Adjuvant Radiation is Associated with Improved Survival for Select Patients with Non-metastatic Adrenocortical Carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy for which surgery is the mainstay of treatment and for which adjuvant radiation is infrequently employed; however, small, single-institution series suggest adjuvant radiation may improve outcomes. METHODS: All patients with non-metastatic ACC treated with either surgery alone or surgery followed by adjuvant radiation were identified in the 2004-2013 National Cancer Database. Factors associated with receipt of radiation and the impact of adjuvant radiation on survival were determined by multivariable analysis. RESULTS: Of 1184 patients, 171 (14.4%) received adjuvant radiation. Patient demographics were similar between the two groups, but those receiving radiation were more likely to have had positive margins following surgery (37.4 vs. 14.6%; p < 0.001), evidence of vascular invasion (14.0 vs. 5.1%; p = 0.05), and receive concurrent chemotherapy (57.3 vs. 28.8%; p < 0.001). After adjustment for tumor and other treatment factors, only positive margins following surgery was associated with an increased likelihood of receiving adjuvant radiation (odds ratio 3.84, 95% confidence interval [CI] 1.95-7.56). Radiation therapy did not confer a difference in median overall survival in the general cohort. However, for patients with positive margins, adjuvant radiation was associated with a 40% decreased yearly risk of death after adjustment for concurrent chemotherapy (hazard ratio 0.60, 95% CI 0.40-0.92; p = 0.02). This survival advantage was not evident for other traditional high-risk features. CONCLUSION: Adjuvant radiation appears to decrease the risk of death in ACC patients with positive margins following surgical resection, but only a small percentage are currently receiving radiation. Multidisciplinary treatment with surgery and radiation should be considered for these patients.

Rheumatologic manifestations of sarcoidosis.

Sarcoidosis is a systemic, clinically heterogeneous disease characterized by the development of granulomas. Any organ system can be involved, and patients may present with any number of rheumatologic symptoms. There are no U.S. Food and Drug Administration-approved therapies for the treatment of sarcoidosis. Diagnosing sarcoidosis becomes challenging, particularly when its complications cause patients' symptoms to mimic other conditions, including polymyositis, Sjögren syndrome, or vasculitis. This review presents an overview of the etiology of and biomarkers associated with sarcoidosis. We then provide a detailed description of the rheumatologic manifestations of sarcoidosis and present a treatment algorithm based on current clinical evidence for patients with sarcoid arthritis. The discussion will focus on characteristic findings in patients with sarcoid arthritis, osseous involvement in sarcoidosis, and sarcoid myopathy. Arthritic conditions that sometimes coexist with sarcoidosis are described as well. We present two cases of sarcoidosis with rheumatologic manifestations. Our intent is to encourage a multidisciplinary, translational approach to meet the challenges and difficulties in understanding and treating sarcoidosis.

Multimarker circulating DNA assay for assessing blood of prostate cancer patients.

BACKGROUND: Prostate cancer (PCa) detection using serum-based prostate specific antigen (PSA) is limited by frequent false-positive and -negative results. Genetic aberrations such as allelic imbalance (AI) and epigenetic changes such as promoter hypermethylation have been detected in circulating DNA of cancer patients. We hypothesized that circulating multimarker DNA assays detecting both genetic and epigenetic markers in serum would be useful in assessing PCa patients. METHODS: We assayed blood from healthy male donors (n = 40) and 83 patients with American Joint Cancer Committee (AJCC) stage I-IV PCa. DNA was assayed for AI of 6 genome microsatellites. We assessed methylation of RASSF1, RARB2, and GSTP1 using a methylation-specific PCR assay and analyzed the sensitivity of each assay for the detection of genetic or epigenetic changes in circulating DNA. The relation between circulating tumor-related DNA detection and prognostic factors was investigated. RESULTS: The proportion of patients demonstrating AI for > or =1 marker was 47% (38 of 81 patients). Methylation biomarkers were detected in 24 of 83 patients (28%). By combining 2 DNA assays, the number of PCa patients positive for > or =1 methylated or LOH marker increased (52 of 83; 63%). The combined assays detected PCa in 15 of 24 patients (63%) with normal PSA concentrations. The combination of the DNA assays detected the presence of PCa regardless of AJCC stage or PSA concentration. Combination of the DNA and PSA assays gave 89% sensitivity. CONCLUSIONS: This pilot study demonstrates that the combined circulating DNA multimarker assay identifies patients with PCa and may yield information independent of AJCC stage or PSA concentration.

