Epidemiological, clinical and endoscopic features of epistaxis severity and quality of life in Hereditary haemorrhagic telangiectasia: a cross-sectional study.

BACKGROUND: Epistaxis is the main complaint in patients with Hereditary haemorrhagic telangiectasia (HHT). Even though the role of epistaxis in affecting the quality of life (QoL) is well-known, little is known about epidemiological and clinical factors contributing to epistaxis severity and QoL. METHODOLOGY: This is a cross-sectional study, including adult patients with HHT with epistaxis. All patients underwent an otolaryngological evaluation with nasal endoscopy. Epistaxis severity was graded using the FID score, and QoL was evaluated with the Short-Form Health Survey (SF-36). Descriptive statistics were produced for demographic characteristics; the Shapiro-Wilk test was used to test the normal distribution of quantitative variables. Correlation between the quantitative variables was evaluated with Pearson's correlation coefficient. Both univariate and multivariate linear regression models were fitted to find associations between demographic or clinical factors and the FID score or SF-36. RESULTS: A total of 234 patients with HHT were included in the study. The univariate analysis highlighted the association between high blood pressure, septal perforation, nocturnal epistaxis, surgery, blood transfusion, hormonal therapy and both FID score and QoL. Sex, allergic rhinitis and nasal polyposis were neither related to epistaxis severity nor perceived health. CONCLUSIONS: Epistaxis severity and QoL in patients with HHT are influenced by several clinical factors both dependent and independent from HHT. Some of the results are consistent with those already published, but for the first time, we extended the analysis to different clinical parameters, such as endoscopic findings, never assessed before.

Malignant transformation of oral proliferative verrucous leukoplakia: a series of 48 patients with suggestions for management.

Proliferative verrucous leukoplakia (PVL) is a rare and refractory form of oral mucosal leukoplakia of unknown origin, characterized by high rates of malignant transformation. Different diagnostic criteria, terminologies, and therapeutic approaches have been proposed since the first report in 1985. There remains no general agreement regarding the clinical and histological diagnosis, prevention, and correct management of this disease. This retrospective study investigated 48 patients affected by PVL showing at least one malignant transformation and followed up at 2-month intervals. Twenty-five were female (52.1%) and 23 (47.9%) were male; their median age was 67 years (range 40-93 years). Follow-up ranged from 18 to 240 months. Clinical examination included the use of Lugol's solution to prevent clinical underestimation of the margins and toluidine blue for suspicious areas. Surgical excision by scalpel was the preferred treatment for suspicious lesions, with only five carcinomas surgically removed by diode laser and two by CO2 laser. All specimens were accurately mapped after formalin fixation. Fifteen patients (31.3%; 10 female, five male) developed one oral carcinoma, while 33 (68.7%) developed two or more primary tumours (range 3-12). Only four patients (8.3%), who developed between 2 and 8 oral squamous cell carcinomas (OSCCs), died of tumour-related causes. The pre-surgical clinical workup, subsequent surgical treatment, and follow-up are key to success for patients affected by PVL with malignant transformation into stage 1 OSCC and/or verrucous carcinoma, leading to a high overall survival rate.

FID Score: an effective tool in Hereditary Haemorrhagic Telangiectasia - related epistaxis.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a rare disease characterized by a multisystemic vascular dysplasia and epistaxis, that is the most common cause of disability and social impairment. Patient management strictly depends on the severity of this symptom; therefore, it is of paramount importance for the clinicians to effectively grade epistaxis severity. The aim of this report was to validate the Frequency, Intensity and Duration score (FID) for grading epistaxis severity in patients with HHT; we studied repeatability and external validity comparing FID score with Epistaxis Severity Score (ESS). METHODS: This is a descriptive, observational study that included 264 adult HHT patients with epistaxis. Diagnosis of HHT was established with Curacao criteria or positivity at genetic testing. Nosebleed severity was evaluated according to the FID score and the ESS. The first 30 patients were included in the validation of the FID score, which was graded on days 0, 1, 3 and 7. In the remaining 234 patients, a comparison between the ESS and FID score was performed. RESULTS: The statistical analysis performed in order to validate the FID score showed very good agreement between scores calculated on different days; analysis comparing the FID score with the ESS revealed a high correlation between the two grading systems. CONCLUSIONS: The FID score is a quick, easy and precise tool for evaluating HHT-related epistaxis and could be a possible alternative to the ESS. The FID score meets the need for an intuitive and smart grading system that is easy to manage in clinicians’ hands.

