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PURPOSE: The Commission on Cancer seeks to promote robust survivorship programs among accredited cancer programs. In practice, cancer programs' survivorship programs range from cursory (eg, developing care plans without robust services) to robust (eg, facilitating follow-up care). To inform cancer programs' future efforts, in this study, we identified the implementation strategies that cancer programs used to achieve robust survivorship programs, distinguishing them from cursory programs. METHODS: We sampled 39 cancer programs across the United States with approaches to survivorship program implementation ranging from cursory to robust on the basis of LIVESTRONG survivorship care consensus elements. Within sampled cancer programs, we conducted in-depth semistructured interviews with a total of 42 health care professionals. We used template analysis to distinguish implementation strategies used in cancer programs with robust survivorship programs from strategies that yielded cursory survivorship programs. RESULTS: Cancer programs with robust survivorship programs established clear systems survivorship care and formal committees to improve the survivorship care processes. They sought buy-in from multiple stakeholders to leverage cancer program resources and defined clear roles with shared accountability among multidisciplinary groups. By contrast, cancer programs with cursory survivorship programs reported less consistency in survivorship care processes and lacked buy-in from key stakeholders. They had limited resources, faced persistent structural concerns, and had insufficient clarity in roles among team members. CONCLUSION: Accrediting bodies may consider incorporating the implementation strategies that robust survivorship programs have used as guidance for supporting cancer programs in operationalizing survivorship care and evaluating the use of these strategies during the accreditation and review process.

Non-fluent variant primary progressive aphasia (nfvPPA), a subtype of frontotemporal lobar dementia syndrome, has been proven to have various pathological diagnoses. A 63-year-old woman and 71-year-old man separately visited our clinic for language dysfunction. Both patients showed non-fluent speech. The female patient showed personality change accompanied by language dysfunction, while the male patient had parkinsonian symptoms such as bradykinesia and cogwheel rigidity. Both patients were clinically diagnosed with nfvPPA. Several years after the first visit, the patients died, and a brain autopsy was performed. On postmortem examination, the female patient was pathologically diagnosed with Pick’s disease, while the male patient was diagnosed with progressive supranuclear palsy. Our report suggests that nfvPPA patients might show distinct clinical features depending on underlying pathologies.

BACKGROUND: A certain proportion of non-small cell lung cancer (NSCLC) with activating EGFR mutations showed resistance to tyrosine kinase inhibitors (TKIs) by transforming their histology into small cell lung cancer (SCLC). In this study, we evaluated the molecular characteristics of transformed SCLCs. METHODS: Eighteen SCLC tissue samples transformed after EGFR TKI treatment were used for the analysis. Immunohistochemistry was conducted to evaluate the molecular subtype using antibodies representative of the major transcriptional factor-based molecular subtypes, ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1. Subtypes were categorized based on a predefined criteria. RESULTS: Among the study population (n=18), most of the patients were initially diagnosed with adenocarcinoma (n=17), and one patient was diagnosed with adenosquamous histology. Eight patients (44.4%) were never-smokers, and nine patients were women (50.0%). Staining of pre-transformation sample was conducted in six patients, and five of them showed no discernible expression for ASCL1, NEUROD1, or POU2F3. However, the proportion of molecular subtypes after SCLC transformation was predominantly SCLC-N (n=9, 50.0%), followed by SCLC-Triple Negative (SCLC-TN; n=5, 27.8%) and SCLC-A (n=4, 22.2%). The median overall survival from TKI initiation was longer in patients who transformed to SCLC-A (P=0.009) than in those who transformed to either SCLC-N or SCLC-TN. However, the overall survival difference since SCLC transformation was not significant (P=0.370). CONCLUSIONS: In our series, SCLC-N subtype was prevalent in SCLC transformed after EGFR TKI treatment. In addition, overall survival and the time to SCLC transformation from the EGFR TKI treatment were longer in patients who transformed to the SCLC-A type. Large-scale data will be required to confirm our findings.