Strategy and Technique of Endonasal Endoscopic Bony Decompression and Selective Tumor Removal in Symptomatic Skull Base Meningiomas of the Cavernous Sinus and Meckel's Cave.

BACKGROUND: Parasellar meningiomas involving the cavernous sinus and Meckel's cave pose a management challenge because of invasion around neurovascular structures and the pituitary gland. The management options range from aggressive resection to focused radiotherapy alone. We present a strategy for these tumors that includes endonasal bony decompression, partial tumor removal, and stereotactic radiotherapy (SRT) in select cases. METHODS: The tumor location, previous treatments, cranial neuropathies, pituitary dysfunction, tumor control rates, use of stereotactic radiosurgery, SRT, and complications were retrospectively evaluated. RESULTS: Twenty patients (age range, 43-81 years; 65% women; 90% with World Health Organization grade I; median follow-up, 57 months; 14 without previous debulking and RT; 6 with previous debulking and RT) underwent endonasal bony decompression and partial tumor removal. The most common tumor locations were cavernous sinus (95%), Meckel's cave (95%), sella (75%), petroclival (60%), and optic canal/orbit (30%). Three patients with large meningiomas underwent staged transcranial and endonasal debulking. Of the 14 patients without previous debulking and RT, 11 had undergone postoperative SRT, with tumor shrinkage in 3 (27%). At the last follow-up examination, for these 14 patients and the 6 patients who had undergone previous surgery and RT, tumor control was 100% and 33% (P < 0.001) and the cranial neuropathies had improved in 57% and 33%, respectively. Major complications occurred in 2 patients: a permanent sixth cranial nerve palsy and cerebrospinal fluid leakage requiring reoperation. CONCLUSIONS: Endonasal bony decompression and selective tumor removal, followed by SRT, appears to be a reasonable treatment option for most previously untreated parasellar meningiomas. For patients who have undergone previous debulking and RT, new targeted treatment strategies are needed.

Brainstem ischemia in acute herniation syndrome.

Brain herniation from hemispheric mass lesions injures mainly the upper brainstem around the tentorial incisura. While mechanical tissue compression is usually the process of deterioration and injury, the primary injury mechanism in some patients is early brainstem ischemia from arterial compromise as demonstrated by this patient's magnetic resonance imaging (MRI) and pathology.

Doxorubicin plus interleukin-2 chemoimmunotherapy against breast cancer in mice.

As recently characterized, following s.c. implantation into syngeneic C57BL/6 mice, E0771 tumor invades locally into dermal layers and peritoneum, metastasizes to the lung, and induces a nonspecific immunosuppression in the host. Using this breast medullar adenocarcinoma model, a therapy consisting of a single moderate dose of doxorubicin followed by twice daily moderate doses of interleukin-2 for 30 days was examined for efficacy and mechanism of action when given to animals with established disease. This combination treatment, but not combinants alone, resulted in tumor-free long-term survival of 40% of the mice without significant toxicity and 83% of survivors had immune memory specific for E0771 cells. Treatment also decreased immune suppression induced by E0771 tumor. Full response to treatment required functional CD8(+) T cells, whereas depletion of natural killer cells caused only a reduction in response rate. A serum "biomarker" profile that correlated with, and seemed predictive of, response to treatment was identified by nuclear magnetic resonance-based metabonomic analysis. The efficacy of this nontoxic treatment and the potential to be able to predict which individual is responding to treatment are characteristics that make this chemoimmunotherapy attractive for clinical testing.

