Exosomes from Von Hippel-Lindau-Null Cancer Cells Promote Metastasis in Renal Cell Carcinoma.

Exosomes are extracellular vesicles that modulate essential physiological and pathological signals. Communication between cancer cells that express the von Hippel-Lindau (VHL) tumor suppressor gene and those that do not is instrumental to distant metastasis in renal cell carcinoma (RCC). In a novel metastasis model, VHL(-) cancer cells are the metastatic driver, while VHL(+) cells receive metastatic signals from VHL(-) cells and undergo aggressive transformation. This study investigates whether exosomes could be mediating metastatic crosstalk. Exosomes isolated from paired VHL(+) and VHL(-) cancer cell lines were assessed for physical, biochemical, and biological characteristics. Compared to the VHL(+) cells, VHL(-) cells produce significantly more exosomes that augment epithelial-to-mesenchymal transition (EMT) and migration of VHL(+) cells. Using a Cre-loxP exosome reporter system, the fluorescent color conversion and migration were correlated with dose-dependent delivery of VHL(-) exosomes. VHL(-) exosomes even induced a complete cascade of distant metastasis when added to VHL(+) tumor xenografts in a duck chorioallantoic membrane (dCAM) model, while VHL(+) exosomes did not. Therefore, this study supports that exosomes from VHL(-) cells could mediate critical cell-to-cell crosstalk to promote metastasis in RCC.

Vaccination as a therapeutic strategy for Nasopharyngeal carcinoma.

Patients with recurrent or metastatic NPC are left with limited treatment options. The close association between EBV and NPC make therapeutic vaccination targeting EBV-antigens an emerging new treatment modality. Therapeutic vaccination provides a stimulus to allow the patient to mount their own targeted immune response against the cancer. The two approaches that have led the field into the clinic are dendritic-cell based vaccines and virus-based vaccines. Clinical trials have shown the vaccines to be well-tolerated, and able to elicit a targeted immune response to tumor specific epitopes. Clinical efficacy data, however, is more limited given the early stage of the trials. Other approaches to developing a therapeutic vaccine for NPC include using cancer stem cell lysates, EBV-antigen peptides, and EBV-antigen plasmid DNA. Readout of ongoing trials and progression of preclinical vaccines into Phase I will shed additional light on the efficacy of vaccines and the feasibility of these different approaches to developing a therapeutic vaccine. Future studies may explore combination therapies with multiple vaccines, adoptive T-cell therapy, or checkpoint inhibitors.

Is There a Bias Against Obese Patients in the Treatment of Breast Cancer?

BACKGROUND: Patient and tumor characteristics often coincide with obesity, potentially affecting treatment decision-making in obese breast cancer patients. Independent of all of these factors, however, it is unclear whether obesity itself impacts the decision to offer patients undergoing mastectomy breast reconstruction, postmastectomy radiation therapy (PMRT), or neoadjuvant chemotherapy. We sought to determine whether implicit bias against obese breast cancer patients undergoing mastectomy plays a role in their treatment. METHODS: Medical records of breast cancer patients undergoing mastectomy from January 2010 to April 2018 from a single institution were retrospectively reviewed, separated into obese (BMI ≥30) and nonobese (BMI <30) categories, and compared using nonparametric statistical analyses. RESULTS: Of 972 patients, 291 (31.2%) were obese. Obese patients were more likely to have node-positive, triple-negative breast cancers (P = .026) and were also more likely to have other comorbidities such as a history of smoking (P = .026), hypertension (P < .001), and diabetes (P < .001). Receipt of immediate reconstruction and contralateral prophylactic mastectomy did not vary between obese and nonobese patients. While obese patients were more likely to undergo neoadjuvant chemotherapy (26.5% vs. 18.1%, P = .004) and PMRT (33.0% vs. 23.4%, P = .003), this did not remain significant when controlling for comorbidities and clinicopathologic confounders. CONCLUSION: Obese patients present with more aggressive tumors and often have concomitant comorbidities. Independent of these factors, however, differences in the treatment of patients undergoing mastectomy do not seem to be affected by an implicit bias against obese patients.

