Estimating the OncotypeDX score: validation of an inexpensive estimation tool.

BACKGROUND: OncotypeDX, a multi-gene expression assay, has been incorporated into clinical practice as a prognostic and predictive tool. However, its use in resource-constrained international healthcare systems is limited. Here we develop and validate a simplified model using clinicopathologic criteria to predict OncotypeDX score. METHODS: Patients with estrogen receptor (ER) and/or progesterone receptor (PR)-positive and HER2-negative invasive ductal carcinoma for whom the OncotypeDX test was successfully performed between 09/2008 and 12/2011 were retrospectively identified. Tumor size, nuclear and histologic grade, lymphovascular invasion, and ER and PR status were extracted from pathology reports. Data were split into a training dataset comprising women tested 09/2008-04/2011, and a validation dataset comprising women tested 04/2011-12/2011. Using the training dataset, linear regression analysis was used to identify factors associated with OncotypeDX score, and to create a simplified risk score and identify risk cutoffs. RESULTS: Estrogen and progesterone receptors, tumor size, nuclear and histologic grades, and lymphovascular involvement were independently associated with OncotypeDX. The full model explained 39% of the variation in the test data, and the simplified risk score and cutoffs assigned 57% of patients in the test data to the correct risk category (OncotypeDX score <18, 18-30, >30). 41% of patients were predicted to have OncotypeDX score <18, of these 83, 16, and 2% had true scores of <18, 18-30, and >30, respectively. CONCLUSIONS: Awaiting an inexpensive test that is prognostic and predictive, our simplified tool allows clinicians to identify a fairly large group of patients (41%) with very low chance of having high-risk disease (2%).

Clinical accuracy of preoperative breast MRI for breast cancer.

BACKGROUND: It is unclear if breast magnetic resonance imaging (MRI) is more accurate than mammography (MGM) and ultrasound (U/S) in aggregate for patients with invasive cancer. METHODS: We compared concordance of combined tumor size and tumor foci between MRI and MGM and U/S combined to pathological tumor size and foci as the gold standard from 2009 to 2015. Tumor size was nonconcordant if it differed from the pathologic size by ≥33% and tumor foci was nonconcordant if >1 foci were seen. If one or both of the MGM or U/S was nonconcordant and the MRI was concordant, MRI provided greater accuracy. RESULTS: Of 471 patients with MGM, US, and MRI, MRI was more accurate for 32.9% of patients for tumor size and for 21.9% for tumor foci. Patients for whom MRI had greater accuracy were compared to those who did not for clinical and tumor factors. The only significant factor was calcifications on mammography. Tumor size, stage, molecular subtype, histology, grade, patient BMI, age, mammographic density, and use of hormone replacement therapy were not significantly different. CONCLUSIONS: Breast MRI provides greater accuracy for a third of patients undergoing preoperative MGM and U/S. Mammographic calcifications were associated with MRI clinical accuracy for patients with invasive cancer.

Impact of Surgical Delay on Tumor Upstaging and Outcomes in Estrogen Receptor-Negative Ductal Carcinoma in Situ Patients.

BACKGROUND: The delay of elective surgeries by the coronavirus 2019 (COVID-19) pandemic prompted concern among surgeons to delay estrogen receptor (ER)-negative ductal carcinoma in situ (DCIS) for fear of missing an ER-negative invasive cancer and compromising survival of patients. STUDY DESIGN: Female patients ≥40 years old diagnosed with ER-negative DCIS from 2004 to 2017 were examined from the National Cancer Database. Multivariable logistic regression, adjusting for patient and tumor factors, was used to determine factors associated with tumor upstage. Multivariable Cox proportional hazards modeling was used to determine if surgical delay impacted overall survival of ER-negative DCIS patients that were upstaged to invasive disease. RESULTS: There were 219,731 patients with DCIS of which 24,338 (11.1%) had tumor upstage. Of these patients, 5,675 (16.2%) of ER-negative and 18,663 (10.1%) of ER-positive DCIS patients were upstaged (p ≤ 0.001). From 2004 to 2017, ER-negative DCIS upstage rates increased from 12.9% to 18.9%. Independent factors associated with tumor upstage were younger age (odds ratio [OR] 0.75 [95% CI 0.69 to 0.81]) and Black race (OR 1.34 [95% CI 1.22 to 1.46]). Compared with patients with ≤30 days between biopsy and surgery, patients with a 31- to 60-day interval (OR 1.13 [95% CI 1.05 to 1.20]) and a >60-day interval (OR 1.12 [95% CI 1.02 to 1.23]) had an increased rate of tumor upstage. Among ER-negative DCIS patients whose tumors were upstaged to invasive disease, Cox proportional hazard regression modeling showed no association between the number of days between biopsy and surgery and overall survival. CONCLUSIONS: Delays in surgery were associated with higher tumor upstage rates but not with worse overall survival.

