Cancer by Sfakianakis Alexandros: 03/22/18

Πέμπτη 22 Μαρτίου 2018

Local Anesthetic Injection Speed and Common Peroneal Nerve Block Duration: A Randomized Controlled Trial in Healthy Volunteers

Background and Objectives The speed of local anesthetic (LA) injections in peripheral regional anesthesia ranges from slow continuous infusions (3–12 mL/h) to rapid manual injections (>7500 mL/h). Optimizing injection speed could augment the spread of LA toward the targeted nerves and influence nerve block characteristics. The objective of this study was to investigate whether injection speed of a single dose of LA affects peripheral nerve block duration. Methods After approval from the Danish Regional Scientific Ethics Committee, we enrolled 60 healthy adult volunteers. We used an ultrasound-guided catheter-based technique to perform a common peroneal nerve block. Participants were randomized to receive 4.0 mL of ropivacaine 0.2% with 1 of 5 injection speeds: 12, 60, 300, 600, or 1800 mL/h. Investigators and participants were blinded to group assignment and intervention. Primary outcome was duration of sensory nerve block defined by insensitivity toward cold. Secondary outcomes were duration of motor nerve block, time to onset of sensory nerve block, and grades of sensory and motor nerve block. Intergroup differences were tested by one-way analysis of variance. Results We found no differences in sensory block duration between the 5 groups. Durations were median [range]: 11 [6–14], 12 [9–14], 10.5 [2–15], 11 [8–17], and 12 [9–18] hours, respectively (P = 0.294). In addition, we found no differences in secondary outcomes. Conclusions Injection speed of LA in the range of 12 to 1800 mL/h did not affect common peroneal nerve block duration. Clinical Trial Registration This study was registered at ClinicalTrials.gov, identifier NCT02801799. Accepted for publication November 13, 2017. Address correspondence to: Mikkel Herold Madsen, MD, Department of Anesthesiology, Nordsjællands Hospital Hillerød, Dyrehavevej 29, Building 52B, 4th Floor, DK-3400 Hillerød, Denmark (e-mail: mhmadsen@gmail.com). This work was funded by Innovation Fund Denmark and by Nordsjællands Hospital Hillerød. This work was presented in part at the American Society of Regional Anesthesia and Pain Medicine 42nd Annual Regional Anesthesiology and Pain Medicine Meeting; San Francisco, CA; April 6 to 8, 2017. The authors declare no conflict of interest. Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.

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Central congenital hypothyroidism caused by maternal thyrotoxicosis

Central congenital hypothyroidism (CCH) is a rare and underdiagnosed disease that sometimes is caused by maternal Graves' disease. We report a case of CCH caused by undiagnosed, initially antibody-negative maternal thyrotoxicosis with possible disruption of fetal hypothalamic-pituitary-thyroid axis maturation. In CCH, maternal thyroid disease should be considered.

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Case of a fractured human bone fragment as an endobronchial foreign body following a traffic incident

Endobronchial foreign bodies (EFBs) are present in various settings, such as eating or dental procedure. Accidental aspiration of foreign bodies is more common in children; however, cases of adult foreign body aspiration exist. Traumatic incidents can precipitate endobronchial aspiration of foreign bodies. Loss of consciousness, such as in coma, can result in foreign bodies being easily inhaled into the airways. Teeth or vehicle parts have been reported as EFBs following traumatic incidents. We report on a patient with chronic, sustained cough following maxillofacial trauma. Chest CT revealed an abnormal calcified endobronchial opacity. Flexible bronchoscopy confirmed the presence of an endobronchial foreign body in the left main bronchus. Following removal by bronchial forceps, the body was identified as a human bone fragment. Successful removal of the endobronchial bone fragment resulted in complete symptom remission. We concluded that post-traumatic respiratory complaints should be comprehensively evaluated, even if mild.

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What does vanishing bone disease look like?

Description

A previously healthy 44-year-old female presented with an acute history of increasing pain and reduced range of movement in her left shoulder. MRI scan revealed an infiltrative lesion in the proximal humerus, with a degree of cortical thinning and soft tissue involvement; however, initial biopsy provided no definitive diagnosis. Due to the suspicion of underlying malignancy, additional biopsies were organised. A second biopsy provided no diagnosis; however, a third biopsy taken 2 months after presentation revealed a benign vascular lesion with callus formation. This was consistent with the suspicion of our radiologist that a pathological fracture of the proximal humerus had been sustained following a minor fall (figure 1).

Figure 1

Radiograph of left humerus and shoulder at presentation.

Twelve months after presentation, with continued pain and swelling in the arm, further investigations were carried out. Radiographs demonstrated a second...

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Klippel-Trenaunay-Weber syndrome as a cause of chronic thromboembolic pulmonary hypertension

Description

A 52-year-old man was referred to an adult cardiovascular genetic clinic for lifelong venous tortuosity of the left leg. His medical history included recurrent deep venous thromboses of the left leg and pulmonary embolism complicated by oxygen-dependent chronic thromboembolic pulmonary hypertension and right-sided heart failure. He was taking warfarin and reported no family history of similar conditions. On examination, crackles were noted at bibasilar lungs. The left leg was slightly longer than the right leg, and giant tortuous veins were observed on the left side (figure 1A). MRI and angiography of the lower extremities revealed diffuse muscular hypertrophy (figure 1B) and bone elongation of the femur, tibia and fibula, as well as multiple capillary-venous malformations and tortuous deep and superficial veins (figure 1C) on the left leg. Chest tomography angiography showed pulmonary artery dilatation and calcified eccentric thrombus in the right pulmonary...

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Testicular torsion in a patient with Ehlers-Danlos syndrome

We present a 19-year-old man with a diagnosis of Ehlers-Danlos syndrome (EDS) and a delayed presentation of testicular torsion. EDS is a rare and heterogeneous condition affecting collagen synthesis and presents multiple difficulties in a surgical setting. Management of this case of testicular torsion was complicated by impaired cognition of the patient, difficulty with intubation, a contralateral undescended testis and postoperative bleeding. We discuss the specific challenges faced in this case of testicular torsion with longstanding ischaemia and perioperative considerations of EDS.

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Two cases of hypokalaemic rhabdomyolysis: same but different

In this paper, we present two women with hypokalaemic rhabdomyolysis in the context of increased diuretic intake and gastroenteritis, respectively. While their clinical manifestations and laboratory results were strikingly similar, two different underlying disorders were subsequently unveiled. The first patient was diagnosed with Conn syndrome, and adrenalectomy led to significant improvement of hypertension and sustained normokalaemia. The diagnosis in the second patient was Gitelman syndrome. Electrolyte supplements improved long-term lassitude and the frequency of muscle cramps declined significantly. These case vignettes illustrate the importance of establishing the underlying cause of hypokalaemia.

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A rare presentation of haematuria: hip prosthesis in the bladder

An 80-year-old woman presented to our department with visible haematuria and stage II acute kidney injury (AKI). She had stage IIB cervical cancer, for which she received chemotherapy and external beam radiotherapy in 2003. Four years later, she had a left dynamic hip screw for an extracapsular neck of femur fracture following a fall. In 2010, she underwent a right total hip replacement owing to osteoarthritis, and it was subsequently revised in 2012 owing to a right acetabular component failure. In this admission, her AKI improved with intravenous fluid administration and her haematuria settled following catheterisation with a three-way catheter and bladder irrigation with saline. She underwent a flexible cystoscopy which revealed that a part of her right hip prosthesis was in the bladder, having eroded through the right bony pelvis. However, she declined any surgical interventions.