Factors Associated With a Delay in Postmastectomy Radiation Therapy.

BACKGROUND: While the optimal time interval between mastectomy and postmastectomy radiation therapy (PMRT) has not been well-elucidated, a delay in PMRT has been associated with increased local recurrence. We sought to determine factors associated with a delay in PMRT beyond 12 weeks in patients not undergoing adjuvant chemotherapy. METHODS: Medical records of breast cancer patients who underwent mastectomy at our institution between January 2010 and December 2017 who subsequently received PMRT were retrospectively reviewed. As adjuvant chemotherapy can delay PMRT, patients receiving adjuvant chemotherapy were excluded. Factors associated with a delay in PMRT (defined as > 12 weeks from the time of mastectomy) were analyzed. RESULTS: Among the 89 patients who met our inclusion criteria, the mean time from mastectomy to PMRT was 11.4 weeks. 24 patients (27.0%) had PMRT > 12 weeks after mastectomy. Factors associated with a delay in PMRT included black race (P = 0.031), younger age (P = 0.047), higher body mass index (P = 0.015), contralateral prophylactic mastectomy (P = 0.033), longer initial hospital length of stay (P = 0.001), and more complications (P = 0.025). On multivariable analysis controlling for all of these factors, only initial hospital length of stay (OR 1.63; 95% CI: 1.07-2.49; P = 0.024) was associated with a delay in PMRT. CONCLUSION: Over a quarter of patients not undergoing adjuvant chemotherapy have a delay in PMRT beyond 12 weeks from the time of mastectomy. Length of initial hospital stay is the key driver in delaying PMRT.

Do Obese Breast Cancer Patients Have More Complications and a Longer Length of Stay After Mastectomy Than Nonobese Patients?

BACKGROUND: While obesity is thought to increase complication rates in general surgery procedures, its effect in mastectomy patients remains to be fully elucidated. We sought to determine if obesity is associated with a higher complication rate and length of stay after mastectomy, independent of clinicopathologic and treatment factors. METHODS: Medical records of breast cancer patients undergoing mastectomy at our institution between January 2010 and December 2017 were retrospectively reviewed. Patients were separated into obese (body mass index [BMI] ≥ 30) and nonobese (BMI < 30) categories and compared using nonparametric statistical analyses. RESULTS: Of 927 patients, 291 (31.2%) were obese. Obese patients had more complications (26.5% vs. 20.0%, P = 0.033) and a greater number of complications per patient (P = 0.025) than nonobese patients. They were more likely to have infections (10.7% vs. 5.7%, P = .009), flap thrombosis/necrosis (5.5% vs. 2.4%, P = .018), and skin breakdown/wound complications (8.6% vs. 4.6%, P = .022). Additionally, obese patients had longer hospital length of stay (LOS; LOS > 2 days: 77.7% vs. 65.2%, P < .001). Controlling for potential confounders, obesity remained associated with a higher rate of thrombosis/necrosis of flap (odds ratio [OR] = 2.26; 95% confidence interval [CI] 1.01-5.08; P = .047) and LOS ≥ 2 days (OR = 1.82; 95% CI 1.23-2.69; P = .003). CONCLUSION: Obese breast cancer patients undergoing mastectomy have more thrombosis/necrosis of flap and a longer hospital LOS than nonobese patients, regardless of other comorbidities and clinicopathologic/treatment factors.

Do Obese Patients Present With More Advanced Breast Cancer?