Oral lesions as first clinical manifestations of Crohn's disease in paediatric patients: a report on 8 cases.

AIM: Oro-facial granulomatosis is a descriptive term commonly encompassing a variety of conditions that exhibit similar clinical and microscopic features. It is generally used to describe persistent enlargement of the soft tissues of the oral and maxillofacial region. MATERIALS AND METHODS: We report on the salient clinical features of 8 cases of Crohn's disease in paediatric patients (age range from 9 to 13 years old), with oral lesions as first clinical manifestations. RESULTS: The clinical presentation of oro-facial granulomatosis is highly variable but usually recurrent facial swelling, mainly in the lips with or without intraoral manifestations, is the single most common clinical sign at onset. The association with systemic conditions such as sarcoidosis and Crohn's disease has been widely reported in literature. In paediatric age, oro-facial granulomatosis may frequently represent an extra-intestinal manifestation of Crohn's disease and oral lesions can be the first sign of an unknown intestinal disease. The diagnosis in paediatric patients is challenging as oro-facial granulomatosis may precede Crohn's disease by several years, frequently remaining the only evident active focus of the disease. CONCLUSION: The detection of specific oral manifestations often preceded by painless gingival enlargement (diffuse lip and buccal mucosal swelling, oral cobblestoning, buccal sulcus ulceration and mucosal tags) and/or unspecific or ancillary ones (cheilitis, scaly perioral erythematous rashes and frank intraoral abscess formation, labial and tongue fissuring, glossitis and aphthous stomatitis) is mandatory for the early diagnosis of intestinal Crohn's disease.

Medication-related osteonecrosis of the jaw: Surgical or non-surgical treatment?

Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of antiresorptive (bisphosphonates and denosumab) and anti-angiogenic therapy used in the management of oncologic and, less frequently, osteoporotic patients. While there is good international agreement on the diagnostic and staging criteria of MRONJ and the cessation of antiresorptive/anti-angiogenic treatments, the gold standard of treatment is still controversial, in particular between non-surgical and surgical approaches. The former usually includes antiseptic mouth rinse, cyclic antibiotic therapy, low-level laser therapy and periodic dental checks; the latter consists of surgical necrotic bone removal. The purpose of this retrospective study was to describe the therapeutic approaches and outcomes of 131 lesions from 106 MRONJ patients treated at the Policlinic of Bari. Non-surgical treatments were chosen for 24 lesions that occurred in 21 patients who, due to comorbidities and/or the impossibility of stopping oncologic therapies, could not undergo surgical treatment. As to the outcome, all the surgically treated lesions (107) showed complete healing, with the exception of 13.5% of the lesions, all of which were stage III, which did not completely heal but showed reduction to stage I. The 24 non-surgically treated lesions never completely healed and, rather, generally remained stable. Only two cases exhibited a reduction in staging. Based on our observations, MRONJ occurring both in neoplastic and non-neoplastic patients benefits more from a surgical treatment approach, whenever deemed possible, as non-surgical treatments do not seem to allow complete healing of the lesions.

Odontogenic tumors: a retrospective clinicopathological study from two Italian centers.