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Importance of source images of time-of-flight magnetic resonance angiography in the diagnosis of low-flow dural arteriovenous fistulae after traumatic brain injury

Three-dimensional time-of-flight (TOF) magnetic resonance angiography (MRA) can reliably detect dural arteriovenous fistula (dAVF); however, TOF source images should be checked in cases with low-flow dAVFs. A 69-year-old woman reported intractable pulsatile tinnitus after head trauma. It was difficult to diagnose dAVF using conventional MRA, but it was confirmed using a TOF source image. Cerebral angiography revealed a dAVF with a small shunted pouch draining into the sigmoid sinus, accompanying the arterial jet flow. Transarterial embolisation of the shunted pouch completely obliterated the dAVF. The patient's tinnitus immediately disappeared after embolisation. This case suggests that a low-flow Borden type I dAVF is undetectable using conventional MRA, and we emphasise the importance of evaluating TOF source images. Transarterial embolisation of the shunted pouch while preserving the normal sinus flow was safe and effective.

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Rhinofacialentomophthoromycosis

Entomopthoromycosis is a rare subcutaneous fungal infection caused by onidiobolus coronatus affecting mainly the upper respiratory mucosa in immunocompetent people.The manifestations of this disease masquerades other clinical entities.Hence, high index of suspicion is required for prompt diagnosis.Histopathological examination and culture are the gold standard diagnostic tools, however no standard treatment protocols ha been mentioned in literature.We present a case of rhinofacial entomopthoromycosis in a yearold ma with a leftsided rhinofacial swelling to highlight the presence of this unusual fungal infection and its treatment.

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Tarsal buckle with conjunctival prolapse following levator plication for unilateral congenital ptosis

An 8-year-old child underwent uneventful levator plication surgery for unilateral congenital ptosis. Postoperative course for initial few days was uneventful but on day 7, the patient was brought with conjunctival prolapse from the undersurface of upper eyelid due to tarsal kinking and eversion. Early medical management was initiated with frequent surface lubrication to avoid conjunctiva dryness. Under general anaesthesia, right-sided conjunctival repositioning was performed with an eyelid spatula supplemented by three forniceal stay sutures to retain the conjunctiva in its anatomical place. To reverse the tarsal kinking, continued downward traction suture was placed for a period of 2 weeks. At the end of 4 weeks, the conjunctival prolapse was completely resolved with a well-formed superior fornix. At the end of 3 months, the symmetric eyelid position was maintained without any additional complications.

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Complication of intraprosthetic dislocation of dual-mobility hip implant following closed reduction

Total hip replacement is a successful operation for the management of hip pain but there are potential complications, of which dislocation is one of the most common. The management of recurrent dislocation is a challenging problem that requires a multimodal approach and the use of dual-mobility implants is one option. We present a patient who was previously revised with a dual-mobility implant for recurrent dislocation, who had a complication after closed reduction of a subsequent intraprosthetic dislocation. Following a missed radiographical diagnosis, the patient experienced mechanical symptoms on hip flexion caused by a disassociated dual-mobility implant. Subsequent surgical removal of the failed implant and revision was required. Careful study of radiographs revealed an eccentric femoral head and evidence of the disassociated implant within the surrounding soft tissues. Radiographs following closed reduction of intraprosthetic dislocations should be scrutinised closely to detect implant failure to prevent further complications.

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Myocarditis secondary to smallpox vaccination

The development of vaccines ushered in the most profound advancement in 20th century medicine, and have widely been regarded as the one of the most important scientific discovery in the history of mankind. However, vaccines are not without risk; reactions can range from injection site reactions to life-threatening anaphylaxis. Among the more serious vaccine-related sequela is myocarditis. Although myocarditis has been reported following many different vaccines, the smallpox vaccine has the strongest association. We report a case of a 36-year-old active duty service member presenting with progressive dyspnoea, substernal chest pain and lower extremity swelling 5 weeks after receiving the vaccinia vaccination. The aetiology of his acute decompensated heart failure was determined to be from myocarditis. Although the majority of cases of myocarditis resolve completely, some patients develop chronic heart failure and even death. Vaccine-associated myocarditis should always be on the differential for patients that exhibit cardiopulmonary symptoms after recent vaccinations.

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Parkinsons disease with hypocalcaemia: adult presentation of 22q11.2 deletion syndrome

A growing amount of evidence indicates that 22q11.2 deletion syndrome (22q11.2DS) increases the risk of early-onset Parkinson's disease (EOPD). Here, we describe a 36-year-old patient with EOPD. The patient presented with 22q11.2DS features, including associated cognitive disabilities, hypocalcaemia and facial dysmorphia that led us to screen for and confirm this deletion. In addition, hypocalcaemia and vitamin D deficiency were the main factors responsible for severe, painful muscle spasms that were non-levodopa (L-Dopa) responsive and remitted after calcium and vitamin D replacement therapy. Many patients with this deletion remain undiagnosed until adulthood due to the absence of 'major' phenotypic hallmarks, which usually present during early childhood. Later onset problems involving various medical subspecialties are increasingly recognised as important components of 22q11.2DS. Therefore, the multisystem nature and associated burden of morbidities demand a high degree of suspicion for this entity from all clinicians regardless of their medical subspecialty.

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Diffusion-weighted imaging is helpful in the accurate non-invasive diagnosis of breast abscess: correlation with necrotic breast cancer

Clinical differentiation of atypical breast abscesses from necrotic tumour in premenopausal women is challenging and may delay appropriate therapy. In this case report, we present a 36-year-old woman with signs, symptoms and conventional imaging features of malignancy who underwent breast MRI. On diffusion-weighted imaging (DWI), profoundly low apparent diffusion coefficient values were a distinguishing sign of breast abscess from necrotic breast cancer, and helped manage the patient conservatively. We present a companion case of necrotic breast tumour highlighting significant differences in DWI.

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Metabolic and Psychological Impact of a Pragmatic Exercise Intervention Program in Adolescent and Young Adult Survivors of Pediatric Cancer-Related Cerebral Insult

Journal of Adolescent and Young Adult Oncology, Ahead of Print.

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Metabolic and Psychological Impact of a Pragmatic Exercise Intervention Program in Adolescent and Young Adult Survivors of Pediatric Cancer-Related Cerebral Insult

Journal of Adolescent and Young Adult Oncology, Ahead of Print.

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Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies

Publication date: Available online 22 March 2018
Source:Cancer Cell
Author(s): Frederick Arce Vargas, Andrew J.S. Furness, Kevin Litchfield, Kroopa Joshi, Rachel Rosenthal, Ehsan Ghorani, Isabelle Solomon, Marta H. Lesko, Nora Ruef, Claire Roddie, Jake Y. Henry, Lavinia Spain, Assma Ben Aissa, Andrew Georgiou, Yien Ning Sophia Wong, Myles Smith, Dirk Strauss, Andrew Hayes, David Nicol, Tim O'Brien, Linda Mårtensson, Anne Ljungars, Ingrid Teige, Björn Frendéus, Martin Pule, Teresa Marafioti, Martin Gore, James Larkin, Samra Turajlic, Charles Swanton, Karl S. Peggs, Sergio A. Quezada
With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8⁺ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.

Graphical abstract

Teaser

Arce Vargas et al. use a mouse model expressing human FcγRs to show that antibodies with isotypes equivalent to ipilimumab increase the CD8⁺ to Treg ratio by depleting intra-tumoral Tregs to promote tumor rejection. In melanoma patients, response to ipilimumab is associated with a high affinity FcγR polymorphism.

