possibility of cerebral ischemic events should be suspected in Danon disease when presenting with neurological deficits even with normal systolic function. Careful assessment for LV apical thrombus is warranted in such cases.

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Capecitabine-based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency

Abstract

Fluoropyrimidines are frequently used anti-cancer drugs. It is known that patients with reduced activity of dihydropyrimidine dehydrogenase (DPD), the key metabolic enzyme in fluoropyrimidine inactivation, are at increased risk of developing severe fluoropyrimidine-related toxicity. Upfront screening for DPD deficiency and dose reduction in patients with partial DPD deficiency is recommended and improves patient safety. For patients with complete DPD deficiency, fluoropyrimidine-treatment has generally been discouraged. During routine pretreatment screening, we identified a 59-year old patient with a sigmoid adenocarcinoma who proved to have a complete DPD deficiency. Genetic analyses showed that this complete absence of DPD activity was likely to be caused by a novel DPYD genotype, consisting of a combination of amplification of exon 17 and 18 of DPYD and heterozygosity for DPYD*2A. Despite absence of DPD activity, the patient was treated with capecitabine-based chemotherapy, but capecitabine dose was drastically reduced to 150 mg once every five days (0.8% of original dose). Pharmacokinetic analyses showed that the area under the concentration-time curve (AUC) and half-life of 5-fluorouracil were respectively ten-fold and four-fold higher compared to control values of patients receiving capecitabine 850 mg/m². When extrapolating from the dosing schedule of once every five days to twice daily, the AUC of 5-fluorouracil was comparable to controls. Treatment was tolerated well for eight cycles by the patient without occurrence of capecitabine-related toxicity. This case report demonstrates that a more comprehensive genotyping and phenotyping approach, combined with pharmacokinetically-guided dose administration, enables save fluoropyrimidine-treatment with adequate drug exposure in completely DPD deficient patients. This article is protected by copyright. All rights reserved.

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Histological subtypes of ovarian cancer associated with parity and breastfeeding in the prospective Million Women Study

Abstract

Ovarian cancer risk is known to be reduced amongst women who have had children, but reported associations with breastfeeding are varied. Few studies have had sufficient power to explore reliably these associations by tumour histotype.

In a prospective study of 1.1 million UK women, 8719 developed ovarian cancer during follow-up. Cox regression yielded adjusted relative risks (RRs) overall and by tumour histotype amongst women with different childbearing patterns.

Nulliparous women had a 24% greater ovarian cancer risk than women with one child, with significant heterogeneity by histotype (p=0.01). There was no significant increase in serous tumours, a modest increase in mucinous tumours, but a substantial increase in endometrioid (RR=1.49, 95% CI: 1.18-1.89) and clear-cell tumours (RR=1.68, 1.29-2.20).

Among parous women, each additional birth was associated with an overall 6% reduction in ovarian cancer risk; this association also varied by histotype (p=0.0006), with the largest reduction in risk for clear-cell tumours (RR per birth=0.75, 0.65-0.85, p<0.001) and weak, if any, effect for endometrioid, high-grade serous, or mucinous tumours. We found little association with age at first or last birth. There was about a 10% risk reduction per 12-months breastfeeding (RR=0.89, 0.84-0.94, p<0.001), with no significant heterogeneity by histotype, but statistical power was limited.

In this large prospective study, ovarian cancer risk associated with parity varied substantially by tumour histotype. Nulliparity was associated with a substantially greater overall risk than expected from the effect of a single birth, especially for clear cell and endometrioid tumours, perhaps suggesting that infertility is associated with these histotypes. This article is protected by copyright. All rights reserved.

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CRHR2/Ucn2 signaling is a novel regulator of miR-7/YY1/Fas circuitry contributing to reversal of colorectal cancer cell resistance to Fas-mediated apoptosis

Abstract

Colorectal cancer (CRC) responds poorly to immuno-mediated cytotoxicity. Underexpression of Corticotropin-releasing-hormone-receptor-2 (CRHR2) in CRC, promotes tumor survival, growth and Epithelial to Mesenchymal Transition (EMT), in vitro and in vivo. We explored the role of CRHR2 downregulation in CRC cell resistance to Fas/FasL-mediated apoptosis and the underlying molecular mechanism.

CRC cell sensitivity to CH11-induced apoptosis was compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing CRC cell lines and targets of CRHR2/Ucn2 signaling were identified through in vitro and ex vivo analyses. Induced CRHR2/Ucn2 signaling in SW620 and DLD1 cells increased specifically their sensitivity to CH11-mediated apoptosis, via Fas mRNA and protein upregulation. CRC compared to control tissues had reduced Fas expression that was associated with lost CRHR2 mRNA, poor tumor differentiation and high risk for distant metastasis. YY1 silencing increased Fas promoter activity in SW620 and re-sensitized them to CH11-apoptosis; suggesting YY1 as a putative transcriptional repressor of Fas in CRC. An inverse correlation between Fas and YY1 expression was confirmed in CRC tissue arrays, while elevated YY1 mRNA was clinically relevant with advanced CRC grade and higher risk for distant metastasis. CRHR2/Ucn2 signaling downregulated specifically YY1 expression through miR-7 elevation, while miR-7 modulation in miR-7^high SW620-CRHR2+ and miR-7^low HCT116 cells, had opposite effects on YY1 and Fas expressions and cell sensitivity to CH11-killing.

