CT Angiography-Guided Needle Insertion for Interstitial Brachytherapy in Locally Advanced Cervical Cancer.

CT angiography might be a suitable procedure to avoid arterial puncture in combined intracavitary and interstitial brachytherapy for cervical cancer curatively treated with combined chemoradiation and brachytherapy boost. Data in the literature about this technique are scarce. We introduced this method and collected brachytherapy data from patients treated in our department between May 2021 and April 2024. We analyzed the applicator subtype, needle insertion (planned versus implanted), implanted depth and the role of CT angiography in selecting needle trajectories and insertion depths. None of the patients managed through this protocol experienced atrial puncture and consequent hemorrhage. Needle positions were accurately selected with the aid of CT angiography with proper coverage of brachytherapy targets and avoidance of organs at risk. CT angiography is a promising method for guiding needle insertion during interstitial brachytherapy.

Unselective Measurement of Tumor-to-Stroma Proportion in Colon Cancer at the Invasion Front-An Elusive Prognostic Factor: Original Patient Data and Review of the Literature.

The tumor-to-stroma ratio is a highly debated prognostic factor in the management of several solid tumors and there is no universal agreement on its practicality. In our study, we proposed confirming or dismissing the hypothesis that a simple measurement of stroma quantity is an easy-to-use and strong prognostic tool. We have included 74 consecutive patients with colorectal cancer who underwent primary curative abdominal surgery. The tumors have been grouped into stroma-poor (stroma < 10%), medium-stroma (between 10 and 50%) and stroma-rich (over 50%). The proportion of tumor stroma ranged from 5% to 70% with a median of 25%. Very few, only 6.8% of patients, had stroma-rich tumors, 4% had stroma-poor tumors and 89.2% had tumors with a medium quantity of stroma. The proportion of stroma, at any cut-off, had no statistically significant influence on the disease-specific survival. This can be explained by the low proportion of stroma-rich tumors in our patient group and the inverse correlation between stroma proportion and tumor grade. The real-life proportion of stroma-rich tumors and the complex nature of the stroma-tumor interaction has to be further elucidated.

Usefulness of Saline Sealing in Preventing Pneumothorax after CT-Guided Biopsies of the Lung.

This study aimed to assess the effectiveness of saline sealing in reducing the incidence of pneumothorax after a CT-guided lung biopsy. This was a retrospective case-control study of patients who underwent CT-guided biopsies for lung tumors using 18 G semiautomatic core needles in conjunction with 17 G coaxial needles. The patients were divided into two consecutive groups: a historical Group A (n = 111), who did not receive saline sealing, and Group B (n = 87), who received saline sealing. In Group B, NaCl 0.9% was injected through the coaxial needle upon its removal. The incidence of pneumothorax and chest tube insertion was compared between the two groups. Multivariate logistic regression was performed to verify the contribution of other pneumothorax risk factors. The study included 198 patients, with 111 in Group A and 87 in Group B. There was a significantly (p = 0.02) higher pneumothorax rate in Group A (35.1%, n = 39) compared to Group B (20.7%, n = 18). The difference regarding chest tube insertion was not significant (p = 0.1), despite a tendency towards more insertions in Group A (5.4%, n = 6), compared to Group B (1.1%, n = 1). Among the risk factors for pneumothorax, only the presence of emphysema (OR = 3.5, p = 0.0007) and belonging to Group A (OR = 2.2, p = 0.02) were significant. Saline sealing of the needle tract after a CT-guided lung biopsy can significantly reduce the incidence of pneumothorax. This technique is safe, readily available, and inexpensive, and should be considered as a routine preventive measure during this procedure.

Preoperative MRI accuracy after neoadjuvant chemoradiation for locally advanced rectal cancer.