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Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies

Publication date: Available online 22 March 2018
Source:Cancer Cell
Author(s): Xiaojie Yu, H.T. Claude Chan, Christian M. Orr, Osman Dadas, Steven G. Booth, Lekh N. Dahal, Christine A. Penfold, Lyn O'Brien, C. Ian Mockridge, Ruth R. French, Patrick Duriez, Leon R. Douglas, Arwen R. Pearson, Mark S. Cragg, Ivo Tews, Martin J. Glennie, Ann L. White
Anti-CD40 monoclonal antibodies (mAbs) that promote or inhibit receptor function hold promise as therapeutics for cancer and autoimmunity. Rules governing their diverse range of functions, however, are lacking. Here we determined characteristics of nine hCD40 mAbs engaging epitopes throughout the CD40 extracellular region expressed as varying isotypes. All mAb formats were strong agonists when hyper-crosslinked; however, only those binding the membrane-distal cysteine-rich domain 1 (CRD1) retained agonistic activity with physiological Fc gamma receptor crosslinking or as human immunoglobulin G2 isotype; agonistic activity decreased as epitopes drew closer to the membrane. In addition, all CRD2-4 binding mAbs blocked CD40 ligand interaction and were potent antagonists. Thus, the membrane distal CRD1 provides a region of choice for selecting CD40 agonists while CRD2-4 provides antagonistic epitopes.

Graphical abstract

Teaser

CD40 agonist mAbs are being investigated for cancer treatment, whereas antagonistic mAbs are under investigation for the treatment of autoimmune and inflammatory conditions. Yu et al. show that the activity of a CD40 mAb is determined by an interplay between the location of its epitope within CD40 and its isotype.

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Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies

Graphical abstract

Teaser

Current status of postmastectomy radiation therapy in T1–2 breast cancer with limited positive lymph nodes in Japan: Japan Clinical Oncology Group Survey

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Melanoma and Immune Checkpoint Inhibitors

Abstract

Purpose of Review

Prognosis of patients with advanced melanoma is dismal with a median overall survival of about 8 months and 5-year overall survival from a diagnosis of metastatic disease of roughly 10%. However, immune checkpoint inhibitors have brought indispensable benefits to melanoma patients. Here we will review the recent clinical efficacy and adverse events of immune checkpoint inhibitors for melanoma patients.

Recent Findings

The immune checkpoint inhibitors increase confirmed objective response and prolong progression-free and overall survival of the afflicted patients in association with maintaining their quality of life. Although diverse immune-related adverse events occur, most of them are manageable by appropriate immunomodulating agents. Clinical efficacy of immune checkpoint inhibitors continues even after discontinuation of drugs.

Summary

Compared with conventional therapeutic options, the immune checkpoint inhibitors appear to prolong the survival of patients with advanced melanoma. Further clinical trials are warranted to determine whether their combinatory use with other treatment options may augment benefits or not.

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Mucosal Melanoma: a Literature Review

Abstract

Purpose of review

Mucosal melanoma is of great interest due to its aggressive behavior and less favorable prognosis. The literature is mainly case reports and case series. Here, we will collect the knowledge on mucosal melanoma from the last decade and review the literature. The main focus is being site-specific clinical features, treatment, and prognosis.

Recent findings

The use of immunotherapy gain ground as for others subsets of melanoma. Anti-CTLA-4 and anti-PD-1/ PD-L1 blockade in mucosal melanoma have been evaluated in recent studies. Clinical trials are ongoing.

Summary

The etiology of mucosal melanomas remains unknown. Head and neck mucosal melanomas are most common. Wide excision surgery is the treatment of choice. The effect of adjuvant therapy on survival remains questionable due to the limited knowledge. Radiotherapy seems to give better local control. The overall five-year survival rate for mucosal melanomas is 0–45%. Recent data indicates that this may be improved by the immunotherapy in the years to come.

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Melanoma and Immune Checkpoint Inhibitors

Abstract

Purpose of Review

Recent Findings

Summary

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Mucosal Melanoma: a Literature Review

Abstract

Purpose of review

Recent findings

Summary

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Quantitative T-cell repertoire analysis of peripheral blood mononuclear cells from lung cancer patients following long-term cancer peptide vaccination

Abstract

Therapeutic cancer peptide vaccination is an immunotherapy designed to elicit cytotoxic T-lymphocyte (CTL) responses in patients. A number of therapeutic vaccination trials have been performed, nevertheless there are only a few reports that have analyzed the T-cell receptors (TCRs) expressed on tumor antigen-specific CTLs. Here, we use next-generation sequencing (NGS) to analyze TCRs of vaccine-induced CTL clones and the TCR repertoire of bulk T cells in peripheral blood mononuclear cells (PBMCs) from two lung cancer patients over the course of long-term vaccine therapy. In both patients, vaccination with two epitope peptides derived from cancer/testis antigens (upregulated lung cancer 10 (URLC10) and cell division associated 1 (CDCA1)) induced specific CTLs expressing various TCRs. All URLC10-specific CTL clones tested showed Ca²⁺ influx, IFN-γ production, and cytotoxicity when co-cultured with URLC10-pulsed tumor cells. Moreover, in CTL clones that were not stained with the URLC10/MHC-multimer, the CD3 ζ chain was not phosphorylated. NGS of the TCR repertoire of bulk PBMCs demonstrated that the frequency of vaccine peptide-specific CTL clones was near the minimum detectable threshold level. These results demonstrate that vaccination induces antigen-specific CTLs expressing various TCRs at different time points in cancer patients, and that some CTL clones are maintained in PBMCs during long-term treatment, including some with TCRs that do not bind peptide/MHC-multimer.

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Population attributable fractions continue to unmask the power of prevention

Population attributable fractions continue to unmask the power of prevention

Population attributable fractions continue to unmask the power of prevention, Published online: 23 March 2018; doi:10.1038/s41416-018-0062-5

Population attributable fractions continue to unmask the power of prevention

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The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015

The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015

The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015, Published online: 23 March 2018; doi:10.1038/s41416-018-0029-6

The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015

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Population attributable fractions continue to unmask the power of prevention

Population attributable fractions continue to unmask the power of prevention

Population attributable fractions continue to unmask the power of prevention, Published online: 23 March 2018; doi:10.1038/s41416-018-0062-5

Population attributable fractions continue to unmask the power of prevention

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The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015

The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015

The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015

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Targeting Brain-Adaptive Cancer Stem Cells Prohibits Brain Metastatic Colonization of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) exhibits more traits possessed by cancer stem cells (CSC) than other breast cancer subtypes and is more likely to develop brain metastases. TNBC patients usually have shorter survival time after diagnosis of brain metastasis, suggesting an innate ability of TNBC tumor cells in adapting to the brain. In this study, we establish novel animal models to investigate early tumor adaptation in brain metastases by introducing both patient-derived and cell line–derived CSC-enriched brain metastasis tumorsphere cells into mice. We discovered astrocyte-involved tumor activation of protocadherin 7 (PCDH7)-PLCβ-Ca2+-CaMKII/S100A4 signaling as a mediator of brain metastatic tumor outgrowth. We further identified and evaluated the efficacy of a known drug, the selective PLC inhibitor edelfosine, in suppressing the PCDH7 signaling pathway to prohibit brain metastases in the animal models. The results of this study reveal a novel signaling pathway for brain metastases in TNBC and indicate a promising strategy of metastatic breast cancer prevention and treatment by targeting organ-adaptive cancer stem cells.Significance: These findings identify a compound to block adaptive signaling between cancer stem cells and brain astrocytes. Cancer Res; 1–13. ©2018 AACR.

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Partial breast irradiation with CyberKnife after breast conserving surgery: a pilot study in early breast cancer

Abstract

Background

Local recurrences after breast conserving treatment are mainly close to the original tumor site, and as such shorter fractionation strategies focused on and nearest mammary gland, i.e. accelerated partial breast irradiation (APBI), have been developed. Stereotactic APBI has been attempted, although there is little experience using CyberKnife (CK) for early breast cancer.

Methods

This pilot study was designed to assess the feasibility of CK-APBI on 20 evaluable patients of 29 eligible, followed for 2 years. The primary endpoint was acute/sub-acute toxicity; secondary endpoints were late toxicity and the cosmetic result.