A pituitary carcinoma secreting TSH and prolactin: a non-secreting adenoma gone awry.

To our knowledge, only one case of a TSH-secreting carcinoma has previously been reported. We describe here a second patient with a pituitary carcinoma producing TSH and prolactin (PRL). A 37-year-old male underwent a left frontotemporal craniotomy in 1996 for a sellar mass. Except for mildly increased PRL and elevated alpha-subunit, hormone evaluation was normal. Pathologic examination revealed a chromophobe adenoma with increased mitotic forms. The patient completed a course of external beam radiation to the pituitary and was prescribed l-thyroxine, bromocriptine, and hydrocortisone. He was lost to follow-up but did well for 6 years, until 2002, when he presented with TSH-dependent thyrotoxicosis and hyperprolactinemia. The patient was started on bromocriptine and propylthiouracil and was, again, lost to follow-up. In 2004, 9 years after his initial presentation, he presented after falling. Magnetic resonance imaging showed two brain masses with associated midline shift. Emergent resection of the larger mass revealed a pituitary cancer with positive staining for PRL, but not for TSH. Nine months later, the patient underwent further debulking of metastatic disease. Although development of a carcinoma from a pituitary adenoma is very rare (<0.5%), macroadenomas that become hormonally active should be suspect for transformation into pituitary cancer.

Synthesis, structure, and conformation of anti-tumor agents in the solid and solution states: hydroxyl derivatives of Ftorafur.

The pyrimidine antimetabolite Ftorafur [FT; 5-fluoro-1-(tetrahydro-2-furyl)uracil] has shown significant antitumor activity in several adenocarcinomas with a spectrum of activity similar to, but less toxic than, 5-fluorouracil (5-FU). It is considered as a prodrug that acts as a depot form of 5-FU, and hence the two drugs exhibit a similar spectrum of chemotherapeutic activity. Ftorafur is metabolized in animals and humans when hydroxyl groups are introduced into the tetrahydrofuran moiety. These metabolites are also thought to be as active as ftorafur but less toxic than 5-FU. Hydroxyl derivatives: 2'-hydroxyftorafur (III), 3'-hydroxyftorafur (IV) and 2',3'-dihydroxyftorafur (II) were synthesized and X-ray and NMR studies of these hydroxyl derivatives were undertaken in our laboratories to study the structural and conformational features of Ftorafur and its metabolites in the solid and solution states. X-ray crystallographic investigations were carried out with data collected on a CAD-4 diffractometer. The structures were solved and refined using the SDP crystallographic package of Enraf-Nonius on PDP 11/34 and Microvax computers. All of the compounds studied had the base in the anti conformation. The glycosidic torsion angles varied from -20 to 60 degrees. There is an inverse correlation between the glycosyl bond distances and the chi angle. Molecules with a lower chi angle have a larger bond distance and vice versa. The sugar rings show a wide variation of conformations ranging from C2'-endo through C3'-endo to C4'-exo. The crystal structures are stabilized by hydrogen bonds involving the base nitrogen atom N3 and the hydroxyl oxygen atoms of the sugar rings as donors and the keto oxygens O2 and O4 of the base and the hydroxyl oxygen atoms O2' and O3' as acceptors. The NMR studies were carried out on Brüker 400 and 600 MHz instruments. Simulated proton spectra were obtained through Laocoon, and pseudorotational parameters were solved by Pseurot. Presence of syn or anti forms was demonstrated with the use of NOE experiments. The glycosyl conformations in solution vary more widely than in the solid state. The conformations of the sugar molecules are in agreement with the values obtained in the solid state. The studies of the structure and conformation in the solid and solution states give a model for the Ftorafur molecule that could be used in structure, function and biological activity correlation studies.

Structural and Biophysical Characterization of a Cyclic Bioadhesive With Cell Attachment Ability.

