BRAFV600E, hypothyroidism, and human relaxin in thyroid carcinogenesis.

PURPOSE: BRAFV600E, a major driver of thyroid cancer, evaluated in the context of thyroid hormones and human relaxin. METHODS: Immunohistochemical expressions of BRAFV600E, TSH, TSH receptor (TSHR), T4, T3 receptor (T3R), RLNH2, and its receptor, RXFP1, were evaluated in thyroid tumors from a retrospective U.S. population of 481 cancer cases diagnosed in 1983-2004. RESULTS: BRAFV600E was expressed in 52% of all thyroid tumors; expression of other markers ranged from 25% for T4 to 98% for RLNH2. Tumors predominantly exhibited hypothyroid-like conditions characterized by elevated TSH and TSHR and reduced T4. BRAFV600E prevalence was significantly higher in tumors expressing TSH, TSHR, T3R, and RXFP1 and lower in tumors expressing T4. The proportion of BRAFV600E mutation in classic papillary tumors significantly increased from 56 to 72% over the 21-year period of diagnoses, while expression of RXFP1, TSH, TSHR, and T3R decreased in non-tumor. Racial/ethnic differences were observed in thyroid hormone marker expression. Non-tumor expression of TSH, TSHR, and T3R were each associated with shorter overall survival, but did not remain significant after adjustment for demographic and clinical factors. CONCLUSIONS: Our study provides the first evidence of the potential interaction of BRAFV600E mutation, relaxin, and thyroid hormones in thyroid carcinogenesis. Moreover, our results suggest that hypothyroidism, influenced by RLNH2 activity, may underlie the development of the majority of thyroid cancers and mediate the role of BRAFV600E in thyroid carcinogenesis. BRAFV600E mutation is increasing in papillary thyroid cancers and may be contributing to the rising incidence of this malignancy.

Surgical management of truncal soft tissue sarcoma and other selected soft tissue neoplasms.

Soft tissue sarcoma (STS) is a heterogeneous entity comprising only 1% of all adult cancers that has received considerable attention since it was initially described after the 1st century as "fleshy" by Claudius Galenus. Nick-named the forgotten cancer, more than 100 histologic subtypes have been identified making treatment paradigms extremely complex. A key principle in the management of truncal STS is a defined multi-disciplinary team consisting of several providers. In most instances, surgery is the cornerstone of treatment. This overview will focus on the management of truncal sarcoma from a surgical perspective that will entail several points of consideration including histologic subtype, degree of differentiation, margin status as well as necessity of reconstruction; it will also include discussion of other unique soft tissue neoplasms relevant to the breast and abdominal wall.

Rare presentations of primary melanoma and special populations: a systematic review.

A subset of patients with melanoma present in rare and unique clinical circumstances requiring specific considerations with respect to diagnostic and therapeutic interventions. Herein, we present our review of patients with: (1) primary mucosal melanoma of the head and neck, gastrointestinal, and genitourinary tracts; (2) primary melanoma of the eye; (3) desmoplastic melanoma; (4) subungual melanoma; (5) melanoma in special populations: children, nonwhites, as well as a discussion of familial melanoma.

Molecular targets in melanoma: time for 'ethnic personalization'.

Worldwide, the incidence of melanoma continues to rise. Although not the most common cutaneous malignancy, it is the most lethal. Until recently, while other oncologic patients benefited from the nuances of targeted therapy, those afflicted with melanoma lacked that option. In 2011, the US FDA approved an oral agent that targets the BRAF oncogene. As this information is promising, it is essential that other populations (in addition to Caucasians) are examined, in order to further comprehend the biology of melanoma. Recent studies profiling various ethnicities, including Asians, have provided novel data with respect to the molecular characterization (c-KIT, BRAF, NRAS) of melanoma. It is hopeful that the management of melanoma will be universally applicable to all ethnic groups.

An unusual case of recurrent hyperparathyroidism and papillary thyroid cancer.