Results

Mean pathological tumor size was 10.5 mm (±4.3, range 3–18), 8 of these patients were classified as LumA-like, 11 as LumB-like, and 1 as LumB-HER2-enriched.

Using CK-APBI with Iris, the treatment time was approximately 60 min (range~ 35 to ~ 120). All patients received 30 Gy in five fractions delivered to the PTV. The median number of beams was 180 (IQR 107–213; range:56–325) with a median PTV isodose prescription of 86.0% (IQR 85.0–88.5; range:82–94). The median PTV was 88.1 cm3 (IQR 63.8–108.6; range:32.3–238.8). The median breast V100 and V50 was 0.6 (IQR 0.1–1.5; range:0–13) and 18.6 (IQR 13.1–21.7; range:7.5–37), respectively. The median PTV minimum dose was 26.2 Gy (IQR 24.7–27.6; range 22.3–29.3). Mild side effects were recorded during the period of observation. Cosmetic evaluations were performed by three observers from the start of radiotherapy up to 2 years. Patients' evaluation progressively increase from 60% to 85% of excellent rating; this trend was similar to that of external observer.

Conclusions

These preliminary results showed the safe feasibility of CK-APBI in early breast cancer, with mild acute and late toxicity and very good cosmetic results.

Trial registration

The present study is registered at Clinicaltrial.gov (NCT02896322). Retrospectively egistered August 4, 2016.

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Targeting Brain-Adaptive Cancer Stem Cells Prohibits Brain Metastatic Colonization of Triple-Negative Breast Cancer

False positive plasma genotyping due to clonal hematopoiesis

Purpose: Plasma cell-free DNA (cfDNA) genotyping is increasingly used in cancer care, but assay accuracy is debated. Because most cfDNA is derived from peripheral blood cells (PBC), we hypothesized that nonmalignant mutations harbored by hematopoietic cells (clonal hematopoiesis, CH) could be a cause of false positive plasma genotyping. Experimental Design: We identified patients with advanced NSCLC with KRAS, JAK2, or TP53 mutations identified in cfDNA. With consent, PBC DNA was tested using droplet digital PCR (ddPCR) or next-generation sequencing (NGS) to test for CH-derived mutations. Results: We first studied plasma ddPCR results from 58 EGFR-mutant NSCLC patients. Two had KRAS G12X detected in cfDNA and both were present in PBC, including one where the KRAS mutation was detected serially for 20 months. We then studied 143 plasma NGS results from 122 NSCLC patients, and identified 5 JAK2 V617F mutations derived from PBC. Additionally, 108 TP53 mutations were detected in cfDNA; for 33 of the TP53 mutations, PBC and tumor NGS were available for comparison, and 5 were present in PBC but absent in tumor, consistent with CH. Conclusions: We find that most JAK2 mutations, some TP53 mutations, and rare KRAS mutations detected in cfDNA are derived from CH not tumor. Clinicians ordering plasma genotyping must be prepared for the possibility that mutations detected in plasma, particularly in genes mutated in CH, may not represent true tumor genotype. Efforts to use plasma genotyping for cancer detection may need paired PBC genotyping so that CH-derived mutations are not misdiagnosed as occult malignancy.

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Epigenome-wide SRC-1 mediated gene silencing represses cellular differentiation in advanced breast cancer

Purpose:Despite the clinical utility of endocrine therapies for estrogen receptor positive (ER) breast cancer, up to 40% of patients eventually develop resistance, leading to disease progression. The molecular determinants that drive this adaptation to treatment remain poorly understood. Methylome aberrations drive cancer growth yet the functional role and mechanism of these epimutations in drug resistance are poorly elucidated. Experimental design: Genome-wide multi-omics sequencing approach identified a differentially methylated hub of pro-differentiation genes in endocrine resistant breast cancer patients and cell models. Clinical relevance of the functionally validated methyl-targets was assessed in a cohort of endocrine treated human breast cancers and patient-derived ex vivo metastatic tumours. Results:Enhanced global hypermethylation was observed in endocrine treatment resistant cells and patient metastasis relative to sensitive parent cells and matched primary breast tumor respectively. Using paired methylation and transcriptional profiles we found that SRC-1-dependent alterations in endocrine resistance lead to aberrant hyper-methylation that resulted in reduced expression of a set of differentiation genes. Analysis of ER positive endocrine treated human breast tumors (n=669) demonstrated that low expression of this pro-differentiation gene set significantly associated with poor clinical outcome (p=0.00009). We demonstrate that the re-activation of these genes in vitro and ex vivo reverses the aggressive phenotype. Conclusion: Our work demonstrates that SRC-1-dependent epigenetic remodeling is a 'high level' regulator of the poorly differentiated state in ER-positive breast cancer. Collectively these data revealed an epigenetic reprograming pathway, whereby concerted differential DNA methylation is potentiated by SRC-1 in the endocrine resistant setting.

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False positive plasma genotyping due to clonal hematopoiesis

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Epigenome-wide SRC-1 mediated gene silencing represses cellular differentiation in advanced breast cancer

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Impact of Radiation Therapy Dose Escalation on Prostate Cancer Outcomes and Toxicities

Objectives: Freedom from biochemical failure (FFBF) is a common primary outcome of randomized-controlled trials of prostate cancer (PCa). We aimed to determine how increasing the PCa biologically equivalent dose (BED) of external radiation therapy (RT) is correlated with FFBF and overall patient outcomes: overall survival (OS), distant metastasis (DM), and cancer-specific mortality (CSM); as well as genitourinary (GU), and gastrointestinal toxicities. Materials and Methods: We performed a meta-analysis of 6884 PCa patients from 12 randomized-controlled trials of external beam RT. Mixed effects regression models were used to estimate weighted linear relationships between BED and observed percentages of 5- and 10-year outcomes. For toxicities, a subset analysis of using 3-dimensional conformal RT (3D-CRT) versus intensity-modulated RT (IMRT) was performed. Results: Increasing BED correlated with improved FFBF: 10-year absolute improvement of 9.6% and 7.2% for low-risk and intermediate-risk patients, respectively (P

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EGFR Exon 19 Deletion is Associated With Favorable Overall Survival After First-line Gefitinib Therapy in Advanced Non–Small Cell Lung Cancer Patients

Objectives: Exon 19 deletion and L858R mutation in exon 21 of the epidermal growth factor receptor (EGFR) are both common mutations that predict a good response to EGFR tyrosine kinase inhibitors in non–small cell lung cancer (NSCLC). However, the existence of clinically significant difference in sensitivity to EGFR tyrosine kinase inhibitors among different EGFR mutation subtypes is still a matter of debate. Materials and Methods: The outcome of 60 EGFR mutation-positive advanced NSCLC patients who received first-line gefitinib therapy (250 mg/d) was retrospectively analyzed according to EGFR mutation subtypes. Results: The median progression-free survival (PFS) and overall survival (OS) after the initiation of gefitinib therapy for all patients was 11 and 26 months, respectively. Univariate analysis showed that patients with exon 19 deletion (n=28) had significantly longer median PFS (20 vs. 8 mo, P=0.004) and OS (36 vs. 22 mo, P=0.001) compared with those with L858R mutation (n=25) and uncommon or dual mutations (n=7). Multivariate analysis revealed that exon 19 deletion (P=0.007) was an independent prognostic factor of favorable PFS, with an independent association with poor PFS of male sex (P=0.049). Exon 19 deletion was also independently associated with favorable OS (P

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Efficacy, Safety, and Potential Biomarkers of Sunitinib and Transarterial Chemoembolization (TACE) Combination in Advanced Hepatocellular Carcinoma (HCC): Phase II Trial