PURPOSE This randomized clinical trial compared a personally tailored, automated telephone symptom management intervention to improve self-management among long-term survivors of prostate cancer with usual care enhanced with a nontailored newsletter about symptom management. We hypothesized that intervention-group participants would have more confident symptom self-management and reduced symptom burden. METHODS A total of 556 prostate cancer survivors who, more than 1 year after treatment, were experiencing symptom burden were recruited from April 2015 to February 2017 across four Veterans Affairs sites. Participants were randomly assigned to intervention (n = 278) or usual care (n = 278) groups. We compared differences in the primary (symptom burden according to Expanded Prostate Cancer Index Composite-26 [EPIC], confidence in self-management) and secondary outcomes between groups using intent-to-treat analyses. We compared domain-specific changes in symptom burden from baseline to 5 and 12 months among the intervention group according to the primary symptom focus area (urinary, bowel, sexual, general) of participants. RESULTS Most of the prostate cancer survivors in this study were married (54.3%), were white (69.2%), were retired (62.4%), and underwent radiation therapy (56.7% v 46.2% who underwent surgery), and the mean age was 67 years. There were no baseline differences in urinary, bowel, sexual, or hormonal domain EPIC scores across groups. We observed higher EPIC scores in the intervention arm in all domain areas at 5 months, though differences were not statistically significant. No differences were found in secondary outcomes; however, coping appraisal was higher (2.8 v 2.6; P = .02) in intervention-arm patients at 5 months. In subgroup analyses, intervention participants reported improvement from baseline at 5 and 12 months in their symptom focus area domains. CONCLUSION This intervention was well received among veterans who were long-term survivors of prostate cancer. Although overall outcome differences were not observed across groups, the intervention tailored to symptom area of choice may hold promise to improve associated burden.

PurposeThe incidence of BRAF V600E mutation in non-small cell lung carcinoma (NSCLC) is lower than 2%, which poses difficulties in finding legitimate patients for targeted therapy. We investigated the predictive factors pertaining to BRAF V600E and the effectiveness of the VE1 antibody as a screening method for patient selection.Materials and MethodsThe study was designed into two steps. In a first group, BRAF-mutated NSCLCs were identified from sequencing data to determine the features of BRAF V600E mutation. The results of the first group helped the collection of adenocarcinomas with a papillary or micropapillary pattern but without EGFR or ALK alterations as a second group so that the frequency of BRAF V600E mutation could be calculated. The sensitivity and specificity of the VE1 were compared with BRAF V600E status. ResultsAmong 39 BRAF-mutated NSCLCs in the first group, 20 (51%) were V600E. BRAF V600E mutation was more common in female patients and showed no significant correlation with smoking status. Nineteen cases were adenocarcinomas without EGFR and ALK alterations. The most common patterns of invasion were papillary and micropapillary along with central fibrosis. The sensitivity and specificity of the VE1 were 90.0% and 92.3%, respectively. In the second group, 6.7% of cases were VE1-positive, indicating that the prevalence was significantly higher than that reported in previous studies (0.3-1.8%). ConclusionBRAF V600E-mutated NSCLCs could be enriched with the application of clinicopathologic parameters, which are not perfect. Therefore, additional VE1 immunohistochemistry may be useful as a screening method.

Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy. Mutations in the GNB4 gene cause dominant intermediate CMT type F (CMTDIF). The aim of this study is to investigate phenotypic heterogeneities and characteristics of CMT patients with GNB4 mutations. We enrolled 1143 Korean CMT families and excluded 344 families with a PMP22 duplication. We further analyzed the 799 remaining families to find their GNB4 mutations using whole-exome sequencing (WES). We identified two mutations (p.Gly77Arg and p.Lys89Glu) in three families, among which a heterozygous p.Gly77Arg mutation was novel. In addition, a significant uncertain variant (p.Thr177Asn) was observed in one family. The frequency of the GNB4 mutation in the Korean population is 0.38% in PMP22 duplication-negative families. All three families showed de novo mutation. Electrophysiological findings regarding the p.Lys89Glu mutation showed that the motor nerve conduction velocity (MNCV) of the median nerve was markedly reduced, indicating demyelinating neuropathy, and sural nerve biopsy revealed severe loss of myelinated axons with onion bulb formation. Lower extremity Magnetic Resonance Imaging (MRI) demonstrated relatively more severe intramuscular fat infiltrations in demyelinating type (p.Lys89Glu mutation) patients compared to intermediate type (p.Gly77Arg mutation) patients. The anterolateral and superficial posterior compartment muscles of the distal calf were preferentially affected in demyelinating type patients. Therefore, it seems that the investigated GNB4 mutations do cause not only the known intermediate type but also demyelinating-type neuropathy. We first presented three Korean families with GNB4 mutations and found phenotypic heterogeneities of both intermediate and demyelinating neuropathy. We suggest that those findings are useful for the differential diagnosis of CMT patients with unknown GNB4 variants.