Background and aims: To evaluate the performance of magnetic resonance imaging (MRI) in restaging locally advanced rectal cancers (LARC) after neoadjuvant chemoradiotherapy (nCRT), with pathologic correlation. Methods: 80 patients with LARC treated with neoadjuvant therapy, with restaging MRI and surgery, were enrolled and prospectively reviewed. The diagnostic accuracy of the restaging MRI was assessed for tumor (ymrT), nodal status (ymrN), circumferential resection margin (ymrCRM), extramural vascular invasion (ymrEMVI) and tumoral deposits (ymrN1c) by calculating the sensitivity (Se), specificity (Sp), negative predictive values (NPV) and positive predictive values (PPV). Response to treatment was classified as good response (complete/near complete) vs. poor response (poor/partial response). The agreement between the tumor regression grade at MRI (mrTRG) and pathology (pTRG) was reported, as well the performance of mrTRG to identify good responders. The correlation between restaging MRI and histopathology was assessed by Spearman correlation coefficient. Results: The MRI accuracy ranged between 63.8% and 92.5% for T stage and was 81.3% for N stage. All MRI parameters evaluated at restaging were statistically significant correlated with histopathology evaluation, but EMVI. There was moderate correlation for N and N1c and a positive strong correlation for T, CRM and TRG (Spearman correlation coefficient of 0.390 for mrN1c-pN1c, 0.428 for mrN-pN, 0.522 for mrCRM-pCRM, 0.550 for mrT-pT and 0.731 for mrTRG-pTRG). Diagnostic accuracy of anal sphincter invasion was 91.3%, with a negative predictive value (NPV) of 100%. Accuracy rate varied between 70% for partial response to 93.75% for complete response after nCRT. Conclusions: MR imaging had good accuracy in restaging LARCs after nCRT. Our results showed high MRI accuracy in detecting anal sphincter involvement for low rectal tumors, with high NPV to exclude tumoral invasion. Restaging MRI predicted well the tumor regression grade, with good diagnostic performance in differentiating good responders from poor/partial responders. The accuracy was high for detecting complete response.

Prevalence of MMTV-like sequences in breast cancer samples in Romanian patients-there is a geographic difference compared to the Western world.

BACKGROUND: Breast cancer, although the most frequently diagnosed malignant tumor in humans, has a less clear etiology compared to other frequent cancer types. Mouse-mammary tumor virus (MMTV) is involved in breast cancer in mice and dogs and might play a role in the etiology of some breast cancers in humans, since an MMTV-like sequence was identified in 20-40% of breast cancer samples in Western Europe, USA, Australia and some other parts of the world. The purpose of our study was to identify MMTV-like DNA sequences in breast tissue samples from breast cancer patients who underwent curative surgery in our regional academic center in Romania, EU. METHODS: We selected 75 patients with non-metastatic breast cancer treated surgically with curative intent, who did not undergo any neoadjuvant treatment. Out of these patients, 50 underwent radical lumpectomy and 25 modified radical mastectomy. Based on previous reports in the literature we searched using PCR the MMTV-like DNA env sequence in the breast cancer tissue and normal breast tissue obtained from the same patients. RESULTS: None of the examined samples was positive for MMTV-like target sequences on PCR. CONCLUSIONS: We could not prove that MMTV plays a role in the etiology of breast cancer in our patient group. This finding is similar to those from publications of other geographically related research groups.

Toward better drug development: Three-dimensional bioprinting in toxicological research.

The importance of three-dimensional (3D) models in pharmacological tests and personalized therapies is significant. These models allow us to gain insight into the cell response during drug absorption, distribution, metabolism, and elimination in an organ-like system and are suitable for toxicological testing. In personalized and regenerative medicine, the precise characterization of artificial tissues or drug metabolism processes is more than crucial to gain the safest and the most effective treatment for the patients. Using these 3D cell cultures derived directly from patient, such as spheroids, organoids, and bioprinted structures, allows for testing drugs before administration to the patient. These methods allow us to select the most appropriate drug for the patient. Moreover, they provide chance for better recovery of patients, since time is not wasted during therapy switching. These models could be used in applied and basic research as well, because their response to treatments is quite similar to that of the native tissue. Furthermore, they may replace animal models in the future because these methods are cheaper and can avoid interspecies differences. This review puts a spotlight on this dynamically evolving area and its application in toxicological testing.

Modulation of monepantel secretion into milk by soy isoflavones.