OBJECTIVE: To report an unusual occurrence of recurrent hyperparathyroidism due to papillary thyroid carcinoma. METHODS: We describe the clinical history, physical examination findings, laboratory values, imaging findings, and pathologic findings of a woman who developed recurrent hyperparathyroidism 13 years after successful parathyroidectomy. RESULTS: A 59-year-old woman presented to our clinic with recurrent primary hyperparathyroidism. In 1994, she presented with nephrolithiasis and underwent resection of a right superior parathyroid adenoma that resulted in clinical and biochemical cure. Her clinical course had been followed at periodic intervals, and she had been symptom-free and normocalcemic. In 2007, she again developed nephrolithiasis and was documented to have recurrent hyperparathyroidism. Imaging studies suggested a parathyroid adenoma near the right inferior pole of the thyroid. The patient had reoperative neck exploration. No obvious parathyroid adenoma was found and a right thyroid lobectomy was performed, which resulted in normalization of intraoperative intact parathyroid hormone levels, and the incision was closed. Final pathology demonstrated no parathyroid adenoma, but instead, a 1-cm papillary thyroid carcinoma that stained positive for parathyroid hormone. More than 6 months after surgery, she remains clinically and biochemically cured. CONCLUSIONS: Recurrent hyperparathyroidism occurs secondary to multiple causes. This case demonstrates the challenge a surgeon faces in managing recurrent disease and highlights a rare phenomenon of papillary thyroid cancer causing recurrent hyperparathyroidism.

Evaluation for concomitant thyroid nodules and primary hyperparathyroidism in patients undergoing parathyroidectomy or thyroidectomy.

BACKGROUND: Previous investigators have reported the incidence of thyroid nodules in patients with primary hyperparathyroidism; others have noted the incidence of primary hyperparathyroidism in patients who underwent thyroidectomy. It is well known that both of these entities coexist. In this article, we present a single-center experience with the incidence of concomitant thyroid nodular disease and primary hyperparathyroidism in patients who underwent parathyroidectomy or thyroidectomy. METHODS: From May 2006 to December 2007, 526 patients underwent thyroidectomy, parathyroidectomy, or both. Operations were performed by surgeons in the Johns Hopkins Endocrine Surgery Section after screening preoperatively for concomitant thyroid nodular disease or primary hyperparathyroidism. RESULTS: Among the 200 patients who underwent a parathyroidectomy, 102 (51.0%) were found to have thyroid nodular disease. Six percent of these 200 patients also had a thyroid malignancy. Of the 326 patients who were primarily seen for thyroid disease, the incidence of primary hyperparathyroidism was 3.1%. CONCLUSION: By implementing a comprehensive approach to patients who present with thyroid disease or primary hyperparathyroidism, concomitant pathology may be elucidated preoperatively. This approach will facilitate the detection of otherwise unsuspected thyroid cancer and hyperparathyroidism as well as prevent unnecessary reoperative surgery.

Twenty-eight-day mortality in critically ill surgical patients is an imprecise temporal end-point measure for in-hospital mortality.

BACKGROUND: The purpose of this study was to determine the incidence of deaths occurring beyond 28 days in critically ill surgical patients and to identify the proportion of these deaths attributable to the original disease process. METHODS: Analysis of 1,360 subjects admitted to a surgical intensive care unit during a 2 year period. Demographics, indication(s) for admission, comorbidities, mortality rate, multiorgan failure development, and cause of death was obtained. RESULTS: Mortality rate in the surgical intensive care unit was 12%. Twenty % of deaths occurred more than 28 days after hospital admission with 76% of deaths related to admission diagnosis. By day 34, 95% of mortalities had occurred. CONCLUSIONS: The 28-day time period used to assess efficacy of therapeutic interventions and to define mortality in the context of quality audits should be questioned. If these findings are validated in other centers another temporal end point for in-hospital mortality should be considered.

Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy.