OBJECTIVE: The aim of this retrospective study was to perform an epidemiological analysis of all odontogenic tumors treated in the University Hospitals "Ospedali Riuniti" in Ancona and "Policlinico" in Bari, from 1990 to 2015. MATERIALS AND METHODS: A retrospective survey of 277 patients treated for odontogenic tumors from 1990 to 2015 was performed. Data were retrieved from the archives of the above quoted Sections of Pathology. The lesions were classified according to 2005 WHO histological classification, and the following variables were analyzed: age, sex, histopathological diagnosis, site distribution, tumor size, and relapses. Peripheral odontogenic tumors were analyzed considering these lesions separately from their central counterparts. RESULTS: In a total of 344 surgical specimens, there were 277 primary tumors and 67 recurrences. As regards primary lesions, there were 185 odontogenic keratocysts (keratocystic odontogenic tumors) (66.8%), 49 ameloblastomas (17.7%), and 40 other benign odontogenic tumors (14.4%). As to malignant tumors, only 3 ameloblastic carcinomas were found (1.1%). The mean age was 46.7 years, with a M:F ratio of 1.8:1. The mandible was the most common site of localization, with 211 cases (76.2%). Also, 21 cases of peripheral odontogenic tumors were found, ameloblastomas being the most common (8 cases, 38.1%). CONCLUSIONS: There is a wide variety of cysts, some of which are subject to variations according to sex, localization, and age. Odontogenic tumors are rare neoplasms and appear to show variations according to sex, localization, and age, and may be useful to the clinicians who need to make clinical judgments before biopsy about the most probable diagnosis.

Diode laser treatment and clinical management of multiple oral lesions in patients with hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is rare, and characterised by vascular dysplasia that leads to various symptoms including visceral arteriovenous malformations and mucocutaneous telangiectatic lesions. Our aim was to describe the clinical features and options for the treatment of multiple oral lesions, and to illustrate the efficacy of the diode laser in the treatment of early (<2mm) and advanced lesions (2mm or more). We report 24 patients with 1200 oral telangiectatic lesions, which were often associated with regular bleeding (from monthly to daily), superinfection, pain, and swelling, and treated with multiple sessions of laser according to the number and size of the lesions. Early lesions were treated with a single laser impulse in ultrapulsed mode, and advanced lesions with repeated laser impulses in pulsed mode (t-on 200ms/t-off 500ms), at a power of 8W. Early lesions healed completely after laser photocoagulation with no operative or postoperative complications, while advanced lesions improved with a remarkable reduction in size but more discomfort. Protective occlusal plates were sometimes used to reduce the incidence of new lesions caused by dental trauma. The treatment of oral telangiectatic lesions is still being debated, and it is important to improve quality of life for patients. Diode laser surgery could be an effective treatment for oral lesions in those with hereditary haemorrhagic telangiectasia.

Tuberous sclerosis: histological analysis with confocal laser scanning microscope of gingival angiofibromatosis.

INTRODUCTION: Tuberous sclerosis (TS) is an autosomal dominant neuro-cutaneous syndrome characterized by multiple hamartomas in various organs, especially on skin and central nervous system. The most common features of TS include facial angiofibromas, hypomelanotic cutaneous macules, shagreen patches in the lumbar area, cerebral cortical tubers, sub-ependymal nodules, sub-ependymal giant cell astrocytomas, cardiac rhabdomyomas, and renal angiomyolipomas. Frequently oral manifestations such as fibrous hyperplasia, angiofibromas and dental enamel pitting are also observed. The aim of this case report was to describe the histological aspects of oral diffuse hyperplastic angiofibromatosis, never reported in the English literature and analyzed by Confocal Laser Scanning Microscope (CLSM), and to highlight the surgical implications of these aspects such as use of Diode Laser. CASE REPORT: A 14-years-old female patient with TS diagnosis came to our attention for diffuse gingival hyperplasia on the mandible. Clinical examination highlighted epidermal hamartomas on the whole body, especially on the face and scalp. Pathologic hyperplastic tissue was removed by pulsed diode laser at the power of 5-6W, and the surgical samples were sent for conventional and CLSM histopathological examination. After laser excision, wounds healed quickly without complications. At CLSM examination collagen fibres, showing intense fluorescence and with variable spatial orientation, and variably sized blood vessels were noticed suggesting the diagnosis of gingival angiofibromatosis, a still unreported finding in TS patients. CONCLUSIONS: CLSM analysis allows to highlight some unusual histopathological features of TS; diode laser is very effective for the treatment of gingival angiofibromatosis.

The contribution of histopathological examination to the diagnosis of cervico-facial actinomycosis: a retrospective analysis of 68 cases.