Monepantel (MNP), a novel anthelmintic drug from amino-acetonitrile derivatives, is a substrate for breast cancer resistance protein (BCRP). BCRP-mediated milk secretion of drugs can be altered by isoflavones. In this study, we aimed to show how soy isoflavones and BCRP inhibitors genistein (GEN) and daidzein (DAI) can modulate the secretion of MNP into milk. Moreover, we observed that the expression of BCRP in the lactating mammary gland of sheep was significantly higher than in non-lactating sheep using Western blot analysis. These properties of MNP and MNPSO2 (monepantel sulfone, the major active metabolite of MNP), identified as a BCRP substrate in determining the interaction with BCRP, were examined by vesicular transport (VT) inhibition assays. In pharmacokinetic studies, we demonstrated the transport of MNP into milk in three experimental groups: G1 fed standard forage; G2 fed soy-enriched forage; G3 fed standard forage paired with orally administered exogenous GEN and DAI. The concentrations of MNP and MNPSO2 were analyzed by high-performance liquid chromatography. Compared to the control group (3.27 ± 1.13 vs. 5.46 ± 2.23), the AUC (0-840 h) milk/plasma ratio decreased by 40% in the soy-enriched diet group. The concentrations of GEN and DAI were determined using liquid chromatography coupled with tandem mass spectrometry in soy. A VT inhibition assay was conducted to determine the IC50 values for MNP and MNPSO2 as BCRP inhibitors. This study showed that milk excretion of a BCRP substrate, such as monepantel, can be diminished by the presence of isoflavones in the diet.

Implementation of advanced radiotherapy techniques: stereotactic body radiotherapy (SBRT) for oligometastatic patients with lung metastasis - a single institution experience.

Background and aims: The treatment of oligometastatic disease has become common practice as advanced radiotherapy techniques became more available. Lung is one of the main metastatic sites for a majority of cancers and many of these patients present with a limited metastatic disease burden. For these patients, SBRT (Stereotactic Body Radiation Therapy) represents a non-invasive treatment alternative. In this report we present our experience with our first series of patients with limited metastatic disease treated with lung SBRT. The purpose of this paper is to provide a qualitative and quantitative assessment of the lung SBRT treatment process and algorithm leading up to treatment delivery in a community-based radiotherapy department. Methods: We have retrospectively reviewed our first series of 41 patients with lung oligometastases from various malignancies, treated using SBRT between March 2019 and December 2020. Demographic, technical and outcome data were analyzed. Results: A number of 45 lung metastases (in 41 patients) were treated with SBRT during the specified time period. The median age was 65.7 years old (range 33-83). 16 patients (39%) were treated for multiple lesions and the mean number of treated lesions was 1 (range1-3). Median dose prescribed was 50 Gy /5 fractions (median BED10 =77 Gy). The median intra-fraction displacements were: Vertical (0.23cm), Longitudinal (-0.27 cm), Lateral (-0.1 cm), Pitch [0.22°], Roll [0.15°], Rotation [0.32°]. The median session time was 40 minutes. All patients completed the prescribed course of treatment.Preliminary clinical data were recorded. With a median follow-up of 9 months, local control was recorded in all but one patient. At the last known follow-up, local control was recorded for 39 (85%) out of 45 treated lesions. Conclusion: For lung SBRT, the required corrections at the time of treatment delivery are small, as long as strict protocols are implemented. Preliminary data for lung metastasis in oligometastatic patients support SBRT as a viable method of achieving high rates of early local control. These results need to be further confirmed in a larger cohort of patients with longer follow-up.

Assessment of Specific Tumoral Markers, Inflammatory Status, and Vitamin D Metabolism before and after the First Chemotherapy Cycle in Patients with Lung Cancer.

BACKGROUND: We aimed to investigate the changes of inflammatory status reflected by serum levels of chitotriosidase (CHT) and neopterin, and how specific tumor markers such as neuron-specific enolase (NSE) and squamous cell carcinoma antigen (SCCA), as well as vitamin D metabolism assessed by vitamin D receptor (VDR) and 25-hydroxy vitamin D3 (25OHD3), were modified after the first cycle of chemotherapy in patients with lung cancer. METHODS: We performed this first pilot study on twenty patients diagnosed with lung cancer by investigating the serum concentrations of CHT, neopterin, NSE, SCCA, VDR and 25OHD3 before and after the first cycle of chemotherapy. RESULTS: The post-treatment values of NSE were significantly lower compared to the pre-treatment levels (14.37 vs. 17.10 ng/mL, p = 0.031). We noticed a similar trend in neopterin levels, but the difference was only marginally significant (1.44 vs. 1.17 ng/mL, p = 0.069). On the contrary, the variations of circulating SCCA, CHT, neopterin, VDR and 25OHD3, before and after treatment, did not reach statistical significance. CONCLUSION: Only circulating NSE was treatment responsive to the first chemotherapy cycle in patients with lung cancer, while inflammatory markers and vitamin D status were not significantly modified.

