Breast cancer detection using enhanced IRI-numerical engine and inverse heat transfer modeling: model description and clinical validation.

Effective treatment of breast cancer relies heavily on early detection. Routine annual mammography is a widely accepted screening technique that has resulted in significantly improving the survival rate. However, it suffers from low sensitivity resulting in high false positives from screening. To overcome this problem, adjunctive technologies such as ultrasound are employed on about 10% of women recalled for additional screening following mammography. These adjunctive techniques still result in a significant number of women, about 1.6%, who undergo biopsy while only 0.4% of women screened have cancers. The main reason for missing cancers during mammography screening arises from the masking effect of dense breast tissue. The presence of a tumor results in the alteration of temperature field in the breast, which is not influenced by the tissue density. In the present paper, the IRI-Numerical Engine is presented as an adjunct for detecting cancer from the surface temperature data. It uses a computerized inverse heat transfer approach based on Pennes's bioheat transfer equations. Validation of this enhanced algorithm is conducted on twenty-three biopsy-proven breast cancer patients after obtaining informed consent under IRB protocol. The algorithm correctly predicted the size and location of cancerous tumors in twenty-four breasts, while twenty-two contralateral breasts were also correctly predicted to have no cancer (one woman had bilateral breast cancer). The tumors are seen as highly perfused and metabolically active heat sources that alter the surface temperatures that are used in heat transfer modeling. Furthermore, the results from this study with twenty-four biopsy-proven cancer cases indicate that the detection of breast cancer is not affected by breast density. This study indicates the potential of the IRI-Numerical Engine as an effective adjunct to mammography. A large scale clinical study in a statistically significant sample size is needed before integrating this approach in the current protocol.

Statistical Learning Algorithm for in situ and invasive breast carcinoma segmentation.

Dynamic Contrast Enhanced MRI (DCE-MRI) has proven to be a highly sensitive imaging modality in diagnosing breast cancers. However, analyzing the DCE-MRI is time-consuming and prone to errors due to the large volume of data. Mathematical models to quantify contrast perfusion, such as the black box methods and pharmacokinetic analysis, are inaccurate, sensitive to noise and depend on a large number of external factors such as imaging parameters, patient physiology, arterial input function, and fitting algorithms, leading to inaccurate diagnosis. In this paper, we have developed a novel Statistical Learning Algorithm for Tumor Segmentation (SLATS) based on Hidden Markov Models to auto-segment regions of angiogenesis, corresponding to tumor. The SLATS algorithm has been trained to identify voxels belonging to the tumor class using the time-intensity curve, first and second derivatives of the intensity curves ("velocity" and "acceleration" respectively) and a composite vector consisting of a concatenation of the intensity, velocity and acceleration vectors. The results of SLATS trained for the four vectors has been shown for 22 Invasive Ductal Carcinoma (IDC) and 19 Ductal Carcinoma In Situ (DCIS) cases. The SLATS trained for the velocity tuple shows the best performance in delineating the tumors when compared with the segmentation performed by an expert radiologist and the output of a commercially available software, CADstream.

Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: incidence, radiographic findings and correlation with clinical outcome.

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors are approved for use in patients with metastatic renal cell carcinoma (mRCC) and are under investigation in several other malignancies. We assessed the incidence, clinical presentation and computed tomography (CT) findings of pneumonitis associated with mTOR inhibitors in mRCC. Correlation between radiological findings of pneumonitis and clinical outcome was also determined. METHODS: We retrospectively reviewed the clinical data and serial CT scans from patients with mRCC treated with either temsirolimus or everolimus. Serial chest CT scans were reviewed in consensus, read by two independent radiologists for the presence of pneumonitis, and corresponding clinical data were reviewed for symptoms and clinical outcome. The baseline and follow up CTs were reviewed to assess outcome to therapy. RESULTS: The study population consisted of 46 pts, 21 treated with temsirolimus and 25 with everolimus (M:F 2.5:1; median 63 years, range 31-79 years). CT evidence of pneumonitis was seen in 14/46 pts (30%), at a median of 56days on mTOR inhibitor treatment (range 31-214 days). Respiratory symptoms at the time of radiographically detected pneumonitis, were observed in 7pts. Stable disease (SD) by Response Evaluation Criteria in Solid Tumours (RECIST) was achieved in 12/14 pts (86%) who developed radiographic pneumonitis compared to 14/32 (44%) without pneumonitis (p=0.01) The mean change of tumour long axis size for target lesions by RECIST, normalised for 30 days on therapy was -2.9% in the pneumonitis group and +4.3% in the non-pneumonitis group (p=.002). CONCLUSIONS: Preliminary data suggest that pneumonitis may be a marker of stable disease by RECIST and therefore, of therapeutic benefit. Careful patient assessment should be undertaken before the drug is discontinued.