BackgroundTumor mutational burden (TMB) measurement is limited by low tumor purity of samples, which can influence prediction of the immunotherapy response, particularly when using whole-exome sequencing-based TMB (wTMB). This issue could be overcome by targeted panel sequencing-based TMB (pTMB) with higher depth of coverage, which remains unexplored.MethodsWe comprehensively reanalyzed four public datasets of immune checkpoint inhibitor (ICI)-treated cohorts (adopting pTMB or wTMB) to test each biomarker’s predictive ability for low purity samples (cut-off: 30%). For validation, paired genomic profiling with the same tumor specimens was performed to directly compare wTMB and pTMB in patients with breast cancer (paired-BRCA, n=165) and ICI-treated patients with advanced non-small-cell lung cancer (paired-NSCLC, n=156).ResultsLow tumor purity was common (range 30%–45%) in real-world samples from ICI-treated patients. In the survival analyzes of public cohorts, wTMB could not predict the clinical benefit of immunotherapy when tumor purity was low (log-rank p=0.874), whereas pTMB could effectively stratify the survival outcome (log-rank p=0.020). In the paired-BRCA and paired-NSCLC cohorts, pTMB was less affected by tumor purity, with significantly more somatic variants identified at low allele frequency (pConclusionsOur data suggest that TMB characterization with targeted deep sequencing might have potential strength in predicting ICI responsiveness due to its enhanced sensitivity for hard-to-detect variants at low-allele fraction. Therefore, pTMB could act as an invaluable biomarker in the setting of both clinical trials and practice outside of trials based on its reliable performance in mitigating the purity-related bias.

Background Clinical practice guidelines recommend active surveillance as the preferred treatment option for low-risk prostate cancer, but only a minority of eligible men receive active surveillance, and practice variation is substantial. The aim of this study is to describe barriers to urologists’ recommendation of active surveillance in low-risk prostate cancer and explore variation of barriers by setting. Methods We conducted semi-structured interviews among 22 practicing urologists, evenly distributed between academic and community practice. We coded barriers to active surveillance according to a conceptual model of determinants of treatment quality to identify potential opportunities for intervention. Results Community and academic urologists were generally in agreement on factors influencing active surveillance. Urologists perceived patient-level factors to have the greatest influence on recommendations, particularly tumor pathology, patient age, and judgements about the patient’s ability to adhere to follow-up protocols. They also noted cross-cutting clinical barriers, including concerns about the adequacy of biopsy samples, inconsistent protocols to guide active surveillance, and side effects of biopsy procedures. Urologists had differing opinions on the impact of environmental factors, such as financial disincentives and fear of litigation. Conclusions Despite national and international recommendations, both academic and community urologists note a variety of barriers to implementing active surveillance in low risk prostate cancer. These barriers will need to be specifically addressed in efforts to help urologists offer active surveillance more consistently.