Signet ring cell gastric carcinoma with breast and leptomeningeal metastases: a case report.

Gastric cancer is the 5th most common malignancy worldwide. Signet ring cell histology represents an aggressive subtype of gastric cancer, presenting at a younger age. Both breast and leptomeningeal metastases are rare locations of tumor dissemination, requiring correct and immediate diagnosis and treatment. We present a case of a 45-year old female with signet ring cell gastric carcinoma who developed both left breast and leptomeningeal metastases, requiring multiple chemotherapy lines. As far as we know, this is the first published case in literature following multiple lines of treatment for both breast and leptomeningeal metastases from signet ring cell gastric carcinoma.

MRI Evaluation of Complete and Near-Complete Response after Neoadjuvant Therapy in Patients with Locally Advanced Rectal Cancer.

Purpose To evaluate MRI performance in restaging locally advanced rectal cancers (LARC) after neoadjuvant chemoradiotherapy (nCRT) and interobserver agreement in identifying complete response (CR) and near-complete response (nCR). Methods 40 patients with CR and nCR on restaging MRI, surgery and/or endoscopy were enrolled. Two radiologists independently scored the restaging MRI and reported the presence of split scar sign (SSS) and MRI tumor regression grade (mrTRG). Diagnostic accuracy and ROC curves were calculated for single and combined sequences, with inter-reader agreement. Results Diagnostic performance was good for detecting CR and weaker for nCR. T2WI had the highest AUCs among individual sequences. There was a significant positive correlation between SSS and CR, with high Sp (89.5%/73.7%) and PPV (90%/79.2%) for both Readers. Similar accuracy rates were observed for the combination of sequences, with AUCs of 0.828-0.847 for CR and 0.690-0.762 for nCR. Interobserver agreement was strong for SSS, moderate for T2WI, weak for the combination of sequences. Conclusions Restaging MRI had good diagnostic performance in identifying CR and nCR. SSS had high Sp and PPV in diagnosing CR, with a strong level of interobserver agreement. T2WI with DWI was the optimal combination of sequences for selecting good responders.

Nanocarriers for Drug Delivery: An Overview with Emphasis on Vitamin D and K Transportation.

Mounting evidence shows that supplementation with vitamin D and K or their analogs induces beneficial effects in various diseases, e.g., osteoarticular, cardiovascular, or carcinogenesis. The use of drugs delivery systems via organic and inorganic nanocarriers increases the bioavailability of vitamins and analogs, enhancing their cellular delivery and effects. The nanotechnology-based dietary supplements and drugs produced by the food and pharmaceutical industries overcome the issues associated with vitamin administration, such as stability, absorption or low bioavailability. Consequently, there is a continuous interest in optimizing the carriers' systems in order to make them more efficient and specific for the targeted tissue. In this pioneer review, we try to circumscribe the most relevant aspects related to nanocarriers for drug delivery, compare different types of nanoparticles for vitamin D and K transportation, and critically address their benefits and disadvantages.

The First Evaluation of Serum Levels of MGP, Gas6 and EGFR after First Dose of Chemotherapy in Lung Cancer.

BACKGROUND: Vitamin K-dependent proteins (VKDPs) and the epidermal growth factor receptor (EGFR) are involved in lung cancer progression. Therefore, we aimed to study the serum concentration of Matrix Gla protein (MGP), Growth Arrest-specific 6 (Gas6), and EGFR before and after the first cycle of chemotherapy and to investigate how MGP, Gas6, and EGFR are modified after one cycle of chemotherapy. METHODS: We performed an observational study on twenty patients diagnosed with lung cancer, by assessing the serum concentration of vitaminK1 (VitK1), MGP, Gas6, and EGFR using the ELISA technique before and after three weeks of the first cycle of chemotherapy. Patients were evaluated using RECIST 1.1 criteria. RESULTS: Serum levels of MGP, Gas6, EGFR, and VK1 before and after treatment were not changed significantly. Regarding the pre-treatment correlation of the MGP values, we found a strong positive relationship between MGP and VK1 pre-treatment values (r = 0.821, 95%CI 0.523; 0.954, p < 0.001). Furthermore, there was a moderately negative correlation between VK1 and EGFR pre-treatment values, with the relationship between them being marginally significant (r = -0.430, 95%CI -0.772; 0.001, p = 0.058). Post-treatment, we found a strong positive relationship between MGP and VK1 post-treatment values (r = 0.758, 95%CI 0.436; 0.900, p < 0.001). We also found a moderate positive relationship between Gas6 and EGFR post-treatment values, but the correlation was only marginally significant (r = 0.442, p = 0.051).