Congenital Absence of the Right Common Iliac Artery.

Cases of vascular anomalies of the iliac and femoral vessels are rare. We report a complete absence of the right common iliac artery in a 21-year-old woman, incidentally discovered by CT during the work-up for acute abdominal pain. A network of prominent collateral arteries reconstituted the distal portion of the right external iliac artery and the common femoral artery, forming the arterial supply of the right lower limb. Multiple collaterals were also observed reconstituting the right internal iliac artery. At the time of presentation, the patient had no signs or symptoms to suggest lower extremity ischemia, however this may become a problem in the future. Recognition of vascular abnormalities can dictate extra caution when planning abdominal surgery.

Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin.

Endothelial cells in growing tumors express activated Akt, which when modeled by transgenic endothelial expression of myrAkt1 was sufficient to recapitulate the abnormal structural and functional features of tumor blood vessels in nontumor tissues. Sustained endothelial Akt activation caused increased blood vessel size and generalized edema from chronic vascular permeability, while acute permeability in response to VEGF-A was unaffected. These changes were reversible, demonstrating an ongoing requirement for Akt signaling for the maintenance of these phenotypes. Furthermore, rapamycin inhibited endothelial Akt signaling, vascular changes from myrAkt1, tumor growth, and tumor vascular permeability. Akt signaling in the tumor vascular stroma was sensitive to rapamycin, suggesting that rapamycin may affect tumor growth in part by acting as a vascular Akt inhibitor.

Comparison of the activities of the truncated halichondrin B analog NSC 707389 (E7389) with those of the parent compound and a proposed binding site on tubulin.

The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. Neither compound seemed to induce an aberrant tubulin assembly reaction, as occurs with vinblastine (tight spirals) or dolastatin 10 (aggregated rings and spirals). We modeled the two compounds into a shared binding site on tubulin consistent with their biochemical properties. Of the two tubulin structures available, we selected for modeling the complex of a stathmin fragment with two tubulin heterodimers with two bound colchicinoid molecules and a single bound vinblastine between the two heterodimers (Nature (Lond) 435:519-522, 2005). Halichondrin B and NSC 707389 fit snugly between the two heterodimers adjacent to the exchangeable site nucleotide. Fitting the compounds into this site, which was also close to the vinblastine site, resulted in enough movement of amino acid residues at the vinblastine site to cause the latter compound to bind less well to tubulin. The model suggests that halichondrin B and NSC 707389 most likely form highly unstable, small aberrant tubulin polymers rather than the massive stable structures observed with vinca alkaloids and antimitotic peptides.

A quantitative evaluation of the effects of inhibitors of tubulin assembly on polymerization induced by discodermolide, epothilone B, and paclitaxel.

PURPOSE: To determine whether inhibitors of microtubule assembly inhibit polymerization induced by discodermolide and epothilone B, as well as paclitaxel, and to quantitatively measure such effects. METHODS: Inhibition was quantitated by measuring polymer formation either by turbidimetry or by centrifugation, and the amount of inhibitor required to inhibit 50% relative to an appropriate control reaction was determined. RESULTS: The inhibitory drugs evaluated were four colchicine site agents (combretastatin A-4, podophyllotoxin, nocodazole, and N-acetylcolchinol- O-methyl ether), maytansine, which competitively inhibits the binding of Catharanthus alkaloids to tubulin, halichondrin B and phomopsin A, which noncompetitively inhibit the binding of Catharanthus alkaloids to tubulin, and the depsipeptide dolastatin 15. While relative inhibitory effects were highly variable, a few broad generalizations can be made. First, assembly reactions that were either enhanced or dependent upon all three stimulatory drugs were subject to inhibition by all inhibitors. Second, the more readily the tubulin assembled, the greater the concentration of inhibitor required to inhibit polymerization. Drug IC50 values were generally lowest with no stimulatory drug and highest when discodermolide was present; IC50 values were higher as reaction temperature increased; and IC50 values were higher as the tubulin concentration increased. Third, inhibition of assembly by inhibitors of Catharanthus alkaloid binding to tubulin changed much less as a function of changes in reaction conditions than inhibition by inhibitors of colchicine binding. CONCLUSIONS: Since there was no apparent quantitative predictability of combined drug interactions with tubulin, any combination of interest must be studied in detail.