Copper transporter 2 regulates endocytosis and controls tumor growth and sensitivity to cisplatin in vivo.

Copper transporter 2 (CTR2) is one of the four copper transporters in mammalian cells that influence the cellular pharmacology of cisplatin and carboplatin. CTR2 was knocked down using a short hairpin RNA interference. Robust expression of CTR2 was observed in parental tumors grown in vivo, whereas no staining was found in the tumors formed from cells in which CTR2 had been knocked down. Knockdown of CTR2 reduced growth rate by 5.8-fold, increased the frequency of apoptotic cells, and decreased the vascular density, but it did not change copper content. Knockdown of CTR2 increased the tumor accumulation of cis-diamminedichloroplatinum(II) [cisplatin (cDDP)] by 9.1-fold and greatly increased its therapeutic efficacy. Because altered endocytosis has been implicated in cDDP resistance, uptake of dextran was used to quantify the rate of macropinocytosis. Knockdown of CTR2 increased dextran uptake 2.5-fold without reducing exocytosis. Inhibition of macropinocytosis with either amiloride or wortmannin blocked the increase in macropinocytosis mediated by CTR2 knockdown. Stimulation of macropinocytosis by platelet-derived growth factor coordinately increased dextran and cDDP uptake. Knockdown of CTR2 was associated with activation of the Rac1 and cdc42 GTPases that control macropinocytosis but not activation of the phosphoinositide-3 kinase pathway. We conclude that CTR2 is required for optimal tumor growth and that it is an unusually strong regulator of cisplatin accumulation and cytotoxicity. CTR2 regulates the transport of cDDP in part through control of the rate of macropinocytosis via activation of Rac1 and cdc42. Selective knockdown of CTR2 in tumors offers a strategy for enhancing the efficacy of cDDP.

Multidisciplinary management of metastatic sarcoma.

Soft tissue sarcomas comprise a heterogeneous group of malignancies of mesenchymal origin. Although sarcomas can arise virtually anywhere, the most common primary site is the extremity. The development of metastatic disease poses a major clinical problem because it is seldom amenable to a curative treatment. However, with careful and expert multidisciplinary team selection of patients with metastatic sarcoma-balancing probability of benefit with certain toxicity-a combined multimodality approach may provide hope to a select few for prolonged survival and even cure.

Heparanase-1 gene expression and regulation by high glucose in renal epithelial cells: a potential role in the pathogenesis of proteinuria in diabetic patients.

The molecular mechanisms of heparan sulfate proteoglycan downregulation in the glomerular basement membrane (GBM) of the kidneys with diabetic nephropathy remain controversial. In the present study, we showed that the expression of heparanase-1 (HPR1), a heparan sulfate-degrading endoglycosidase, was upregulated in the renal epithelial cells in the kidney with diabetic nephropathy. Urinary HPR1 levels were elevated in patients with diabetic nephropathy. In vitro cell culture studies revealed that HPR1 promoter-driven luciferase reporter gene expression, HPR1 mRNA, and protein were upregulated in renal epithelial cells under high glucose conditions. Induction of HPR1 expression by high glucose led to decreased cell surface heparan sulfate expression. HPR1 inhibitors were able to restore cell surface heparan sulfate expression. Functional analysis revealed that renal epithelial cells grown under high glucose conditions resulted in an increase of basement membrane permeability to albumin. Our studies suggest that loss of heparan sulfate in the GBM with diabetic nephropathy is attributable to accelerated heparan sulfate degradation by increased HPR1 expression.