Objectives: To evaluate the safety/efficacy and explore biomarkers for a rationally designed combination of sunitinib and transarterial chemoembolization (TACE) in a prospective phase 2 study of advanced hepatocellular carcinoma (HCC). Methods: Inoperable HCC patients with Child-Pugh A disease received 37.5 mg sunitinib from days 1 to 7 followed by TACE on day 8. Sunitinib was resumed from days 15 to 36 followed by 2 weeks off. Patients received subsequent sunitinib cycles of 4 weeks on and 2 weeks off. Dynamic contrast-enhanced magnetic resonance imaging and circulating soluble biomarkers were assessed at baseline, day 8, day 10, and day 36. Results: Sixteen patients with liver only (n=10) and extrahepatic disease (n=6) were enrolled. After a median follow-up of 12.8 months, 2 partial responses, 11 stable disease, and 3 clinical deteriorations were seen for a clinical benefit rate of 81%. Median progression-free survival (PFS) was 8 months (95% CI, 4.3-9.3) and overall survival was 14.9 months (95% CI, 6.3-27.1). Eleven of 16 patients (69%) had grade 3/4 toxicities attributable to sunitinib, the most frequent being thrombocytopenia, amylase/lipase elevations, lymphopenia, and fatigue. Mean Ktrans (volume transfer constant) and viable tumor percent in consented patients decreased by 27% and 14.8%, respectively, with combination therapy. Soluble vascular endothelial growth factor receptor-2 (sVEGFR2) levels, cytokines (interleukin-8, interleukin-21), and monocytes decreased with combination therapy. Estimated sunitinib IC50 values of 15 and 10 ng/mL modulated Ktrans and AUC90. sVEGFR2 levels decreased with Ktrans and AUC90. Conclusions: Encouraging progression-free survival and overall survival were seen with acceptable toxicity in our study of sunitinib and TACE combination in advanced HCC. Potential imaging and serum biomarkers showed increased benefit with combination therapy.

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A Phase I/II Study of Docetaxel, Oxaliplatin, and Fluorouracil (D-FOX) Chemotherapy in Patients With Untreated Locally Unresectable or Metastatic Adenocarcinoma of the Stomach and Gastroesophageal Junction

Background: A randomized phase III study established docetaxel, cisplatin, and 5-fluorouracil (DCF) as one of the standard treatments for patients with untreated advanced gastric cancer (AGC). However, DCF use is limited due toxicity. With the purpose to evaluate a less toxic regimen, we conducted a single arm, phase I/II trial of modified DCF (oxaliplatin, 5-fluorouracil, and docetaxel [D-FOX]) for untreated AGC patients. The primary objective of the phase I study was to determine the maximum tolerated dose of docetaxel and for the phase II study was to assess the progression-free survival (PFS) at 6 months and overall survival (OS). Patients and Methods: We enrolled a total of 98 patients with AGC. Docetaxel and oxaliplatin were administered intravenously on day 1 and 5-fluorouracil was infused starting on day 1 over 48 hours. Cycles were repeated every 2 weeks and patients were monitored for toxicities. Kaplan-Meir curve was used to estimate unadjusted OS and PFS. Results: The maximum tolerated dose of docetaxel was 50 mg/m2. In total, 24 (45%) patients experienced grade 2 adverse events, 22 (41%) experienced grade 3, and 1 (1.9%) experienced grade 4 toxicity. The median PFS in the phase II portion of the study was approximately 6.5 (95% confidence interval, 5.5-9.5) months and the median OS was 11.1 (95% confidence interval, 9.4-18.8) months. Conclusions: D-FOX administered every 2 weeks is a well-tolerated and active regimen in untreated AGC patients.

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A Meta-Analysis of the Association Between Radiation Therapy and Survival for Surgically Resected Soft-Tissue Sarcoma

Objectives: Radiotherapy for soft-tissue sarcoma (STS) has been shown to reduce local recurrence, but without clear improvement in survival. We conducted a meta-analysis to study the association between radiotherapy and survival in patients undergoing surgery for STS. Methods: A systematic review was conducted from PubMed, EMBASE, Web of Science, and Cochrane databases. Our population of interest consisted of adults with primary extremity, chest wall, trunk, or back STS. Our metameters were either an odds or hazard ratio for mortality. A bias score was generated for each study based on margin status and grade. Results: Of 1044 studies, 30 met inclusion criteria for final analysis. The pooled odds ratio in patients receiving radiation was 0.94 (95% confidence interval [CI], 0.78-1.14). The pooled estimate of the hazards ratio in patients receiving radiation was 0.87 (95% CI, 0.73-1.03) overall and 0.65 (95% CI, 0.52-0.82) for studies judged to be at low risk of bias. Significant publication bias was not seen. Conclusions: High-quality studies reporting adjusted hazard ratios are associated with improved survival in patients receiving radiotherapy for STS. Studies in which odds ratios are calculated from event data and those that do not report adjusted outcomes do not show the same association, likely due to confounding by indication.

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Analysis of the Relationship Between Response to Chemotherapy and Response to Radiation Therapy in Patients With Non–Small Cell Lung Cancer Receiving Sequential Treatment

Objectives: We examine whether induction chemotherapy response predicts thoracic radiotherapy response in locally advanced or oligometastatic non–small cell lung cancer. Materials and Methods: Between January 2001 to August 2010, 25 consecutive patients were identified who received systemic dose chemotherapy followed by definitive thoracic radiotherapy alone. All patients had measurable disease after chemotherapy that was evaluable for response to radiotherapy. Response to each modality was scored by RECIST as stable disease (SD), progressive disease (PD), partial response (PR), or complete response (CR). Results: Patients had adenocarcinoma (n=13), squamous cell carcinoma (n=8), or other histologies (n=4). They had stage IIIA (n=6), IIIB (n=14), and IV (n=5) disease. Patients received 2 to 6 cycles (median 4) of platinum-based chemotherapy followed by radiotherapy (median 66.6/1.8 Gy [range 50 to 84 Gy]). Median time between chemotherapy end and radiotherapy start was 6.7 weeks (range, 1.6 to 53.4 wk). Twelve patients responded to chemotherapy (all were PRs) and 13 did not (SD+PD). Fifteen patients responded to radiotherapy (7 CR, 8 PR) and 10 did not (SD+PD). Of the 12 patients who responded to chemotherapy, 8 also responded to radiotherapy (4 CR, 4 PR). Of the 13 chemotherapy nonresponders, 7 responded to radiotherapy (3 CR, 4 PR). χ2 analysis did not find any association between chemotherapy and radiotherapy response (P=0.513). Regression analysis also failed to identify any correlation between chemotherapy and radiotherapy response (r2=0.008). Conclusions: This study suggests that response to chemotherapy does not predict response to radiotherapy in locally advanced or oligometastatic non–small cell lung cancer. Lack of response to chemotherapy, therefore, should not preclude treatment with definitive radiotherapy.

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Prognostic Impact of Missed Chemotherapy Doses During Chemoradiation Therapy for Non–Small Cell Lung Cancer

Objective: The aim of this study is to investigate the impact of missed chemotherapy administrations (MCA) on the prognosis of non–small cell lung cancer (NSCLC) patients treated with definitive chemoradiation therapy (CRT). Materials and Methods: In total, 97 patients with NSCLC treated with definitive CRT were assessed for MCA due to toxicities. Logistic regression was used to determine factors associated with MCA. Kaplan-Meier curves, log-rank tests, and Cox Proportional Hazards models were conducted. Results: MCA occurred in 39% (n=38) of the patients. Median overall survival was 9.6 months for patients with MCA compared with 24.3 months for those receiving all doses (P=0.004). MCA due to decline in performance status was associated with the worst survival (4.6 mo) followed by allergic reaction (10.0 mo), hematologic toxicity (11 mo), and esophagitis (17.2 mo, P=0.027). In multivariate models, MCA was associated with higher mortality (hazard ratio, 1.97; P=0.01) and worse progression-free survival (hazard ratio, 1.96; P=0. 009). Conclusions: MCA correlated with worse prognosis and increased mortality. Methods to reduce toxicity may improve administration of all chemotherapy doses and increase overall survival in NSCLC treated with CRT.