BACKGROUND: Obesity is a known risk factor for breast cancer development; however, it is unclear whether obesity is associated with more aggressive disease. We sought to determine the relationship between obesity and tumor characteristics in breast cancer patients. METHODS: Medical records of invasive breast cancer patients undergoing mastectomy at our institution between January 2010 and April 2018 were reviewed. Patients who had received neoadjuvant therapy were excluded. Patients were separated into obese (body mass index [BMI] ≥ 30 kg/m2) and nonobese (BMI < 30 kg/m2) categories and compared using nonparametric statistical analyses. RESULTS: Of the 415 patients in this cohort, 124 (29.9%) were obese. Obese patients were more likely to present with larger tumors (tumor size ≥ 2 cm: 53.2% vs 41.0%, P = .024) and more node-positive disease (46.8% vs 28.9%, P = .001). Controlling for confounders, obesity was independently associated with node-positive disease (odds ratio [OR] = 2.00; 95% CI 1.24-3.21, P = .004), but not with tumor size ≥ 2 cm (OR = 1.38; 95% CI 0.87-2.21, P = .174). CONCLUSION: Obesity is associated with node-positive disease at presentation independent of other factors.

Factors Affecting Total Operating Time in Patients Undergoing Mastectomy With and Without Reconstruction.

BACKGROUND: Operating room (OR) time varies significantly in patients undergoing mastectomy. We sought to determine factors influencing OR time such that more accurate predictions could be made. METHODS: Records of patients undergoing mastectomy at our institution between January 2010 and June 2018 were reviewed. Operating Room time was defined as time from incision to dressing. Nonparametric analyses were performed to determine factors associated with OR time. A predictive model using linear regression was created on a training set and evaluated in a separate testing set. RESULTS: Our cohort included 1008 female patients who underwent either unilateral or bilateral mastectomy (BM), with or without reconstruction, and with or without concomitant axillary lymph node staging at our institution. The median OR time was 4.67 hours (range; .70-16.35 hours). To create a predictive model, we divided our cohort into a training set of 504 patients and a testing set of 504 patients. Across the training set, body mass index (BMI), BM, nonconventional mastectomies, intraoperative frozen sections, receipt of neoadjuvant chemotherapy, and reconstruction were associated with longer OR times on linear regression. A model generated from these findings on the training set was run on the testing set (Pearson correlation = .743 for predicted vs. actual OR times, P < .001). CONCLUSION: A number of preoperative factors such as BMI, unilateral vs. BM, type of mastectomy and reconstruction, use of intraoperative frozen sections, and receipt of neoadjuvant chemotherapy can influence OR times. Accurate predictions can be made using a simple model incorporating these factors.

Circulating tumor cell analysis in locally advanced and metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Circulating tumors cells (CTCs) are considered an early step towards metastasis and have been linked to poor prognosis in several types of cancer. CTCs in squamous cell carcinoma of the head and neck (SCCHN) have an unclear role. METHODS: In this prospective study, patients with locally advanced or metastatic SCCHN had CTC counts assessed before starting systemic treatment using the CellSearch System. Select cases also had sequential CTC evaluation. Presence of CTCs was correlated with patient characteristics and outcomes. RESULTS: Forty-eight patients enrolled, and 36 had evaluable clinical data and baseline CTC counts. Twenty-five patients had locally advanced disease (LAD) and 11 had metastatic disease. ≥1 CTCs were detected in six patients with LAD (24%) and four with metastatic disease (36%). On univariate analysis, smoking was associated with CTCs. CONCLUSION: CTCs are not associated with prognosis in patients with LAD and metastatic disease; however, they are present in this patient population, and ≥1 CTCs is associated with a history of smoking. LEVEL OF EVIDENCE: 1b; individual prospective cohort study.

Factors Associated with Reconstruction in Patients Undergoing Mastectomy.

Postmastectomy reconstruction has been shown to be oncologically safe, but few studies have investigated factors influencing the type of reconstruction chosen, if at all. Records of female patients with stages 0 to 3 breast cancer undergoing mastectomy at a large academic institution between January 2010 and March 2018 were reviewed. Nine hundred sixty patients were included in this cohort; 784 patients had reconstruction. Younger age, earlier disease stage, private insurance, no history of diabetes, and bilateral mastectomy (BM) were associated with reconstruction. On multivariate analysis, younger age, BM, private insurance, and earlier disease stage predicted reconstruction. Of reconstruction patients, 453 had implants. Race, BMI, and later disease stage influenced the type of reconstruction; on multivariate analysis, higher BMI and later disease stage predicted flap reconstruction. Younger age, BM, private insurance, and earlier disease stage were associated with reconstruction, but the type of reconstruction was affected primarily by BMI and disease stage.