Ductal carcinoma in situ of the breast and heparanase-1 expression: a molecular explanation for more aggressive subtypes.

BACKGROUND: Ductal carcinoma in situ of the breast (DCIS) forms a heterogeneous group of lesions with varying invasive potential. This study tested whether heparanase-1 (HPR1), an endoglycosidase that specifically degrades the heparan sulfate (HS) proteoglycans in the breast extracellular matrix, was associated with the most aggressive DCIS subtypes. STUDY DESIGN: Fifty-seven DCIS specimens and 10 normal breast specimens were examined for HPR1 expression using immunohistochemical staining. Twenty-seven arbitrarily selected specimens were also examined for HS deposition by immunofluorescence staining, confirming HPR1 activity. Patient medical records were obtained to explore a possible association between biologic potential using Van Nuys Prognostic Index (VNPI) and HPR1 expression. RESULTS: Twenty-one (75%) of 28 comedo and microinvasive DCIS specimens stained HPR1 positive; 4 (14%) of 29 other subtypes (papillary, cribriform, and solid subtypes) stained HPR1 positive on immunohistochemistry (p = 0.003). Among 27 DCIS stained for HS, we found that 8 (67%) of 12 HPR1-negative DCIS had intact HS deposition in the extracellular basement membrane; none of the 15 HPR1-positive DCIS stained HS positive. Six (86%) of seven DCIS with VNPI scores 8 to 9 and 14 (50%) of 28 DCIS with VNPI scores 5 to 7 were HPR1 positive; only 3 (17%) of 18 DCIS with VNPI scores 3 to 4 were HPR1 positive. Median VNPI score in patients with HPR1-positive DCIS was 7 (range 3 to 9), compared with 4.5 (range 3 to 7) in patients with HPR1-negative DCIS (p < 0.001). CONCLUSIONS: HPR1 was expressed at a significantly higher frequency in the invasive comedo and DCIS with microinvasion subtypes than in the noninvasive subtypes. HPR1 expression was inversely associated with HS deposition in the extracellular basement membrane of the DCIS. HPR1 expression was associated with a higher VNPI score. These observations suggest that HPR1 expression in DCIS can play an important role in development of DCIS into an invasive breast cancer.

Intraoperative parathyroid hormone levels in thyroid surgery are predictive of postoperative hypoparathyroidism and need for vitamin D supplementation.

BACKGROUND: Intraoperative parathyroid hormone (ioPTH) levels are not monitored routinely in thyroid surgery, although they are used widely during parathyroidectomy as an indicator of parathyroid gland function. This prospective study evaluated the occurrence of hypoparathyroidism after thyroid surgery and the use of ioPTH levels to predict the need for postoperative vitamin D supplementation. METHODS: Seventy-two patients underwent thyroidectomy or neck dissection by 1 surgeon. Forty-five patients had a total thyroidectomy, 16 patients had a hemithyroidectomy, 9 patients had a completion thyroidectomy, and 2 patients had a neck dissection alone for recurrent thyroid cancer. ioPTH and serum calcium (SCa) levels were obtained during the course of surgery and 1 month after surgery. Levels from these time points were compared, and correlated with the need for vitamin D supplementation at the 1-month follow-up evaluation using the Fisher exact test. RESULTS: Of the 72 patients, 14 had an ioPTH level less than 10 pg/mL at closure. At the 1-month evaluation, 11 of these 14 patients required vitamin D supplementation because of persistent hypoparathyroidism or hypocalcemia (P <.001). The remaining 3 of the 14 patients with ioPTH levels less than 10 pg/mL at closure did not require vitamin D supplementation at the 1-month evaluation because they were asymptomatic and their PTH and SCa levels had normalized. None of the 58 patients with an ioPTH level greater than 10 pg/mL at closure needed vitamin D supplementation at the 1-month follow-up evaluation. CONCLUSIONS: An ioPTH level less than 10 pg/mL at closure is a strong predictor of hypoparathyroidism after thyroid surgery. Patients with ioPTH levels less than 10 pg/mL at closure should be placed on vitamin D supplementation after surgery to anticipate decreased parathyroid gland function and to avoid symptomatic hypocalcemia.