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Age Bias in Time From Diagnosis Comparisons of Prostate Cancer Treatment

Objectives: Observational studies of prostate cancer treatment have demonstrated a major survival benefit with prostatectomy; randomized trials have been less certain in this regard. This discrepancy is hypothesized to be due to the use survival calculations based on time from diagnosis (TFD), which can bias toward better survival for younger cohorts. Attained age is an alternative timescale that can mitigate this effect. A Surveillance, Epidemiology and End Results comparison of prostatectomy, radiotherapy (XRT), and conservative management for localized prostatic cancer was conducted to compare these 2 timescales. Methods: Kaplan-Meier analysis was used to contrast overall survival based on TFD and attained age from 279,064 prostate cancer cases. Proportional hazards models were constructed and baseline hazard functions estimated. Results: The prostatectomy cohort averaged 9 to 12 years younger than the radiotherapy or conservative management cohorts, and the baseline hazard depended more strongly upon age than TFD. Survival calculations based on TFD demonstrated a major benefit with prostatectomy compared with XRT and conservative management, consistent with prior observational studies. Calculations based on attained age, however, demonstrated lesser differences between treatment cohorts and were more consistent with published randomized trials. Conclusions: The survival benefit apparent to prostatectomy in conventional observational cohort studies could reflect an age-related bias attributable to their use of TFD analysis. Care is warranted in the choice of timescale in observational analysis if large age differences exist between treatment cohorts. Randomized controlled trials remain the most reliable means to compare prostate cancer treatments.

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Thyroid Paraganglioma: Our Experience and Systematic Review of the Literature on a Rare Tumor

Introduction: Primary paraganglioma (PG) of the thyroid gland is an extremely rare neuroendocrine tumor with potential for misdiagnosis. We describe 2 cases of thyroid PG, suggest a possible diagnostic and therapeutic management strategy, and present a systematic review of the literature. Case Reports: Two 67-year-old women presented similarly with asymptomatic but rapidly growing thyroid nodules in which malignancy was suspected after fine needle aspiration biopsy, "THY 4" according to the 2014 SIAPEC classification, both undergoing total thyroidectomy. Unexpectedly, immunohistochemistry showed neuroendocrine cellular architecture that was negative for common markers of well-differentiated follicular neoplasms, thyroglobulin, thyroid transcription factor 1, cytokeratins and medullary thyroid cancer, calcitonin, carcinoembryonic antigen, whereas neuron-specific enolase, synaptophysin, chromogranin A, and S-100 protein were highly expressed, confirming the diagnosis of primary thyroid PG. The patients were both discharged on postoperative day 2, without any other therapy and are currently well without evidence of local recurrence of metastatic disease, after 4 years and 3 months of follow-up, respectively. Discussion: These are the only 2 cases of thyroid PG experienced in our center which specializes in thyroid surgery. Thyroid PG is a rare neuroendocrine neoplasm first described by Van Miert in 1964 with just over 50 cases reported in the literature. Our experience is concordant with the literature that the diagnosis of the primary PG of the thyroid is challenging, due to its low prevalence and the cytologic and histopathologic similarities with other more frequently diagnosed benign and malignant thyroid tumors. Immunohistochemistry is required for definitive diagnosis but gross tumor characteristics are also helpful for diagnosis. Surgical resection is the recommended standard treatment.

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Impact of Radiation Therapy Dose Escalation on Prostate Cancer Outcomes and Toxicities

EGFR Exon 19 Deletion is Associated With Favorable Overall Survival After First-line Gefitinib Therapy in Advanced Non–Small Cell Lung Cancer Patients

Phase I Trial of Dose-escalated Whole Liver Irradiation With Hepatic Arterial Fluorodeoxyuridine/Leucovorin and Streptozotocin Followed by Fluorodeoxyuridine/Leucovorin and Chemoembolization for Patients With Neuroendocrine Hepatic Metastases

Objectives: We have previously shown that refractory neuroendocrine tumors can respond to moderate doses of chemoradiotherapy. We completed a dose-escalation phase I/II trial combining hepatic arterial (HA) chemotherapy, chemoembolization, and dose-escalated whole liver radiotherapy to determine the maximum safe dose of radiation that could be delivered and to make a preliminary assessment of response. Materials and Methods: From 2002 to 2009, 19 patients with symptomatic neuroendocrine liver metastases who failed somatostatin analog therapy were enrolled. HA fluorodeoxyuridine, leucovorin, and streptozotocin were delivered, as concurrent whole liver radiotherapy was dose escalated from 24 to 32 Gy in 2 Gy fractions, with a target rate of dose-limiting grade ≥3 radiation-induced liver disease of 10%. Eight weeks later, for patients without grade ≥3 liver or grade ≥4 any toxicity, a 72-hour infusion of HA fluorodeoxyuridine and leucovorin was given, followed by transarterial chemoembolization. Results: Eleven patients completed the entire protocol and received 24 to 32 Gy. No patients developed radiation-induced liver disease; 7 had grade 3 to 4 transiently increased liver function tests, and 4 had other grade 4 toxicities. Three patients (14%) had partial response, 16 (84%) stable disease. Median freedom from local progression and overall survival were 35.3 and 54.6 months, respectively. Conclusions: Thirty-two in 2 Gy daily fractions can be delivered safely when combined with HA chemotherapy and subsequent transarterial chemoembolization. However, although objective responses were observed, this combination was not significantly better than our prior approaches. Further treatment intensification strategies, including individualized dose escalation for radiation-tolerant livers, and improved radiosensitization should be investigated, along with improved systemic therapy.

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Utility of the ACE Inhibitor Captopril in Mitigating Radiation-associated Pulmonary Toxicity in Lung Cancer: Results From NRG Oncology RTOG 0123

Objectives: The primary objective of NRG Oncology Radiation Therapy Oncology Group 0123 was to test the ability of the angiotensin-converting enzyme inhibitor captopril to alter the incidence of pulmonary damage after radiation therapy for lung cancer; secondary objectives included analyzing pulmonary cytokine expression, quality of life, and the long-term effects of captopril. Materials and Methods: Eligible patients included stage II-IIIB non–small cell lung cancer, stage I central non–small cell lung cancer, or limited-stage small cell. Patients who met eligibility for randomization at the end of radiotherapy received either captopril or standard care for 1 year. The captopril was to be escalated to 50 mg three times a day. Primary endpoint was incidence of grade 2+ radiation-induced pulmonary toxicity in the first year. Results: Eighty-one patients were accrued between June 2003 and August 2007. Given the low accrual rate, the study was closed early. No significant safety issues were encountered. Eight patients were ineligible for registration or withdrew consent before randomization and 40 patients were not randomized postradiation. Major reasons for nonrandomization included patients' refusal and physician preference. Of the 33 randomized patients, 20 were analyzable (13 observation, 7 captopril). The incidence of grade 2+ pulmonary toxicity attributable to radiation therapy was 23% (3/13) in the observation arm and 14% (1/7) in the captopril arm. Conclusions: Despite significant resources and multiple amendments, NRG Oncology Radiation Therapy Oncology Group 0123 was unable to test the hypothesis that captopril mitigates radiation-induced pulmonary toxicity. It did show the safety of such an approach and the use of newer angiotensin-converting enzyme inhibitors started during radiotherapy may solve the accrual problems.