PURPOSE: Over the past 60 years, cytotoxic chemotherapy has targeted the cancer cell. Despite this, there have been few cancer cures. A new approach to cancer therapy is to target the multicellular biological entity of the tumor microenvironment. EXPERIMENTAL DESIGN: Lenalidomide, an immunomodulatory drug, sunitinib, a tyrosine kinase inhibitor, and low-dose metronomic cyclophosphamide, were tested alone and in combination for their abilities to inhibit endothelial cell tube formation, rat aortic ring outgrowth, tumor growth, and metastatic development in mice. In addition, ectopic tumor lysates were evaluated for the presence of proangiogenic proteins. RESULTS: The three agents alone were shown to significantly inhibit endothelial cells' ability to form tubes and significantly inhibit the multicellular microenvironment in the rat aortic ring assay (P < 0.01 and P < 0.001). This effect was also significantly augmented when the agents were combined. Furthermore, the three-drug combination was able halt the progression of tumor growth almost completely in xenograft models of ocular melanoma, colon cancer, pancreatic cancer, and cutaneous melanoma. These agents significantly decrease the number of proliferating cells in tumors, significantly increase the number of cells undergoing active cell death in tumors, and significantly decrease the number of blood vessels in treated tumors (P < 0.05). Combination therapy shows a decrease in the compensatory up-regulation of proangiogenic proteins after treatment when compared with single-agent therapy. CONCLUSIONS: This combination of agents causes an inhospitable microenvironment for tumor cells and shows great promise for use in the clinic.

Increased fatalities and cost of traumatic injuries in elderly pedestrians in Hawaii: a challenge for prevention and outreach.

This study was carried out to evaluate and quantify risk factors, mechanisms, and cost of traumatic injuries in Hawaii's elderly and to identify potential preventive strategies. A retrospective review of a prospective database of patients admitted to the only Trauma Center in the Pacific Basin, between January 2000 and December 2001, was conducted. Of 2634 trauma admissions, 11% were >or=65 years of age. Mechanisms of injury included falls, motor vehicle crashes (MVCs), pedestrians hit by automobiles, and miscellaneous causes. The incidence of elderly pedestrians hit by automobiles in Hawaii is higher than previously reported. Hospital mortality rate was highest for the pedestrian hit group, followed by falls, and then MVCs. The pedestrian hit group consumed the largest quantity of resources and MVCs the least. Given the high mortality rate and associated resource consumption in the pedestrian hit group, it would be appropriate to give priority to this group while developing preventive measures for this age group.

Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs).

BACKGROUND: von Hippel-Lindau (vHL) disease is an autosomal dominant syndrome associated with neoplasms in multiple organs, which includes the pancreas. Here, we report the greatest single center experience in patients with vHL pancreatic endocrine neoplasm (PNETs). METHODS: Between December 1998 and November 2006, 633 patients with vHL were evaluated and those with PNETs were enrolled on a prospective protocol. RESULTS: Overall, 108 vHL patients had PNETs (17%). Nine patients had metastatic disease (8.3%) from their PNET. Patients with lesions greater than 3 cm (n = 25) were more likely to develop metastases than patients with lesions less than 3 cm (n = 83) (P < .005). Thirty-nine patients underwent resection. Germline sequencing showed that 78% of patients with metastases (7/9) had exon 3 mutations compared with 46% of patients without metastases (32/98; P < .01). Tumor doubling time was calculated for the largest PNET. The group with metastases had an average tumor doubling time of 337 days (range, 180-463 days) compared with 2630 days (range, 103-9614 days) for those without metastases (P < .0001). CONCLUSIONS: By implementing a system of selective operative resection based on defined criteria, vHL patients with PNETs can be managed safely. For patients with small primary lesions (<3 cm), without a mutation of exon 3 and slow tumor doubling time (>500 days), a nonoperative approach may be appropriate for these nonfunctional neoplasms.

Transcutaneous pressure of oxygen: a noninvasive and early detector of peripheral shock and outcome.