Changing surgical trends in young patients with early stage breast cancer, 2003 to 2010: a report from the National Cancer Data Base.

BACKGROUND: Young patients with breast cancer represent a unique cohort of patients who often have different treatment plans than older patients. We hypothesized that the rates of contralateral prophylactic mastectomy (CPM) were significantly higher and those of lumpectomy were significantly lower in young patients compared with older patients and that this trend persists when adjusting for patient, tumor, and facility factors. STUDY DESIGN: We used the National Cancer Data Base (NCDB) to study 553,593 patients from all ages with American Joint Committee on Cancer (AJCC) stage 0 to II breast tumors, who underwent lumpectomy, unilateral mastectomy, or CPM from 2003 to 2010. RESULTS: Over the entire cohort, lumpectomy rates decreased from 67.7% in 2003 to 66.4% in 2010 in contrast to women 45 years old or less, in whom the lumpectomy rates went from 61.3% in 2003 to 49.4% in 2010. Unilateral mastectomy went from 28.2% to 23.9% and CPM from 4.1% to 9.7% compared with women 45 years old or less, in whom unilateral mastectomy rates went from 29.3% to 26.4% and CPM rates from 9.3% to 26.4%. Age was the most significant factor related to increasing CPM rates: 19.7% of women between 41 and 45 years old underwent CPM vs 5.1% of women between 66 and 70 years old. There was substantial regional variation in surgical procedures for young women: lumpectomy rates were lowest in the West and CPM rates were highest in the Midwest. Multivariate logistic regression showed that women 45 years old or younger compared with women more than 45 years who underwent CPM were more likely to be Caucasian, treated at an academic/research institution, have larger tumors, higher grade, higher stage, and lobular histology. CONCLUSIONS: The rate of CPM continues to increase, with one-quarter of younger women undergoing CPM. This trend persists across all patient, tumor, and facility characteristics.

Lower vitamin D levels in surgical hyperparathyroidism versus thyroid patients.

Low vitamin D levels have been shown to be associated with primary hyperparathyroidism, but it is unclear whether vitamin D deficiency may be an etiologic factor in the development of primary hyperparathyroidism. To investigate this, we compared preoperative vitamin D levels of patients undergoing surgery for primary hyperparathyroidism with those of patients undergoing surgery for benign thyroid disease. With Institutional Review Board approval, data were collected prospectively on patients undergoing parathyroidectomy or thyroidectomy by one surgeon between March 2006 and July 2011. Patients were excluded if they underwent simultaneous thyroid and parathyroid surgery, had secondary or tertiary hyperparathyroidism, if no preoperative vitamin D level was measured, or if they took vitamin D supplements. Inclusion criteria were met by 219 patients who underwent parathyroidectomy and 186 patients who underwent thyroid surgery. Patient age, sex, race, and preoperative vitamin D levels (vitamin D 25-OH; normal, 32 to 100 pg/mL) were collected. Statistical analysis was performed using linear regression. Vitamin D levels were significantly lower in the parathyroid group compared with the thyroid group (23.8 vs 28.5 pg/mL; P < 0.001). This difference was also observed after adjustment for age, sex, and race with a mean difference of 4.87 pg/mL (P < 0.001). Statistically significant associations between lower vitamin D levels and patients younger than 50 years (P = 0.048), male sex (P = 0.03), and nonwhite race were identified (P < 0.001). Patients with primary hyperparathyroidism are more likely to have lower vitamin D levels than a control surgical population. Further study is needed to determine whether low vitamin D levels may be an etiologic factor associated with the development of hyperparathyroidism.

Postoperative hypocalcemia after thyroidectomy for Graves' disease.