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Medicare Cancer Screening in the Context of Clinical Guidelines: 2000 to 2012

Objectives: Cancer screening is a ubiquitous and controversial public health issue, particularly in the elderly population. Despite extensive evidence-based guidelines for screening, it is unclear how cancer screening has changed in the Medicare population over time. We characterize trends in cancer screening for the most common cancer types in the Medicare fee-for-service (FFS) program in the context of conflicting guidelines from 2000 to 2012. Materials and Methods: We performed a descriptive analysis of retrospective claims data from the Medicare FFS program based on billing codes. Our data include all claims for Medicare part B beneficiaries who received breast, colorectal (CRC), or prostate cancer screening from 2000 to 2012 based on billing codes. We utilize a Monte Carlo permutation method to detect changes in screening trends. Results: In total, 231,416,732 screening tests were analyzed from 2000 to 2012, representing an average of 436.8 tests per 1000 beneficiaries per year. Mammography rates declined 7.4%, with digital mammography extensively replacing film. CRC cancer screening rates declined overall. As a percentage of all CRC screening tests, colonoscopy grew from 32% to 71%. Prostate screening rates increased 16% from 2000 to 2007, and then declined to 7% less than its 2000 rate by 2012. Discussion: Both the aggressiveness of screening guidelines and screening rates for the Medicare FFS population peaked and then declined from 2000 to 2012. However, guideline publications did not consistently precede utilization trend shifts. Technology adoption, practical and financial concerns, and patient preferences may have also contributed to the observed trends. Further research should be performed on the impact of multiple, conflicting guidelines in cancer screening.

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A Phase I/II Study of Docetaxel, Oxaliplatin, and Fluorouracil (D-FOX) Chemotherapy in Patients With Untreated Locally Unresectable or Metastatic Adenocarcinoma of the Stomach and Gastroesophageal Junction

A Meta-Analysis of the Association Between Radiation Therapy and Survival for Surgically Resected Soft-Tissue Sarcoma

Chemotherapy is of Value in Second Line and Beyond, Relapsed High-grade, Serous Epithelial Ovarian Cancer: An Analysis of Outcomes Obtained With Oral Etoposide

Background: Epithelial ovarian cancer is chemotherapy responsive, and multiple lines of chemotherapy are often given. However, there are few data with regard to its effectiveness in later lines. Our aim was to assess its benefit in the high-grade, serous subtype relative to the line of therapy, using etoposide as the example. Methods: Women treated with oral etoposide at the British Columbia Cancer Agency upon recurrence/progression in the years 2000 to 2010 were reviewed. Kaplan-Meier and Cox regression methods were used to correlate line of therapy with overall survival, progression-free survival, and interval between etoposide initiation and next progression or death (EPFS). Results: A total of 219 women, median age 61, received etoposide as second (17%), third (30%), fourth (26%), fifth (17%), and sixth to eighth (11%) lines of therapy. The median number of cycles was 2 to 4. Patients who received etoposide as fourth-line to eighth-line treatment had a significantly longer median overall survival and initial progression-free survival (from diagnosis to first relapse) when compared with those who received it as second-line to third-line treatment (47.8 vs. 25.8 mo, P

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Myoepithelioma of Soft Tissues: A Single Institution Retrospective Case Series

Background: Myoepithelioma of the soft tissues is a rare entity and little is known about how best to manage locally recurrent and high-grade disease. Here, we retrospectively examined outcomes of surgery, chemotherapy, and radiation therapy (RT) for treatment of low-grade and high-grade myoepithelioma of soft tissues. Methods: We reviewed 20 cases of myoepithelioma of soft tissues seen at Mayo Clinic between 1994 and 2014. The effect of histologic grade and therapies received on relapse and survival were assessed. Results: We identified 13 patients with low-grade disease and 7 patients with high-grade disease. We found that low-grade disease was frequently effectively managed with surgical resection alone, whereas high-grade disease frequently metastasized and was often fatal. The 5-year event-free survival was 88% (confidence interval, 46%-98%) for low-grade disease versus 36% (confidence interval, 7%-75%; P=0.04) for high-grade disease. The relapse rate in low-grade disease was 29% at 5 years versus 64% (P=0.04) in high-grade disease. No significant responses to chemotherapy were noted, however, excellent responses to perioperative RT were seen. Conclusions: Surgery continues as the primary modality of treatment for myoepithelioma of soft tissues. Our study did not show a clear benefit of chemotherapy in the metastatic disease setting, but supports the use of perioperative RT in the management of high-grade disease; further investigation is warranted.

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Analysis of the Relationship Between Response to Chemotherapy and Response to Radiation Therapy in Patients With Non–Small Cell Lung Cancer Receiving Sequential Treatment

Prognostic Impact of Missed Chemotherapy Doses During Chemoradiation Therapy for Non–Small Cell Lung Cancer

Age Bias in Time From Diagnosis Comparisons of Prostate Cancer Treatment

Pre-ESRD Care and Mortality in Incident ESRD Patients With Multiple Myeloma

Objectives: The relationship between mortality and pre-ESRD (end-stage renal disease) nephrology care in incident ESRD patients with multiple myeloma (MM) as the primary cause of renal failure has not been examined. Materials and Methods: Among 439,206 incident US hemodialysis patients with MM as the primary cause of ESRD (June 1, 2005 to May 31, 2009) identified using the US Renal Data System, adjusted odds ratios (OR) for reported pre-ESRD nephrology care for ESRD due to MM (n=4561) versus other causes (n=434,645) were calculated. The association of pre-ESRD nephrology care with subsequent mortality in MM-ESRD patients was examined. Results: MM-ESRD patients were less likely to have any predialysis nephrology care in the year before initiation of dialysis (34.8% vs. 58.5%; OR=0.38; 95% confidence interval [CI], 0.34-0.43) compared with patients with ESRD due to other causes. MM-ESRD patients compared with others were more likely to have catheters on first dialysis (91.8% vs. 75.6%; OR=4.15; 95% CI, 3.54-4.86). Incident MM-ESRD patients receiving predialysis care for ≥6 months had significantly lower 1-year mortality (hazard ratio 0.89; 95% CI, 0.82-0.97 and 0.88; 95% CI, 0.80-0.96, respectively), relative to those without this care. A catheter for dialysis access was associated with a 1.6-fold increase in 1-year mortality in incident MM-ESRD (hazard ratio 1.55; 95% CI, 1.32-1.83). Conclusions: MM-ESRD patients were less likely to have predialysis nephrology care and more likely to use catheters on first dialysis. However, predialysis care is independently associated with lower mortality in MM-ESRD patients. Predialysis care should be prioritized in MM patients approaching ESRD.

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Thyroid Paraganglioma: Our Experience and Systematic Review of the Literature on a Rare Tumor

Immunotherapy for Merkel cell carcinoma: a turning point in patient care

Abstract

Merkel Cell carcinoma (MCC) is a rare but aggressive cancer, with an estimated disease-associated mortality as high as 46%. MCC has proven to be an immunologically responsive disease and the advent of immune checkpoint inhibitors has changed the treatment landscape for patients with advanced MCC. In this review, we discuss the rationale for the use of immune checkpoint inhibition, review current single agent therapies tested in and approved for MCC, and discuss emerging immunotherapeutic options for these patients.

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Punch biopsies shorten time to clearance of high-risk human papillomavirus infections of the uterine cervix

Abstract

Background

The primary objective was to determine human papilloma virus (HPV) clearance rate after cervical biopsy among women with persistent high-risk HPV infection compared with spontaneous HPV clearance rate in the absence of biopsy.

Methods

We collected data from a dedicated screening program of women aged 30–70 years old. Inclusion criteria for the baseline non-interventional cohort were a positive HPV test (hybrid capture 2, HC2) and normal cytology. In the baseline cohort women were followed with approximately yearly HPV-tests and cytology until HPV regressed (one negative HPV test) or interventions in the form of diagnostic biopsies or therapy. Women who had a diagnostic biopsy were included in the biopsy cohort and followed until HPV regression or therapy. Observed HPV regression rates and time to HPV regression were compared between baseline and biopsy cohorts. For the comparison, we used Fisher's exact test for the HPV regression rates and interval-censored, accelerated failure time model for time to HPV regression.