CRHR2/Ucn2 signaling is a negative regulator of CRC cell resistance to Fas/FasL-apoptosis via targeting the miR-7/YY1/Fas circuitry. CRHR2 restoration might prove effective in managing CRC response to immune-mediated apoptotic stimuli. This article is protected by copyright. All rights reserved.

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Post-marketing research and its outcome for novel anticancer agents approved by both the FDA and EMA between 2005 and 2010: A cross-sectional study

Abstract

Post-marketing research in oncology has rarely been described. We aimed to characterize post-marketing trials for a consistent set of anticancer agents over a long period. We performed a cross-sectional analysis of post-marketing trials registered at ClinicalTrials.gov through September 2014 for novel anticancer agents approved by both the US Food and Drug Administration and the European Medicines Agency between 2005 and 2010. All relevant post-marketing trials were classified according to indication, primary outcome, starting date, sponsors, and planned enrollment. Supplemental indications were retrieved from regulatory documents and publication rate was assessed by two different methods. Ten novel anticancer agents were eligible: five were indicated for hematologic malignancies and the remaining five for solid cancers (three for kidney cancer). We identified 2345 post-marketing trials; 1362 (58.1%) targeted an indication other than the originally approved one. We observed extreme variations among drugs in both number of post-marketing trials [range 8–530] and overall population to be enrolled per trial [1–8381]. Post-marketing trials assessed almost all types of cancers, the three most frequently studied cancers being leukemia, kidney cancer and myeloma. In all, 6.6% of post-marketing trials had a clinical endpoint as a primary outcome, and 35.9% and 54.1% had a safety or surrogate endpoint, respectively, as a primary outcome. Nine drugs obtained approval for supplemental indications. The publication rate at 10 years was 12.3% to 26.1% depending on the analysis method. In conclusion, we found that post-marketing research in oncology is highly heterogeneous and the publication rate of launched trials is low. This article is protected by copyright. All rights reserved.

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Potent antitumor effect of tumor microenvironment-targeted oncolytic adenovirus against desmoplastic pancreatic cancer

Abstract

Pancreatic cancer is a leading cause of cancer-related death. Desmoplastic pancreatic tumors exhibit excessive extracellular matrix (ECM) and are thus highly resistant to anticancer therapeutics, since the ECM restricts drug penetration and dispersion. Here, we designed and generated two hypoxia-responsive and cancer-specific hybrid promoters, H(mT)E and H(E)mT. Transgene expression driven by each hybrid promoter was markedly higher under hypoxic conditions than normoxic conditions. Moreover, H(E)mT-driven transgene expression was highly cancer-specific and was superior to that of H(mT)E-driven expression. A decorin-expressing oncolytic adenovirus (Ad; oH(E)mT-DCN) replicating under the control of the H(E)mT promoter induced more potent and highly cancer-specific cell death compared with its cognate control oncolytic Ad, which harbored the endogenous Ad E1A promoter. Moreover, oH(E)mT-DCN exhibited enhanced antitumor efficacy compared with both the clinically approved oncolytic Ad ONYX-015 and its cognate control oncolytic Ad lacking DCN. oH(E)mT-DCN treatment also attenuated the expression of major ECM components, such as collagen I/III, elastin, and fibronectin, and induced tumor cell apoptosis, leading to extensive viral dispersion within orthotopic pancreatic tumors and pancreatic cancer patient-derived tumor spheroids. Collectively, these findings demonstrate that oH(E)mT-DCN exhibits potent antitumor efficacy by degrading the ECM and inducing apoptosis in a multifunctional process. This process facilitates the dispersion and replication of oncolytic Ad, making it an attractive candidate for the treatment of aggressive and desmoplastic pancreatic cancer. This article is protected by copyright. All rights reserved.

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Migraine and invasive epithelial ovarian cancer risk in the Nurses' Health Study II and the Women's Health Study

Abstract

Migraine is a common primary headache disorder, which predominantly impacts women. Recently, migraine has been hypothesized to be associated with hormonally related cancers; however the potential association between migraine and ovarian cancer has not been studied.