BACKGROUND: It is believed that patients who undergo thyroidectomy for Graves' disease are more likely to experience postoperative hypocalcemia than patients undergoing total thyroidectomy for other indications. However, no study has directly compared these two groups of patients. The aim of this study was to determine whether there was an increased incidence or severity of postoperative hypocalcemia in patients who underwent thyroidectomy for Graves' disease. METHODS: An institutional review board-approved database was created of all patients who underwent thyroidectomy from 1998 to 2009 at the Johns Hopkins Hospital. There were a total of 68 patients with Graves' disease who underwent surgery. Fifty-five patients who underwent total thyroidectomy were randomly selected and served as control subjects. An analysis was conducted that examined potential covariates for postoperative hypocalcemia, including age, gender, ethnicity, preoperative alkaline phosphatase level, size of goiter, whether parathyroid tissue or glands were present in the specimen, and the reason the patient underwent surgery. Specific outcomes examined were calcium levels on postoperative day 1, whether or not patients experienced symptoms of hypocalcemia, whether or not Rocaltrol was required, the number of calcium tablets prescribed upon discharge, whether or not postoperative tetany occurred, and calcium levels 1 month after discharge. RESULTS: Each outcome was analyzed using a logistic regression. Graves' disease patients had a significantly (p-value < 0.001) higher odds of greater number of calcium tablets prescribed upon discharge. Further, 6 of 68 patients with Graves' disease and no patient in the control group were readmitted with tetany (p = 0.033). There was a trend, though not significant, toward patients with Graves' disease having a higher prevalence of hypocalcemia the day after thyroidectomy and 1 month later. CONCLUSIONS: Patients with Graves' disease are more likely to require increased dosages of calcium as well as experience tetany postoperatively than patients undergoing total thyroidectomy for other indications. This suggests that patients operated upon for Graves' disease warrant close followup as both inpatients and outpatients for signs and symptoms of hypocalcemia.

Do intraoperative total serum and ionized calcium levels, like intraoperative intact PTH levels, correlate with cure of hyperparathyroidism?

Intraoperative parathyroid hormone (ioPTH) monitoring is useful in the operative management of hyperparathyroidism. Measurement of intraoperative total serum calcium (TSC) and ionized calcium (ICa) levels may be less expensive and more readily available methods of intraoperative guidance during neck dissection than ioPTH levels, the gold standard. We compared the accuracy of monitoring intraoperative TSC and ICa to that of ioPTH for predicting surgical cure during parathyroidectomy. Over a 10-month period, 47 parathyroidectomies were performed, during which ioPTH, TSC, and ICa were measured. Samples were obtained at the start of the operation and 5 and 10 minutes after gland removal. Data were compared and trends analyzed with respect to removal of abnormal parathyroid tissue as confirmed by pathology. The Wilcoxon signed rank test was used to determine if decreases in TSC and ICa were significant. The mean baseline ioPTH level (253 +/- 247 pg/ml) dropped by 70% at 5 minutes after removal of the abnormal glands (68 +/- 85 pg/ml) and by 83% at 10 minutes (32 +/- 25 pg/ml). The mean baseline TSC level (10.1 +/- 0.9 mg/dl) dropped by 4% at 5 minutes after removal of the abnormal glands (9.7 +/- 0.8 mg/dl) and remained at 4% at 10 minutes (9.6 +/- 0.7 mg/dl). The mean baseline ICa level (1.4 +/- 0.1 mmol/dl) also dropped by 4% at 5 minutes after removal of the abnormal glands (1.3 +/- 0.1 mmol/dl) and remained at 4% at 10 minutes (1.3 +/- 0.1 mg/dl). ioPTH dropped by > or = 50% in 39 patients (83%) at 5 minutes and in 46 patients (98%) at 10 minutes after gland resection. TSC decreased below baseline at 5 minutes and remained below baseline at 10 minutes in only 37 patients (79%). In the remaining 21% of patients, TSC decreased inconsistently, if at all, with respect to baseline at both the 5- and 10-minute time points. ICa decreased below baseline at 5 minutes and remained below baseline at 10 minutes in only 35 patients (77%). In the remaining 23% of patients, ICa, like TSC, changed inconsistently at 5 and 10 minutes after parathyroidectomy with respect to baseline levels. Decreases in TSC and ICa during parathyroidectomy, if present, are thus minimal. Unlike ioPTH levels, TSC and ICa levels do not consistently decrease at 5 and 10 minutes after gland resection. Although inexpensive and readily available, monitoring the intraoperative TSC and ICa is not clinically reliable for confirming removal of hyperfunctioning parathyroid glands.