Structural and cellular attachment analysis identified overall bent helical regions of adhesive peptides identified within mussel adhesive protein (MAP) capable of also attaching cells. DOPA (L-DOPA, 3,4-dihydroxyphenylalanine) is frequently identified and credited for the attachment ability of several marine proteins [Olivieri, MP, et al. (2002), Biofouling18, 149-159]. Newly designed cyclic peptides (DOPA-G-G-C-G-K-A-K-G-C [cyc-DOPA] & Y-G-G-C-G-K-A-K-G-C [cyc-Y]) derived from structurally conserved regions of several MAP peptides were examined to assist in the understanding of both surface and cellular attachment. Solution-state proton nuclear magnetic resonance (NMR) spectroscopy coupled with molecular modeling and dynamics revealed minimal differences in the structures of the proposed cellular attachment domain within these two peptides. Multiple attenuated internal reflection infrared (MAIR-IR) spectroscopy, ellipsometry and advancing contact angle analyses showed that formation of thin films by these peptides was L-DOPA and pH dependent. When compared to control surfaces, undifferentiated leukocyte cells (MOLT-4) significantly attached and spread onto films created from the cyc-DOPA. The culmination of these structural, biophysical and cellular attachment techniques reveal a conformation of cyc-DOPA that is capable of both adsorbing to surfaces and then attaching cells that spread. This work supports the sequence, K-A-K, as the cellular attachment domain, especially when held in a reliable structural conformation.,.

Transformation of a pituitary macroadenoma into to a corticotropin-secreting carcinoma over 16 years.

OBJECTIVE: To describe a case of a pituitary macroadenoma that differentiated into a corticotropin (ACTH)-secreting carcinoma with metastasis to the thigh. METHODS: We present a case report with a 16-year follow-up that includes anatomic and endocrine documentation of the history of an ACTH-secreting carcinoma. RESULTS: A 32-year-old woman presented for evaluation in 1989 because of visual field defects. Magnetic resonance imaging revealed a locally invasive 3-cm macroadenoma. She had no clinical signs of cortisol excess. The patient underwent surgical debulking followed by a course of radiation directed to the pituitary. Results from retrospective immunohistochemical staining with antibodies against ACTH, prolactin, and MIB-1 were negative. Postoperatively, she could not be weaned from exogenous steroids without developing symptoms of adrenal insufficiency. In 1995, she developed left facial palsy and diplopia caused by tumor growth. In 1997, the patient developed progressive symptoms of cortisol excess, which continued after exogenous steroid replacement was discontinued. The patient's clinical status continued to deteriorate because of local mass effect from tumor growth and uncontrolled hypercortisolism. She underwent bilateral adrenalectomy in 2003. The patient remained debilitated in a long-term care facility for 2 years when she was found to have a mass on her left hip. Biopsy results of the obturator muscle revealed metastatic tumor of neuroendocrine origin with strong reactivity to ACTH antibodies and MIB-1 labeling in 8% of tumor cell nuclei. CONCLUSION: A pituitary tumor can transform into an ACTH-secreting carcinoma in an indolent manner. Patients with invasive pituitary adenomas require long-term surveillance to monitor for differentiation into pituitary carcinoma.

Detection of epithelial ovarian cancer using 1H-NMR-based metabonomics.