Therefore, we evaluated the association between migraine and invasive epithelial ovarian cancer risk in two prospective cohorts, the Nurses' Health Study II (NHSII) and the Women's Health Study (WHS). Our prospective analysis included 113,124 NHSII participants aged 25-42 at study baseline as well as 33,490 participants in the WHS who were 45 years or older at study entry. We used Cox proportional hazards models to estimate the hazard ratios (HR) and 95% confidence intervals (CIs) for the association between migraine and ovarian cancer risk in each cohort. In secondary analyses, we stratified by age and menopausal status. After adjusting for potential covariates, there was no statistically significant association between migraine and ovarian cancer risk in either the NHSII (HR=1.29, 95%CI: 0.96, 1.74) or the WHS (HR=0.60, 95%CI: 0.34, 1.06). In stratified analysis in the NHSII, there was a statistically significant positive association between migraine and ovarian cancer risk among women < 45 years of age (HR=1.76, 95%CI: 1.01, 3.07). We did not observe a clear association between migraine and ovarian cancer risk in two large prospective cohort studies. This article is protected by copyright. All rights reserved.

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Association between long-term low-intensity cigarette smoking and incidence of smoking-related cancer in the National Institutes of Health-AARP cohort

Abstract

An increasing proportion of US smokers smoke ≤10 cigarettes per day (CPD) or do not smoke every day, yet the health effects of low-intensity smoking are poorly understood. We identified lifelong smokers of <1 or 1-10 CPD and evaluated risk of incident cancer among 238,525 cancer-free adults, aged 59-82, in the NIH-AARP Diet and Health Study. A questionnaire administered in 2004-2005 assessed CPD during nine age-periods (<15 to ≥70). We estimated hazard ratios (HR) and 95% confidence intervals (CI) using multivariable-adjusted Cox proportional hazards regression with age as the underlying time metric. Of the 18,233 current smokers (7.6%), 137 and 1,243 reported consistently smoking <1 CPD and 1-10 CPD, respectively. Relative to never smokers, current smokers who reported consistently smoking 1-10 CPD over their lifetime were 2.34 (95% CI=1.86-2.93) times more likely to develop smoking-related cancer. Current lifetime smokers of <1 CPD were 1.89 (95% CI=0.90-3.96) times more likely to develop tobacco-related cancer, although the association did not reach statistical significance. Associations were observed for lifelong smoking of ≤10 CPD with lung cancer (HR=9.65, 95% CI=6.93-13.43); bladder cancer (HR=2.22, 95% CI=1.22-4.05); and pancreatic cancer (HR=2.03, 95%CI: 1.05-3.95). Among lifelong ≤10 CPD smokers, former smokers had lower risks of smoking-related cancer with longer time since cessation and longer smoking duration. Lifelong <1 and 1-10 CPD smokers are at increased risk of incident cancer relative to never smokers and would benefit from cessation, providing further evidence that even even low-levels of cigarette smoking cause cancer. This article is protected by copyright. All rights reserved.

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Capecitabine-based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency

Abstract

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Histological subtypes of ovarian cancer associated with parity and breastfeeding in the prospective Million Women Study

Abstract

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CRHR2/Ucn2 signaling is a novel regulator of miR-7/YY1/Fas circuitry contributing to reversal of colorectal cancer cell resistance to Fas-mediated apoptosis

Abstract

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Post-marketing research and its outcome for novel anticancer agents approved by both the FDA and EMA between 2005 and 2010: A cross-sectional study

Abstract

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Potent antitumor effect of tumor microenvironment-targeted oncolytic adenovirus against desmoplastic pancreatic cancer

Abstract

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Migraine and invasive epithelial ovarian cancer risk in the Nurses' Health Study II and the Women's Health Study

Abstract

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Association between long-term low-intensity cigarette smoking and incidence of smoking-related cancer in the National Institutes of Health-AARP cohort

Abstract

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Regorafenib in advanced hepatocellular carcinoma (HCC): considerations for treatment

Abstract

Purpose

We report our institutional observations of ten patients with advanced hepatocellular carcinoma (HCC) (seven and three were Child–Pugh class A and B, respectively) who received compassionate regorafenib therapy between June 2016 and January 2017. These patients did not fit the rigid criteria of a clinical trial and represented the use of regorafenib in an everyday clinic situation.

Methods

Regorafenib (160 mg P.O. daily) was administered to patients on a 4-week cycle (3 weeks on, 1 week off) until disease progression (assessed using mRECIST criteria) or discontinuation secondary to toxicity (assessed using CTCAE criteria). Relevant clinical data were abstracted from patient medical records and reviewed retrospectively.

Results

The median duration of patient treatment was 6.6 weeks, and the median time to disease progression was 12.5 weeks. Most common treatment emergent adverse events were fatigue, diarrhea, and hand–foot skin reaction. Elevated AST and ALT were the most commonly observed laboratory-assessed adverse events, which reached grade 3 status in the Child–Pugh class B patients only. We observed intolerance to regorafenib treatment in one patient who had previously received a liver transplant. We also saw lithium toxicity in one patient receiving long-term lithium treatment, suggesting a potential and unexpected drug–drug interaction with regorafenib.

Conclusions

Taken together, our observations indicate that regorafenib is beneficial in the treatment of patients with advanced HCC who progressed on or demonstrated intolerance to sorafenib therapy; however, careful selection and close monitoring of patients is necessary to maximize the benefit while minimizing the toxicities of regorafenib treatment.

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