Citations

The “Things We Do for No Reason” series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

Abstract Background: Mixed hepatocellular cholangiocarcinoma (HCC-CCA) is a rare primary malignancy of the liver which is distinct from hepatocellular carcinoma (HCC) or cholangiocarcinoma. HCC-CCA is presumed to have a poor prognosis and is not recommended for transplantation. The clinical and radiological presentation of HCC-CCA overlaps with HCC; thus, patients with these cancers may be mis-diagnosed as HCC and undergo liver transplantation, with the precise diagnosis ultimately determined on explant pathology. Patients undergoing transplant for presumed HCC receive loco-regional therapy (LRT), such as transarterial chemoembolization and radiofrequency ablation pre-transplant. Our goals were to (1) evaluate pre-transplant response to LRT, as predictors of recurrence and survival after transplant in HCC-CCA, and to (2) compare outcomes of transplant with adjuvant LRT in HCC-CCA and HCC. Methods: A retrospective study of 57 patients with presumed HCC who underwent liver transplantation and had pre-transplant LRT was performed. The study included 19 HCC-CCA cases and 38 HCC cases diagnosed on explant pathology, and individually matched (1:2) on age, sex, and Milan criteria. Response to LRT was determined by MRI performed before and after LRT. The response evaluation criterion in solid tumors (RECIST) was used to categorize treatment responses as “responders” if a patient had a complete or partial response or “non-responders” if a patient had stable or progressive disease. Recurrence rates, recurrence-free survival (RFS), and overall survival (OS) following LRT and transplant were compared between groups using Fisher’s exact tests. Results: The overall 1- and 3-year survival rates were 84% and 74% for HCC-CCA, and 95% and 87% for HCC, respectively. RFS at 1 and 3 years was 79% and 74% for HCC-CCA, and 92% and 87% for HCC (p-values >0.05). For HCC-CCA, one-year OS and RFS in LRT responders were 92% and 83%, whereas for LRT non-responders, OS and RFS were 71% each. In contrast, for HCC, one-year OS and RFS in LRT responders were both 97%, whereas among non-responders, they were 83% and 67%, respectively. At three years, OS and RFS in responders were 92% and 75% for HCC-CCA and 88% and 90% for HCC, respectively; whereas among non-responders, OS and RFS rates were 43% and 57% for HCC-CCA and 83% and 50% for HCC, respectively (all p-value >0.05). Conclusions: Short-term, post-transplant survival was poorer for HCC-CCA than HCC. However, OS among LRT responders for both cancers was similar. Response to LRT predicts favorable RFS in both HCC-CCA and HCC. Among non-responders, recurrence rate and RFS at three years were dismal and similar for both HCC-CCA and HCC, although OS is much lower for HCC-CCA patients. Response to pre-transplant LRT can be used for identifying HCC-CCA patients at high risk of recurrence and poor survival after liver transplantation. Citation Format: Yacob Y. Habboush, Samuel O. Antwi, Lori Chase, Tushar C. Patel. Response to loco-regional therapy as predictors of outcomes after transplantation for mixed hepatocellular cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-237. doi:10.1158/1538-7445.AM2017-LB-237