A noninvasive tool to recognize early shock would improve outcome by providing prompt recognition of tissue ischemia and precise resuscitation endpoint. The skin is the first tissue bed to vasoconstrict in shock states. Studies have demonstrated that transcutaneous partial pressure of oxygen (PtCO2) increases with higher FiO2 in nonshock states as arterial pressure of oxygen (PaO2) increases, but in shock situations, PtCO2 mirrors changes in cardiac output and oxygen delivery with minimum response to increasing FiO2 and PaO2. This study examined the relationship of hemodynamic variables and the degree of PtCO2 response to FiO2 of 1.0 (identified as the "oxygen challenge test") to mortality and organ failure. This prospective observational study examined 38 patients requiring at least 24 h of cardiac output monitoring for shock resuscitation in the Surgical Intensive Care Unit. Patients were resuscitated to the standard protocol of blood pressure, urine output, oxygen delivery (DO2), and mixed venous O2 (SvO2). Seventy-nine percent of the patients (30/38) with a mean age of 59 +/- 21 years had septic shock or severe sepsis with a 26% mortality (10/38). Measurements included hemodynamic variables, PtCO2, and outcome (mortality and organ failure). In this study, the ability of PtCO2 value to increase by 21 mmHg on a FiO2 of 1.0, at 24 h of resuscitation, divided survivors from nonsurvivors, P <.001. The PtCO2 response to FiO2 may provide an additional noninvasive method of detecting early shock as well as a specific endpoint of resuscitation.

Uncompensated metabolic acidosis: an underrecognized risk factor for subsequent intubation requirement.

BACKGROUND: There are no published reports identifying an inadequate ventilatory response to metabolic acidosis as a predictor of impending respiratory failure. Metabolic acidosis should induce a respiratory alkalosis in which the partial pressure of carbon dioxide (Paco2) is (1.5 [HCO3-] + 8) +/- 2. This study examined the relation between inadequate ventilatory compensation and intubation among trauma patients. METHODS: A retrospective chart review was performed for trauma patients admitted between January 1999 and December 2000. Age, gender, Injury Severity Score and combined Trauma and Injury Severity Score, chest injury, history of cardiac or pulmonary disease, partial pressure of oxygen (Pao2), Paco2, Glasgow Coma Score, respiratory rate, systolic blood pressure, base deficit, and ability to compensate were analyzed with respect to intubation and need for ventilator support. RESULTS: Of 140 patients with metabolic acidosis, 45 ultimately were intubated. The mean Paco2 for the unintubated patients was 34 +/- 7 mm Hg, as compared with 41 +/- 11 mm Hg for the intubated patients (p < 0.001). Only injury severity and ability to compensate for metabolic acidosis were independent predictors of intubation. Patients with inadequate compensation were 4.2 times more likely to require intubation when control was used for the Injury Severity Score (95% confidence interval, 1.8-9.7; p < 0.001). CONCLUSIONS: Inability to mount an adequate hyperventilatory response to metabolic acidosis is associated with an increased likelihood of respiratory failure and a need for ventilatory support. Recognition of this relation should lead to closer monitoring of patients with this condition, and could help to avert unforeseen crisis intubations. This observation needs to be validated in a prospective study.

Malignant melanoma in non-Caucasians: experience from Hawaii.

Data from the Hawaii Tumor Registry suggest that the incidence of melanoma in the non-Caucasian population of Hawaii is not substantially different from that of the remainder of the United States. Our experience indicates that melanoma in this population, although unusual, is not rare. Although lesions on the palms and soles are more common. as are subungal melanomas, primary tumors on other skin sites account for the majority of patients with cutaneous melanoma in the non-Caucasian population. The substantial difference in primary tumor thickness suggests the reported poorer outcomes for non-Caucasian patients with cutaneous melanoma may be explained, at least in part, by a delay in diagnosis. Given the evidence that preventive measures and educational efforts have dramatically impacted the diagnosis and outcome of melanoma patients, it is critical to recognize that similar efforts should be directed at the non-Caucasian population.

Time dependent ethnic convergence in colorectal cancer survival in Hawaii.