Results

Among the 1079 women included in the baseline cohort, 499 (46.3%) had HPV clearance and 475 were referred for colposcopy with biopsy. The biopsy cohort comprised all women who were not treated and had at least one HC2 test after biopsy (201/475; 42.3%). Of those, 138 (68.7%) experienced HPV regression. In the biopsy cohort, time to clearance of HPV infection was approximately halved (0.46, 95% CI 0.38–0.56) compared with the baseline cohort. This result was robust in a wide range of sensitivity analyses.

Conclusions

A higher proportion of women cleared their HPV infection, and time to HPV clearance was shorter in the biopsy cohort than in the baseline cohort. It is reassuring for clinicians to know that conservative management of patients with HPV persistency is successful when colposcopy with biopsies excludes high-grade disease.

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Immunotherapy for Merkel cell carcinoma: a turning point in patient care

Abstract

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The characteristics of ctDNA reveal the high complexity in matching the corresponding tumor tissues

Abstract

Background

Next-generation sequencing (NGS) is an efficient and sensitive method to detect mutations from ctDNA. Many features and clinical conditions could significantly affect the concordance between ctDNA and corresponding tumor tissues. Our goal was to systematically investigate the critical factors contributing to different concordance between ctDNA and corresponding tumor tissues.

Methods

We recruited two groups of IIIB or IV lung cancer patients: The standard group to evaluate the accuracy of our method and the concordance between ctDNA and tumor tissues, and the study group with various clinical conditions. We applied our unique identification (UID) indexed capturing-based sequencing (UC-Seq) to ctDNA samples, and confirm the results by Droplet digital PCR (ddPCR).

Results

Considering mutations detected from NGS of tumor tissues as golden standard, UC-Seq achieved overall 93.6% sensitivity for SNVs and Indels, and 0.8 Pearson correlation between tumor TMB and bTMB. Efficacious treatments, long sampling date (more than 2 weeks) between tumor tissues and ctDNA and low concentrations of cfDNA (less than 9 ng/ml) could significantly decrease the concordance between ctDNA and tumor tissues. About 84% mutations showed shorter mutant fragment length than that of wild-type fragments, and the AFs of mutations could be significantly enriched in small-size ctDNA.

Conclusions

In late-stage lung cancer patients, ctDNA generally has high concordance with tumor tissues. However it could be significantly affected by three clinical conditions which could dynamically change the content of ctDNA. Moreover, the detection limit could be further extended by enriching small-size ctDNA in the preparation of samples.

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Punch biopsies shorten time to clearance of high-risk human papillomavirus infections of the uterine cervix

Abstract

Background

Methods

Results

Conclusions

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The DNA methylation profile of liver tumors in C3H mice and identification of differentially methylated regions involved in the regulation of tumorigenic genes

Abstract

Background

C3H mice have been frequently used in cancer studies as animal models of spontaneous liver tumors and chemically induced hepatocellular carcinoma (HCC). Epigenetic modifications, including DNA methylation, are among pivotal control mechanisms of gene expression leading to carcinogenesis. Although information on somatic mutations in liver tumors of C3H mice is available, epigenetic aspects are yet to be clarified.

Methods

We performed next generation sequencing-based analysis of DNA methylation and microarray analysis of gene expression to explore genes regulated by DNA methylation in spontaneous liver tumors of C3H mice. Overlaying these data, we selected cancer-related genes whose expressions are inversely correlated with DNA methylation levels in the associated differentially methylated regions (DMRs) located around transcription start sites (TSSs) (promoter DMRs). We further assessed mutuality of the selected genes for expression and DNA methylation in human HCC using the Cancer Genome Atlas (TCGA) database.

Results

We obtained data on genome-wide DNA methylation profiles in the normal and tumor livers of C3H mice. We identified promoter DMRs of genes which are reported to be related to cancer and whose expressions are inversely correlated with the DNA methylation, including Mst1r, Slpi and Extl1. The association between DNA methylation and gene expression was confirmed using a DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-aza-dC) in Hepa1c1c7 cells and Hepa1-6 cells. Overexpression of Mst1r in Hepa1c1c7 cells illuminated a novel downstream pathway via IL-33 upregulation. Database search indicated that gene expressions of Mst1r and Slpi are upregulated and the TSS upstream regions are hypomethylated also in human HCC. These results suggest that DMRs, including those of Mst1r and Slpi, are involved in liver tumorigenesis in C3H mice, and also possibly in human HCC.

Conclusions

Our study clarified genome wide DNA methylation landscape of C3H mice. The data provide useful information for further epigenetic studies of mice models of HCC. The present study particularly proposed novel DNA methylation-regulated pathways for Mst1r and Slpi, which may be applied not only to mouse HCC but also to human HCC.

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Author Correction: Opium Consumption and the Incidence of Cancer: Does Opium Account as an Emerging Risk Factor for Gastrointestinal Cancer?

Abstract

The original version of this article unfortunately contained a mistake in the author group section. The correct name of the fourth author is "Reza Shirkoohi."The original article has been corrected.

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Age greater than 60 years portends a worse prognosis in patients with papillary thyroid cancer: should there be three age categories for staging?

Abstract

Background

Age is an important prognostic factor in papillary thyroid cancer (PTC), with better survival observed in patients < 45 years of age, regardless of stage. Although the impact of increasing age on PTC-related survival is well-known, previous studies have focused on survival relative to age 45 years only. As the number of patients entering their 7th decade of life increases, PTC-related survival in this demographic becomes increasingly important. Survival in patients ≥ 60 years specifically compared to other groups has not previously been examined. We sought to determine whether age ≥ 60 years is an adverse prognostic factor for disease-specific survival and recurrence in patients with PTC.

Methods

The California Cancer Registry database was linked to inpatient and ambulatory patient records from the Office of Statewide Health Planning and Development for the years 2000–2011. This linked database was queried for patients diagnosed with papillary thyroid cancer and treated with surgery. We then identified prognostic factors related to both 5-year and 10-year disease-specific survival and disease-free survival in patients ≤ 45, 45–59, and ≥ 60 years. Multivariable Cox proportional hazard models were created to test the effect of age ≥ 60 on disease-specific and disease-free survival, controlling for clinical, treatment, and demographic factors.

Results

The final cohort included 15,675 patients. Of the group, 46.3% were between 18 and 44 years of age, 33.6% were 45–59 years, and 20.1% were ≥ 60. Univariate analysis showed that compared to other groups, patients ≥ 60 were more likely to be male (p < 0.001), present with tumors > 5 cm (p < 0.001), more likely to have metastatic disease (p < 0.001), less likely to receive radioactive iodine (p < 0.001), and more likely to receive external beam radiation therapy (p < 0.001). In multivariable Cox proportional hazards models for 5 and 10-year disease-free survival, age ≥ 60 was associated with higher risk of disease at 5 and 10-years (HR 2.3 and 1.9 respectively, p < 0.001). Similar results were observed for 5 and 10-year disease-specific survival (HR 38.0 and 30.0 respectively, p < 0.001) after controlling for gender, race, co-morbidity, stage, surgical procedure, radioactive iodine, insurance, and hospital volume.

Conclusions

Patients ≥ 60 years of age have worse DSS and DFS after a diagnosis of PTC, across all stages of disease. Given that patients over the age of 45 years have progressively worse survival as they age, these data support having three age groups, 18–44 years of age, 45–59 years, and ≥ 60 as an independent predictor of survival and recurrence to current staging guidelines.

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