Is nipple sparing mastectomy associated with increased complications, readmission and length of stay compared to skin sparing mastectomy?

INTRODUCTION: We sought to determine rates of complications, reoperation, and length of stay (LOS) between nipple-sparing (NSM) and skin-sparing (SSM) mastectomy patients, hypothesizing that rates would be higher in the former. METHODS: Patients undergoing NSM or SSM at our institution between January 1, 2010 and December 31, 2017 were compared. RESULTS: 217 patients underwent NSM; 581 underwent SSM. NSM patients were more likely to be younger, with private insurance, lower BMI, lighter breasts, have bilateral mastectomy, with implant-based reconstruction, for BRCA, and/or lower stage disease and were less likely to have diabetes, axillary dissection, and/or neoadjuvant therapy. Controlling for these factors, NSM patients had a higher complication rate than SSM patients (OR: 1.822; 95% CI: 1.163-2.853, p = 0.009). Length of stay and reoperation rates were not significantly different between the two groups. CONCLUSION: NSM and SSM patients have similar reoperation rates and LOS; however, complication rate is higher in NSM patients.

Effect of decision-making resources on satisfaction with decision to undergo contralateral prophylactic mastectomy (CPM).

BACKGROUND: Rates of contralateral prophylactic mastectomy (CPM) are increasing, and there are many resources available to help patients with decision-making. We sought to determine how often these were used, and whether their use influenced satisfaction with decision to pursue CPM. METHODS: CPM patients at a large academic institution were surveyed regarding factors associated with their CPM decision, and their satisfaction with the same. RESULTS: Of 58 CPM patients approached to participate, 55 completed the survey with a mean SWD score of 4.85 (range 3.00-5.00). Partner opinion (47.3%), family opinion (45.5%), other cancer patients' experiences (38.2%), and informational websites (38.2%) were the most frequently cited resources used by CPM patients. On multivariate analysis, controlling for other factors affecting SWD, use of other cancer patients' experiences predicted above average SWD (p = 0.049). CONCLUSION: Those who use other cancer patients' experiences to aid in their surgical decision-making enjoy a higher satisfaction with their decision.

Treatment of Aggressive Thyroid Cancer.

Although thyroid cancer generally has a good prognosis, there is a subset of patients for whom standard care (ie, treatment limited to surgery or surgery plus radioactive iodine) is either not appropriate because of the aggressive nature of their disease or not sufficient because of disease progression through standard treatment. Most of these tumors are in 3 groups: radioactive iodine-refractory differentiated thyroid carcinoma including poorly differentiated thyroid carcinoma anaplastic thyroid carcinoma, and progressive medullary thyroid carcinoma. Major classes of treatments in clinical development for these aggressive thyroid tumors include tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and mitogen-activated protein kinase kinase inhibitors.

Can I Keep My Nipple? Factors Influencing the Surgical Decision between Skin-Sparing and Nipple-Sparing Mastectomy.

Both skin-sparing mastectomy (SSM) and nipple-sparing mastectomy (NSM) are well accepted in the management of breast cancer. Factors that influence the decision of choosing one of these techniques over the other, however, remain to be well elucidated. From January 2010 to December 2017, 734 patients at our institution underwent one of these two procedures. Factors differentiating these patient cohorts were compared. In this study, 196 (26.7%) underwent NSM and 538 (73.3%) underwent SSM. The median age of patients at the time of surgery was 50 years (range, 22-78 years). On multivariate analysis, younger patient age, insurance type, BRCA+ mutation status, smaller breast size (by weight), and those who did not undergo neoadjuvant chemotherapy were more likely to undergo NSM. Surgeon also was an independent predictor of whether patients had NSM or SSM. There may be many factors that play into the decision to pursue NSM versus SSM, but younger patient age, BRCA mutation status, breast size, and whether the patient had neoadjuvant chemotherapy may be key among them. Insurance status may also be a factor for some patients. Aside from these factors, some surgeons may be more or less inclined to perform NSM.