BACKGROUND: Although colorectal cancer death rates have been declining, this trend is not consistent across all ethnic groups. Biological, environmental, behavioral and socioeconomic explanations exist, but the reason for this discrepancy remains inconclusive. We examined the hypothesis that improved cancer screening across all ethnic groups will reduce ethnic differences in colorectal cancer survival. METHODS: Through the Hawaii Tumor Registry 16,424 patients diagnosed with colorectal cancer were identified during the years 1960-2000. Cox regression analyses were performed for each of three cohorts stratified by ethnicity (Caucasian, Japanese, Hawaiian, Filipino, and Chinese). The models included stage of diagnosis, year of diagnosis, age, and sex as predictors of survival. RESULTS: Mortality rates improved significantly for all ethnic groups. Moreover, with the exception of Hawaiians, rates for all ethnic groups converged over time. Persistently lower survival for Hawaiians appeared linked with more cancer treatment. CONCLUSION: Ethnic disparities in colorectal cancer mortality rates appear primarily the result of differential utilization of health care. If modern screening procedures can be provided equally to all ethnic groups, ethnic outcome differences can be virtually eliminated.

Timing of sentinel lymphadenectomy in cutaneous melanoma.

PURPOSE: The conduct of sentinel lymphadenectomy for cutaneous melanoma varies substantially among the medical disciplines. The authors sought to characterize the number of hot spots identified during preoperative lymphoscintigraphy for cutaneous melanoma and to determine its relation to the harvesting of sentinel lymph nodes. METHODS: Sixty-nine patients with cutaneous melanoma underwent lymphoscintigraphy with filtered Tc-99m sulfur colloid before sentinel lymphadenectomy. The lymphoscintigrams were reviewed and the number of hot spots visualized over time and the number of sentinel nodes harvested were determined. RESULTS: Lymphoscintigraphy identified 79 patients with 87 lymphatic basins at risk for metastatic disease. Lymphoscintigraphy was performed in a mean time of 30 minutes (range, 15 to 40 minutes). The mean number of hot spots increased from 0.2 to 2.0 hot spots 40 minutes after the initial static image, but the number of hot spots stabilized between 20 and 40 minutes. The same number of sentinel nodes as hot spots visualized were harvested in 58% of patients. Fewer sentinel nodes were identified at the time of surgery than were visualized by lymphoscintigrams in 39% of patients. CONCLUSIONS: More hot spots were identified up to 40 minutes after the initiation of lymphoscintigraphy. Sentinel lymphadenectomy can be performed as near to 40 minutes after the initiation of lymphoscintigraphy as is logistically reasonable. However, there may be substantial latitude in delayed performance of sentinel lymphadenectomy.

Volume of lymphatic metastases does not independently influence prognosis in colorectal cancer.

PURPOSE: To evaluate the prognostic relevance of the volume of nodal metastatic disease in colorectal cancer patients. PATIENTS AND METHODS: One hundred node-positive patients with T2 or T3 carcinoma of the colon or rectum after routine histologic examination of the regional nodes were studied. The metastatic tumor was measured with an ocular micrometer, and the tumor volume was determined. RESULTS: The mean lymph node metastatic tumor volume was 5.1 +/- 4.99 mm(3) (range, 0.05 to 83,434 mm(3)). There was only a weak positive correlation with number of nodes involved with metastatic disease and tumor volume in nodes (r =.45). Median follow-up was 39 months (range, 1 to 87 months). The number of nodes was highly predictive of outcome. Individuals with one to three positive nodes had a substantially better survival than individuals with four or more positive nodes (P <.001). The volume of nodal metastatic disease correlated with outcome (P =.019). Patients dying as a result of disease had substantially greater mean metastatic nodal volume than those who were alive (3,705 v 1,783 mm(3); P =.036). However, the total metastatic nodal volume did not, independent of positive nodes or number of positive nodes, predict outcome. Individuals with micrometastatic nodal volume did not have improved survival when compared with individuals with macrometastatic nodal volume (P =.79). CONCLUSION: The number of nodes involved with metastatic tumor, rather the volume of metastatic involvement of the regional lymph nodes, predicts outcome. These results suggest that micrometastatic disease may have a similar prognosis as macrometastatic disease when the same number of lymph nodes are involved with metastatic tumor.