Amphiregulin (AREG) is a transmembrane glycoprotein recently implicated in kidney fibrosis. Previously, we reported that the AREG-targeting Self-Assembled-Micelle inhibitory RNA (SAMiRNA-AREG) alleviated fibrosis by stably silencing the AREG gene, and reduced the side effects of conventional siRNA treatment of pulmonary fibrosis. However, the therapeutic effect of SAMiRNA-AREG in renal fibrosis has not been studied until now. We used two animal models of renal fibrosis generated by a unilateral ureteral obstruction (UUO) and an adenine diet (AD) to investigate whether SAMiRNA-AREG inhibited renal fibrosis. To investigate the delivery of SAMiRNA-AREG to the kidney, Cy5-labeled SAMiRNA-AREG was injected into UUO- and AD-induced renal fibrosis models. In both kidney disease models, SAMiRNA-AREG was delivered primarily to the damaged kidney. We also confirmed the protective effect of SAMiRNA-AREG in renal fibrosis models. SAMiRNA-AREG markedly decreased the UUO- and AD-induced AREG mRNA expression. Furthermore, the mRNA expression of fibrosis markers, including α-smooth muscle actin, fibronectin, α1(I) collagen, and α1(III) collagen in the UUO and AD-induced kidneys, was diminished in the SAMiRNA-AREG-treated mice. The transcription of inflammatory markers (tumor necrosis factor-α and monocyte chemoattractant protein-1) and adhesion markers (vascular cell adhesion molecule 1 and intercellular adhesion molecule 1) was attenuated. The hematoxylin and eosin, Masson’s trichrome, and immunohistochemical staining results showed that SAMiRNA-AREG decreased renal fibrosis, AREG expression, and epidermal growth factor receptor (EGFR) phosphorylation in the UUO- and AD-induced models. Moreover, we studied the effects of SAMiRNA-AREG in response to TGF-β1 in mouse and human proximal tubule cells, and mouse fibroblasts. TGF-β1-induced extracellular matrix production and myofibroblast differentiation were attenuated by SAMiRNA-AREG. Finally, we confirmed that upregulated AREG in the UUO or AD models was mainly localized in the distal tubules. In conclusion, SAMiRNA-AREG represents a novel siRNA therapeutic for renal fibrosis by suppressing EGFR signals.

Summary Exome and transcriptome analyses of clinically homogeneous early-stage never-smoker female patients with lung adenocarcinoma were performed to understand tumor-T cell interactions and immune escape points. Using our novel gene panels of eight functional categories in the cancer-immunity cycle, three distinct subgroups were identified in this immune checkpoint blockade-refractory cohort by defective gene expression in two major domains, i.e., type I interferon production/signaling pathway and antigen-presenting machinery. Our approach could play a critical role in understanding immune evasion mechanisms, developing a method for effective selection of rare immune checkpoint blockade responders, and finding new treatment strategies., Graphical Abstract, Highlights • GMM-based clustering of cancer-immune gene expression helps to find LUAD classifiers • Classifiers are found in the earlier-phased cancer-immunity cycle • Classifiers include ubiquitination, Ag-presenting machinery, and type I IFN signaling • Tumor-intrinsic classifiers strongly influence the outcome of cancer immunity, Immunology; Cancer Systems Biology; Genomics

Ovarian gynandroblastoma (GAB) is an extremely rare sex cord-stromal tumor showing morphological evidence of both female (granulosa cell tumor) and male (Sertoli–Leydig cell tumor (SLCT)) components. Almost all GAB cases have been reported in children, adolescents, or women of reproductive age, and most of them typically have adult granulosa cell tumors as the female component. In contrast, GAB with a juvenile granulosa cell tumor (JGCT) component is a very rare condition; to the best of our knowledge, only one case of GAB with JGCT in a postmenopausal woman has been reported. In this report, we present an extremely rare case of ovarian GAB with JGCT in an elderly patient. A 65-year-old woman presented with an abdominal mass. Abdominopelvic magnetic resonance imaging revealed a large multiseptated cystic mass measuring 20 cm. No peritoneal seeding, lymph node enlargement, or hematogenous metastasis was identified. Laboratory test showed a slight elevation of serum CA 125 level (37.1 U/mL). Based on the preoperative clinical impression of ovarian cancer, she underwent a total hysterectomy with bilateral salpingo-oophorectomy. Grossly, the ovarian mass had a smooth and glistening surface without excrescences. The cut sections showed yellow-to-tan solid areas with foci of necrosis, myxoid degeneration, and hemorrhage, as well as multilocular cystic cavities filled with serosanguinous fluid. Histologically, the female component was characterized by JGCT displaying nodular growth patterns with follicle-like structures of various shapes and sizes. Most of the microcysts contained eosinophilic or basophilic secretions. The JGCT cells had indistinct cell borders, an abundant eosinophilic cytoplasm, and round-to-oval hyperchromatic nuclei with many mitotic figures. The SLCT component consisted predominantly of intermediately differentiated Sertoli cells forming lobulated solid nodules. They were arranged in cords, solid tubules, or nests, and possessed oval-to-spindle-shaped darkly stained nuclei and scant cytoplasm. In several foci, well-formed Sertoli cell tubules were loosely aggregated within areas of moderately differentiated SLCT. In summary, we described GAB in a postmenopausal woman with JGCT and SLCT as the female and male components, respectively. This is the second case of GAB with JGCT occurring in an elderly patient. Our findings can help pathologists and clinicians make accurate histological diagnoses of GAB with a JGCT component and plan an adequate treatment strategy for this rare tumor.