Abstract Background: There have been varying reports on risk of different cancers, other than pancreatic cancer (PC), among first-degree relatives (FDRs) of PC patients. Because the pattern and scope of aggregation of PC with other malignancies in families of PC patients are not entirely clear, we investigated risk of 15 common malignancies among FDRs of unselected PC probands. Methods: The study included 17,181 FDRs with more than 336,000 person-years at risk. The FDRs were identified through sequentially enrolled PC probands (n=2,305) in the Mayo Clinic prospective pancreatic cancer patient registry from 2000-2016. Data on family history of cancer were provided by the probands at the time of enrollment in structured risk factor questionnaires. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing cases of each cancer type observed among the FDRs with those expected using data from the Surveillance Epidemiology and End Results Program (SEER). Stratified analyses were performed among siblings of the probands based on whether the related proband tested positive for a mutation in ATM, BARD1, BRCA1, BRCA2, CDKN2A, CHEK2, MUTYH, NBN, PALB2, or PMS2; or tested negative for mutation in a total of 25 sequenced cancer susceptibility genes. Results: Compared to the SEER reference population, risk of PC was two-fold higher than expected among the FDRs (SIR=2.04, 95% CI: 1.78-2.31) and 12-fold higher than expected among FDRs with history of PC in at least two blood relatives (SIR=11.99, 95% CI: 10.48-13.64). Siblings of mutation-positive probands had higher risk of PC (SIR=13.57, 95% CI: 6.19-25.76) than siblings of mutation-negative probands (SIR=8.91, 95% CI=6.73-11.57). For other cancer types, primary liver cancer was elevated among female FDRs (SIR=2.10, 95% CI: 1.34-3.12), whereas breast (SIR=3.16, 95% CI: 1.63-5.52) and ovarian (SIR =6.61, 95% CI: 1.33-19.31) cancers were elevated only among siblings of the mutation-positive probands. There also were suggestions of lower than expected risk of other malignancies, such as bladder, colorectal and prostate cancers, among the FDRs as compared with the SEER population. Conclusions: These findings confirm familial aggregation of PC with breast and ovarian cancers, and further suggest a potential aggregation of PC and primary liver cancer among female FDRs of PC probands. The elevated risks of breast cancer and ovarian cancer among siblings of the mutation-positive probands suggests a strong influence of genetic susceptibility shared with the related proband, possibly due to an inherited mutation in BRCA1, BRCA2, or PALB2. These findings lend support to genetic counseling and targeted screening of certain cancers in high-risk families. Citation Format: Samuel O. Antwi, Sarah E. Fagan, Kari G. Chaffee, William R. Bamlet, McWilliams R. Robert, Ann L. Oberg, Gloria M. Petersen. Risk of different cancers among first-degree relatives of pancreatic cancer patients and impact of probands’ germline mutation on sibling cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4269. doi:10.1158/1538-7445.AM2017-4269

Abstract Expression of DLL3 was examined in additional tumor types, as it was found to be highly expressed in tumor-initiating cells (TIC) in small cell lung cancer (SCLC), where a DLL3-targeted antibody drug conjugate (ADC), rovalpituzumab tesirine (Rova-T; SC16LD6.5; Saunders et al. 2015 Sci Transl Med 7:302ra136)) exerted clinically meaningful anti-tumor effects in a phase I trial (Spigel et al. 2016 Lancet Oncology; In Press). DLL3 expression was profiled by qRT-PCR, ELISA and immunohistochemistry in multiple tumor types. Patient-derived xenografts (PDX) from melanoma and ovarian small cell carcinoma were established and used for efficacy studies to determine the ability of Rova-T to impact tumor growth and TIC frequency. DLL3 expression was seen in metastatic melanoma (55%), low grade gliomas (90%), glioblastoma (70%), medullary thyroid cancer (65%), carcinoids (33%), dispersed neuroendocrine tumors in the pancreas (9%), bladder (57%) and prostate (24%), testicular cancer (90%), and lung adenocarcinomas with neuroendocrine features (80%). Unlike SCLC, where DLL3 does not predict clinical outcome on standard therapies, DLL3 expression negatively correlates with overall survival in melanoma and small cell bladder cancer. In mice bearing DLL3 positive melanoma PDX, treatment with a single dose of Rova-T resulted in effective and durable responses (>100 days), which correlated with a significant impact on TIC frequency. Similarly, in mice bearing DLL3-positive ovarian small cell PDX, a single dose of Rova-T resulted in effective and durable responses (>100 days). Our results show that DLL3 is expressed in many neuroendocrine tumors (lung, ovarian, prostate, bladder, etc), metastatic melanoma, medullary thyroid cancer, low-grade gliomas and glioblastoma. Given pre-clinical results showing efficacy of Rova-T in melanoma and ovarian small cell carcinoma, as well as encouraging clinical data with Rova-T in patients with recurrent/refractory SCLC, clinical evaluation of Rova-T in DLL3-positive melanoma, glioblastoma, medullary thyroid cancer and other high-grade neuroendocrine carcinomas is warranted. A “basket” trial enrolling patients with DLL3-positive solid tumors is now recruiting patients (NCT02709889). Citation Format: Laura R. Saunders, Samuel A. Williams, Sheila Bheddah, Kumiko Isse, Sarah Fong, Marybeth A. Pysz, Himisha Beltran, Loredana Puca, Verena Sailer, Juan M. Mosquera, Yu Yin, Jiaoti Huang, Andrew J. Armstrong, Jorge Garcia, Cristina Magi-Galluzzi, Vadim Koshkin, Petros Grivas, Farhad Kosari, John Cheville, Justin C. Moser, Thomas J. Flotte, Thorvardur Halfdanarson, Aaron Mansfield, Konstantinos N. Leventakos, Julian R. Molina, Douglas W. Ball, Barry D. Nelkin, Jill E. Shea, Courtney L. Scaife, Scott J. Dylla. Expression of DLL3 in metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas as potential indications for rovalpituzumab tesirine (Rova-T; SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody drug conjugate (ADC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3093. doi:10.1158/1538-7445.AM2017-3093