Active Participation in Decision-Making in Contralateral Prophylactic Mastectomy for Patients With Breast Cancer.

BACKGROUND: We sought to determine how patient-physician communication affects patients' decision-making when choosing between contralateral prophylactic mastectomy (CPM) and unilateral mastectomy (UM). METHODS: atients with breast cancer who underwent mastectomy at our institution were approached with a survey regarding patient-physician communication in CPM. RESULTS: Of 101 patients who completed the survey, 55 underwent CPM (54.5%). Thirty-three patients (33%) stated that their physician recommended UM, six (6%) stated their physician recommended CPM, and 61 (61%) stated they engaged in active participation in decision-making. Most patients whose doctors recommended UM chose UM (78.8%); similarly, 83.3% of those whose doctors recommended CPM chose CPM. Of 39 patients whose doctors recommended a particular surgical option, eight (20.5%) did not follow their doctor's advice. These patients were equally as satisfied with their decisions as those who followed their doctor's advice (P = 0.441). Patients engaging in active participation in decision-making tended to choose CPM (68.3% versus 30.8%, P < 0.001). Patients who did not engage in active participation were similarly satisfied with their decision as those who did (P = 0.286). Twelve patients (12%) stated they preferred their doctor to provide a recommendation, seven (7%) preferred to make the decision on their own, and 81 (81%) preferred to actively participate in their decision-making with the physician. CONCLUSIONS: Patients tend to follow physicians' recommendation of UM or CPM; patients engaging in SDM tend to choose CPM. Most patients prefer to engage in active participation in decision-making with their physician but were equally satisfied with their surgical decision whether they engaged in active participation or not.

Everolimus in Anaplastic Thyroid Cancer: A Case Series.

Background: Anaplastic thyroid cancer (ATC) is a very aggressive disease and accounts for over 50% of thyroid-cancer related deaths. mTOR inhibition has shown anti-tumor activity in ATC. We report our experience treating patients with ATC with everolimus off-protocol. Methods: Patients with confirmed ATC and treated with everolimus at DFCI were identified and reviewed retrospectively. NexGen sequencing was performed, and radiologic responses were correlated with mutational profile. Results: Five patients were treated from 2013 to 2016. Three patients had a response, which included one patient who achieved a partial response for 27.9 months, and two patients who had stable disease for 3.7 and 5.9 months, respectively. Genomic analysis was available in two patients and revealed that the partial responder had mutations involving the PI3K/mTOR pathway. Conclusion: Everolimus has anti-tumor activity in ATC, and responses may correlate with mutations involving the PI3K/mTOR pathway. Further studies are warranted.

Factors associated with decision to undergo contralateral prophylactic mastectomy versus unilateral mastectomy.

BACKGROUND: Factors associated with the decision to pursue unilateral mastectomy (UM) versus contralateral prophylactic mastectomy (CPM) in unilateral breast cancer (UBC) patients, and satisfaction with this decision, remain to be elucidated. METHODS: UBC patients who underwent mastectomy were surveyed regarding factors affecting their surgical decision and satisfaction with the same. RESULTS: Both UM (n = 46) and CPM (n = 55) patients were satisfied with their surgical decision (mean 4.72 and 4.85 out of 5 on Satisfaction With Decision scale, respectively, p = 0.078). Most CPM patients cited the desire to lower their risk of contralateral breast cancer (96.4%) and the desire for peace of mind (94.5%) as "very important" drivers of their decision; whereas most UM patients felt not wanting to remove a normal breast (67.4%) was a "very important" driver for their decision. CONCLUSIONS: Both UM and CPM patients reported high satisfaction with their surgical decisions, despite differing reasons for their respective surgeries.