Survival and quality of life after whole brain radiotherapy with 3D conformal boost in the treatment of brain metastases.

BACKGROUND: Brain metastases are the most frequent intracranial neoplasms in adults. Although overall survival (OS) is an important endpoint in patients receiving radiotherapy, given their poor life expectancy in general, quality of life is becoming an increasingly useful endpoint. Objectives: to evaluate whole brain radiotherapy (WBRT) with 3D conformal boost in brain metastases patients with regard to OS and quality of life. METHODS: During April 2015-May 2017, a total of 35 patients with ≤5, previously untreated, inoperable brain metastases were included prospectively. All patients underwent WBRT followed by 3D conformal boost to the metastatic lesions. EORTC quality of life questionnaires QLQ-C30 and QLQ-BN20 were used at baseline and at end of treatment. The mean initial and final scores were compared using Student test. One-year OS with brain metastases was computed with Kaplan Maier method. RESULTS: Median survival with brain metastases was 4.43 months (0.73-78.53). The one-year OS for patients with one metastasis was 42% versus 15% for more than one (p<0.04). The presence of extracerebral metastases significantly decreased OS from 39% without extracerebral metastases to 19%. (p<0.05). Quality of life improved significantly in several functional domains: physical (48 vs 60.29), role functioning (28.1 vs 44.7), emotional (47.1 vs 80.2), global health status (40.9 vs 62.3). Symptom scores decreased significantly in most items, corresponding to an improvement in the symptom burden: headache (61.9 vs 0.9), nausea and vomiting (45.7 vs 7.1), visual disorder (26.3 vs 9.2), seizures (30.4 vs 0.9), motor dysfunction (46.6 vs 17.1). Symptom scores for fatigue and drowsiness increased significantly (51.1 vs 74.9, respectively 37.1 vs 70.4), indicating worsening of symptoms. CONCLUSIONS: WBRT with 3D conformal boost is a feasible technique which improves quality of life in brain metastases patients. Since survival is limited, the assessment of quality of life is a good indicator of the treatment outcome.

Inhibitor selectivity of CNTs and ENTs.

The concentrative nucleoside transporters (CNT; solute carrier family 28 (SLC28)) and the equilibrative nucleoside transporters (ENT; solute carrier family 29 (SLC29)) are important therapeutic targets but may also mediate toxicity or adverse events. To explore the relative role of the base and the monosaccharide moiety in inhibitor selectivity we selected compounds that either harbor an arabinose moiety or a cytosine moiety, as these groups had several commercially available drug members. The screening data showed that more compounds harboring a cytosine moiety displayed potent interactions with the CNTs than compounds harboring the arabinose moiety. In contrast, ENTs showed a preference for compounds with an arabinose moiety. The correlation between CNT1 and CNT3 was good as five of six compounds displayed IC50 values within the threefold threshold and one displayed a borderline 4-fold difference. For CNT1 and CNT2 as well as for CNT2 and CNT3 only two of six IC50 values correlated and one displayed a borderline 4-fold difference. Interestingly, of the six compounds that potently interacted with both ENT1 and ENT2 only nelarabine displayed selectivity. Our data show differences between inhibitor selectivities of CNTs and ENTs as well as differences within the CNT family members.

Correlation Analysis of Potential Breast Cancer Resistance Protein Probes in Different Monolayer Systems.

Breast cancer resistance protein (BCRP) is a point of interest in drug-drug interaction safety testing. Therefore, a consensus probe that can be applied as victim in multiple experimental settings is of great benefit. Identification of candidates has been driven by the amount and quality of available clinical data, and as a result, drugs such as sulfasalazine and rosuvastatin have been suggested. In this article, the in vitro performance of 5 possible alternatives was evaluated: atorvastatin, chlorothiazide, dantrolene, topotecan, and teriflunomide, and benchmarked against sulfasalazine and rosuvastatin in reference in vitro assays for BCRP drug-drug interaction testing. Based on the results, teriflunomide is proposed as an alternate in vitro BCRP probe.