Depression was examined in 45 patients evaluated within 2 months of diagnosis of MS. At the time of testing, 40% of the MS sample met the diagnostic criteria for major depression, 22% had adjustment disorder with depressed mood and 37% showed no evidence of mood disorder. Personal and family history of depression in patients with MS was also examined and compared with a sample of patients with chronic low back pain (CLBP) who were matched for age, gender, marital and employment status and current level of depression. Fifty-two per cent of patients whit MS reported experiencing a depressive episode before the onset of MS compared with 17% of patients with CLBP (P<0.001). Sixteen patients with MS (35%) reported family history (parent or sibling) of treatment for depression compared with seven (15%) of patients with CLBP (P<0.05). MS patients with a history of depression reported more initial symptoms than MS patients without a history of depression. Clinical and theoretical implications of the findings are discussed.

Objectives/HypothesisSarcomatoid carcinoma is a rare variant of squamous cell carcinoma of the head and neck. No consensus exists on its management. Our aim was to present our outcomes.Study DesignRetrospective study. Median follow‐up 45 months.MethodsThere were 38 patients with pathologically confirmed sarcomatoid carcinoma of the larynx treated at the Mayo Clinic from 1990 to 2014. Statistical analysis of overall survival (OS), progression‐free survival (PFS), and local control (LC) were conducted using the Kaplan‐Meier method.ResultsThe majority of patients were elderly males (92%) with a smoking history (74%) presenting with early‐stage disease (71%). Surgery alone was the primary treatment in 27 patients (71%). Nine patients (25%) were treated with adjuvant radiation due to initial stage or high‐risk pathologic features. Median radiation dose to the primary/surgical bed was 65 Gy (range, 60.3–75.0 Gy). A total of 15 patients (39%) had tumor recurrence, majority being local (n = 12). Sixty percent (n = 9) had multiple local recurrences. Five‐year OS, PFS, and LC were 63%, 46%, and 72%, respectively. Subgroup analysis by stage I versus higher stages (II–IV) showed an OS of 80% versus 43% (P = .030), PFS of 65% versus 18% (P = .003), and LC of 84% versus 57% (P = .039).ConclusionsSarcomatoid carcinoma of the larynx is rare, and frequently presents at an early stage in older men with history of smoking. Based on our outcomes and patterns of failure, it appears early‐stage tumors are treated appropriately with single‐modality therapy, whereas more advanced tumors require multimodality therapy. Validation in a larger cohort is warranted.Level of Evidence4. Laryngoscope, 128:373–377, 2018