12 Background: The National Comprehensive Cancer Network (NCCN) guideline offers a guideline for follow-up care for patients with low-risk prostate cancer on active surveillance (AS). However, in practice, 70% of patients receive follow-up care that is not guideline-adherent, characterized by insufficient or excessive surveillance testing, potentially diminishing AS effectiveness and contributing to poor patient outcomes. The objective of this study is to identify provider- and organization-level determinants of guideline-adherent AS follow-up care. Methods: We used in-depth semi-structured qualitative interviews with 13 United States urologists to examine determinants of urologists’ adherence to the active surveillance follow-up guideline. Guided by the combined use of the Consolidated Framework for Implementation Research, which focuses on organization-level determinants, and the Theoretical Domains Framework, which focuses on provider-level determinants, we used template analysis to identify multilevel determinants of urologists’ adherence to guideline-recommended AS follow-up care. Results: Relevant determinants were comfort with varied utilization behaviors of the guideline, perspectives on the prostate biopsy procedure, and the degree of structure within the practice setting. At the provider level, there was variation in how urologists provided AS follow-up care. All urologists referred to the NCCN guideline; however, most urologists adapted the guidelines to their needs and/or comfort level (e.g., following a subset of recommendations; adapting the interval/frequency of serial tests). Most providers felt that strictly adhering to the repeated biopsy aspect of the guideline was difficult because of concerns about fitting everybody to one type of frequency that does not stratify patients by risk. Others reflected on patients expressing physical discomfort and concerns of infection stemming from the biopsy procedure. At the organization level, urologists in a structured practice environment had the tendency towards providing NCCN guideline-adherent care whereas urologists practicing in settings with less organization relied more on individual discretion, which created room for flexibility with the care that they provide. Conclusions: Both provider- and organization-level determinants affected urologists’ provision of NCCN guideline-adherent follow-up care which may partially explain why patients eventually fail to receive guideline-adherent AS follow-up care. Findings call on the need for multilevel strategies to increase adherence or to modify existing guidelines to reflect the need at multiple levels.

The Gleason grading system, currently the most powerful prognostic predictor of prostate cancer, is based solely on the tumor&rsquo, s histological architecture and has high inter-observer variability. We propose an automated Gleason scoring system based on deep neural networks for diagnosis of prostate core needle biopsy samples. To verify its efficacy, the system was trained using 1133 cases of prostate core needle biopsy samples and validated on 700 cases. Further, system-based diagnosis results were compared with reference standards derived from three certified pathologists. In addition, the system&rsquo, s ability to quantify cancer in terms of tumor length was also evaluated via comparison with pathologist-based measurements. The results showed a substantial diagnostic concordance between the system-grade group classification and the reference standard (0.907 quadratic-weighted Cohen&rsquo, s kappa coefficient). The system tumor length measurements were also notably closer to the reference standard (correlation coefficient, R = 0.97) than the original hospital diagnoses (R = 0.90). We expect this system to assist pathologists to reduce the probability of over- or under-diagnosis by providing pathologist-level second opinions on the Gleason score when diagnosing prostate biopsy, and to support research on prostate cancer treatment and prognosis by providing reproducible diagnosis based on the consistent standards.