Dose escalation using contact X-ray brachytherapy (Papillon) for rectal cancer: does it improve the chance of organ preservation?

OBJECTIVE: A watch and wait policy for patients with a clinical complete response (cCR) after external beam chemoradiotherapy (EBCRT) for rectal cancer is an attractive option. However, approximately one-third of tumours will regrow, which requires surgical salvage for cure. We assessed whether contact X-ray brachytherapy (CXB) can improve organ preservation by avoiding surgery for local regrowth. METHODS: From our institutional database, we identified 200 of 573 patients treated by CXB from 2003 to 2012. Median age was 74 years (range 32-94), and 134 (67%) patients were males. Histology was confirmed in all patients and was staged using CT scan, MRI or endorectal ultrasound. All patients received combined CXB and EBCRT, except 17 (8.5%) who had CXB alone. RESULTS: Initial cCR was achieved in 144/200 (72%) patients. 38/56 (68%) patients who had residual tumour received immediate salvage surgery. 16/144 (11%) patients developed local relapse after cCR, and 124/144 (86%) maintained cCR. At median follow up of 2.7 years, 161 (80.5%) patients were free of cancer. The main late toxicity was bleeding (28%). Organ preservation was achieved in 124/200 (62%) patients. CONCLUSION: Our data suggest that CXB can reduce local regrowth to 11% compared with around 30% after EBCRT alone. Organ preservation of 62% achieved was higher than reported in most published watch and wait studies. Advances in knowledge: CXB is a promising treatment option to avoid salvage surgery for local regrowth, which can improve the chance of organ preservation in patients who are not suitable for or refuse surgery.

The importance of a multidisciplinary team in rectal cancer management.

INTRODUCTION: The aim of this study was to evaluate the impact of the interval between surgery and adjuvant treatments regarding the overall survival and recurrence-free survival in patients from a developing country. For stages II and III rectal cancer, international guidelines recommend neoadjuvant chemoradiotherapy (CRT) regardless of the tumor location. In the developing countries there is a shortage of radiotherapy centers, specialists, which lead to long waiting lists for radiotherapy. These problems might lead to protocol deviations. METHODS: We conducted a retrospective study on 161 patients with rectal cancer treated with surgery, postoperative CRT and with or without chemotherapy for a total of 6 months, at The Oncology Institute Cluj-Napoca between 2006-2010. All patients had 5 years of follow-up. RESULTS: A total of 161 patients were enrolled in this study. The majority of patients were locally advanced stages (89.44%). The well known prognostic factors, such as TNM stage, performance status, CEA serum level, perineural, vascular and lymphatic invasion, and node capsular effraction had a statistically significant influence on overall survival. In 21.12% of patients the first adjuvant treatment was started in the first 4 weeks after surgery. Only 13.04% of patients started the concomitant CRT within the limit of 6 weeks after surgery. Concerning the time between surgery and CRT, we did not observe a statistically significantly difference in OS if the radiotherapy started after the first 6 weeks (p=0.701). The OS rate for locally advanced rectal cancer patients was 69.44%. CONCLUSIONS: In rectal cancer, the importance of the first therapeutic act is crucial. Following international guidelines provides a survival advantage and a better quality of life. In case of adjuvant treatment, it is recommended to start this treatment as soon as the local infrastructure allows it.

How to Diagnose and Treat a Cancer of Unknown Primary Site.

Almost one in every three patients with advanced tumors have distant metastasis at the time of clinical diagnosis. In most cases, the primary tumor site is identified immediately, within a few days. But for some patients, the primary lesion cannot be found after the initial clinical assessment. These cases are called cancers of unknown primary origin (CUPs), a clinical diagnosis very difficult to manage by physicians due to the absence of a standard-of-care for the initial therapeutic regimen, as well as due to the impossibility to include these cases in randomized clinical trials. A cancer of unknown primary site is often associated with a poor prognosis as patients are usually treated with a non-selective empirical therapy. In the current paper, we summarize both the diagnostic challenges for patients with a cancer of unknown primary site as well as the current available therapeutic options, with emphasis on the management of this unique disease entity.