Currently available serum biomarkers are insufficiently reliable to distinguish patients with epithelial ovarian cancer (EOC) from healthy individuals. Metabonomics, the study of metabolic processes in biologic systems, is based on the use of (1)H-NMR spectroscopy and multivariate statistics for biochemical data generation and interpretation and may provide a characteristic fingerprint in disease. In an effort to examine the utility of the metabonomic approach for discriminating sera from women with EOC from healthy controls, we performed (1)H-NMR spectroscopic analysis on preoperative serum specimens obtained from 38 patients with EOC, 12 patients with benign ovarian cysts and 53 healthy women. After data reduction, we applied both unsupervised Principal Component Analysis (PCA) and supervised Soft Independent Modeling of Class Analogy (SIMCA) for pattern recognition. The sensitivity and specificity tradeoffs were summarized for each variable using the area under the receiver-operating characteristic (ROC) curve. In addition, we analyzed the regions of NMR spectra that most strongly influence separation of sera of EOC patients from healthy controls. PCA analysis allowed correct separation of all serum specimens from 38 patients with EOC (100%) from all of the 21 premenopausal normal samples (100%) and from all the sera from patients with benign ovarian disease (100%). In addition, it was possible to correctly separate 37 of 38 (97.4%) cancer specimens from 31 of 32 (97%) postmenopausal control sera. SIMCA analysis using the Cooman's plot demonstrated that sera classes from patients with EOC, benign ovarian cysts and the postmenopausal healthy controls did not share multivariate space, providing validation for the class separation. ROC analysis indicated that the sera from patients with and without disease could be identified with 100% sensitivity and specificity at the (1)H-NMR regions 2.77 parts per million (ppm) and 2.04 ppm from the origin (AUC of ROC curve = 1.0). In addition, the regression coefficients most influential for the EOC samples compared to postmenopausal controls lie around delta3.7 ppm (due mainly to sugar hydrogens). Other loadings most influential for the EOC samples lie around delta2.25 ppm and delta1.18 ppm. These findings indicate that (1)H-NMR metabonomic analysis of serum achieves complete separation of EOC patients from healthy controls. The metabonomic approach deserves further evaluation as a potential novel strategy for the early detection of epithelial ovarian cancer.

Recurrence of symptoms after Chiari decompression and duraplasty with nonautologous graft material.

Nonautologous material is commonly used for dural grafting. Although good results have been reported with the use of some of these materials in cranial surgery, there is a paucity of information regarding their use in craniocervical decompressive surgery. We report three cases of patients with Chiari malformation type I who experienced recurrent or new-onset Chiari symptoms after surgical decompression and duraplasty with bovine pericardium, Gore-Tex or cadaveric dura. We review the use of these materials and propose possible mechanisms by which a reaction to a nonautologous graft could cause recurrent Chiari symptoms. The preferential use of autologous material for dural grafts during posterior fossa decompressive surgery should prevent this cause of symptom recurrence.

Treatment outcomes of three-dimensional conformal radiotherapy for localized prostate carcinoma: a large community-based experience.

BACKGROUND: The current study documented the implementation of three-dimensional conformal radiotherapy and assessed the tumor control and toxicity of such treatment in a large, multisite community practice. METHODS: The authors retrospectively reviewed their first 222 consecutive patients with clinically localized (N0) prostate carcinoma treated with a 6-field conformal technique from October 1993 through March 2000. Standardized target definitions, dose planning constraints, and gantry angles were utilized to develop the treatment plan. Patients were categorized by low, intermediate, and high risk. Low risk was defined as T1a-T2a disease, a Gleason score < 7, and prostate-specific antigen (PSA) level 6, or PSA level > 10.01 ng/mL (n = 60 [27%]). High risk was defined as 2 of the above risk factors or as T3 disease, a Gleason score > 7, or a PSA level > 20 (n = 115 [52%]). Biochemical disease recurrence was defined in accordance with the American Society for Therapeutic Radiology and Oncology definition. Urinary and bowel toxicity were graded using the Radiation Therapy Oncology Group morbidity scoring system. RESULTS: The median follow-up after radiotherapy for surviving patients was 47 months (range, 0-99 months). The 2 and 5-year actuarial biochemical control rates for all patients were 84% and 78%, respectively. Using logistic regression analysis, lower dose (< 75.6 gray [Gy] vs. 75.6 Gy; P = 0.006), higher risk group (P = 0.033), higher stage (P = 0.045), and higher PSA level (P = 0.001) were significantly associated with biochemical disease recurrence. Toxicity was not significantly correlated with a higher radiotherapy dose. CONCLUSIONS: Dose escalation to 75.6 Gy using a 6-field conformal technique was feasible in the authors' community practice and resulted in acceptable toxicity and early biochemical outcomes.