BACKGROUND We reviewed a series of 188 resected pulmonary mucinous adenocarcinomas (MAs) to clarify the prognostic significance of lepidic and non-lepidic patterns. METHODS Non-lepidic patterns were divided into bland, non-distorted acini with uncertain invasiveness (pattern 1), unequivocal invasion into stroma (pattern 2), or invasion into alveolar spaces (pattern 3). RESULTS The mean proportion of invasive patterns (patterns 2 and 3) was lowest in small (≤ 3 cm) tumors, and gradually increased in intermediate (> 3 cm and ≤ 7 cm) and large (> 7 cm) tumors (8.4%, 34.3%, and 50.1%, respectively). Adjusted T (aT) stage, as determined by the size of invasive patterns, was positively correlated with adverse histologic and clinical features including older age, male sex, and ever smokers. aTis tumors, which were exclusively composed of lepidic pattern (n = 9), or a mixture of lepidic and pattern 1 (n = 40) without any invasive patterns, showed 100% disease- free survival (DFS). The aT1mi tumors, with minimal (≤ 5 mm) invasive patterns (n = 63), showed a 95.2% 5-year DFS, with recurrences (n = 2) limited to tumors greater than 3 cm in total size (n = 23). Both T and aT stage were significantly associated with DFS; however, survival within the separate T-stage subgroups was stratified according to the aT stage, most notably in the intermediatestage subgroups. In multivariate analysis, the size of invasive patterns (p = .020), pleural invasion (p < .001), and vascular invasion (p = .048) were independent predictors of recurrence, whereas total size failed to achieve statistical significance (p = .121). CONCLUSIONS This study provides a rationale for histologic risk stratification in pulmonary MA based on the extent of invasive growth patterns with refined criteria for invasion.

Acute placental villitis is very rare and believed to reflect overwhelming fetal sepsis in utero, commonly caused by Escherichia coli or group B streptococci. We present a case of intrauterine fetal death associated with acute placental villitis and acute necrotizing chorioamnionitis by early-onset group B streptococcal infection. A 36-year-old woman presented with decreased fetal movement and fever at 21 weeks of gestation. ultrasound demonstrated intrauterine fetal death. After delivery, the placenta revealed multifocal neutrophilic infiltration in chorionic villi, most prominently beneath the trophoblast basement membrane, which was also accompanied by acute necrotizing chorioamnionitis. Gram-positive microorganisms were detected in villous vessels as well as in the major organs of the fetus, which was consistent with Streptococcus agalactiae (group B) cultured from maternal blood. Acute placental villitis should be recognized as evidence of fetal sepsis that often has lethal clinical outcome, as compared to intra-amniotic infection associated with acute chorioamnionitis alone.

Background Although prostate cancer is the most common cancer among veterans receiving care in the Veterans Health Administration (VA), more needs to be done to understand and improve survivorship care for this large population. This study, funded by VA Health Services Research & Development (HSR&D), seeks to address the need to improve patient-centered survivorship care for veterans with prostate cancer. Methods/Design This is a two-armed randomized controlled trial (RCT) with a target enrollment of up to 325 prostate cancer survivors per study arm (total anticipated n = 600). Patients will be recruited from four VA sites. Patient eligibility criteria include age range of 40–80 years, one to ten years post-treatment, and currently experiencing prostate cancer symptom burden. We will compare the “Building Your New Normal” program, a personally-tailored automated telephone symptom management intervention for improving symptom self-management to usual care enhanced with a non-tailored newsletter about symptom management. Primary outcomes include changes in symptom burden, bother, and health services utilization at five and 12 months after enrollment. Secondary outcomes include long-term psychosocial outcomes (e.g. subjective health, perceived cancer control). We will use multivariable regression analysis to evaluate the impact of the intervention on primary and secondary outcomes. We will conduct a process evaluation to understand the effective intervention components and explore possibilities for broader implementation and dissemination. Discussion Our central hypothesis is that intervention group participants will have improved and more confident symptom self-management and prostate cancer quality of life following the intervention and that these outcomes will translate to more efficient use of health services. The study results will provide much needed information about how to optimize the quality of care, and life, of veteran prostate cancer survivors. Trial registration ClinicalTrials.gov ID NCT01900561; Registered on 22 July 2013. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1925-4) contains supplementary material, which is available to authorized users.

5011Background: The purpose of this randomized trial was to compare a personally-tailored symptom management intervention consisting of 4 automated telephone assessments and tailored education for ...