Cervico-facial actinomycosis is an infectious, suppurative, and granulomatous disease due to Actinomyces species. Usually, the diagnosis is confirmed by microbiological cultures; however, the need for careful anaerobic handling of specimens often makes it difficult to obtain an effective microbial growth. Therefore, we conducted a retrospective study on biopsy samples from patients with a clinical suspicion of cervico-facial actinomycosis, in order to determine whether accurate histopathological examination could reliably confirm the diagnosis. A retrospective revision of formalin-fixed, paraffin-embedded archival material from 68 cases of cervico-facial lesions, with negative culture for anaerobic/microaerophilic microorganisms, was performed. Twelve serial sections for each case were cut from the paraffin blocks, individually collected on positively charged slides to obtain good section-to-slide adhesion, and stained with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS). Histopathological examination of the serial sections allowed the identification of bacterial colonies consistent with actinomycetes in 22 cases (32 %). The proposed histopathological examination allowed the retrospective diagnosis of cervical actinomycosis in one-third of clinical specimens that remained misdiagnosed following traditional H&E examination.

Histopathological features of tissue alterations induced by low frequency ultrasound with cavitational effects on human adipose tissue.

Low frequency, high energy level ultrasound (US) induces physical effects on tissues called ultrasonic cavitation (UC). Endermic US therapy has recently been proposed as a method to reduce non-invasively the amount of adipose tissue. Very few published studies have dealt with the biological effects of such therapies on human adipose tissue. The aim of this study is to evaluate, through histopathological examination, the effects of various levels of ultrasonic radiation on supravital human adipose tissue. Four ex vivo human tissue samples were treated as follows: sample 1: no US radiation; sample 2: US radiation 2,5 W/cm2 for 15 minutes; sample 3: US radiation 5 W/cm2 for 15 minutes; sample 4: infiltration of 30 ml physiological saline and US radiation, 5 W/cm2 for 15 minutes. For lower levels of ultrasonic energy, interruption of the adipocytic membranes was evident both in the surface and in the deeper cutaneous and subcutaneous layers, with focal dissolution and homogenization of the surface dermal fascia. For higher levels of ultrasonic energy, alterations of the adipocytes and of the collagen fibers were greater, resulting in the dissolution of the cells and of the interlobular fibrous septa. Both effects were amplified by tumescent saline infiltration. The histological lesions demonstrated in adipocytes confirm the theoretical premises of a possible usefulness in the treatment of localized adiposis. The alterations observed in the connective stroma could have positive effects on the structural re-organization and consequently on the in vivo external appearance of the treated areas.

Which patients benefit most from adjuvant aromatase inhibitors? Results using a composite measure of prognostic risk in the BIG 1-98 randomized trial.

BACKGROUND: On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which aromatase inhibitors may be more or less important. PATIENTS AND METHODS: Breast International Group 1-98 trial randomized 6182 women among four groups comparing letrozole and tamoxifen with sequences of each agent; 5177 (84%) had centrally confirmed estrogen receptor (ER) positivity. We assessed whether centrally determined ER, progesterone receptor (PgR), human epidermal growth factor receptor 2, and Ki-67 labeling index, alone or in combination with other prognostic features, predicted the magnitude of letrozole effectiveness compared with either sequence or tamoxifen monotherapy. RESULTS: Individually, none of the markers significantly predicted differential treatment effects. Subpopulation treatment effect pattern plot analysis of a composite measure of prognostic risk revealed three patterns. Estimated 5-year disease-free survival for letrozole monotherapy, letrozole→tamoxifen, tamoxifen→letrozole, and tamoxifen monotherapy were 96%, 94%, 93%, and 94%, respectively, for patients at lowest risk; 90%, 91%, 93%, and 86%, respectively, for patients at intermediate risk; and 80%, 76%, 74%, and 69%, respectively, for patients at highest risk. CONCLUSION: A composite measure of risk informs treatment selection better than individual biomarkers and supports the choice of 5 years of letrozole for patients at highest risk for recurrence.

Adverse prognostic value of peritumoral vascular invasion: is it abrogated by adequate endocrine adjuvant therapy? Results from two International Breast Cancer Study Group randomized trials of chemoendocrine adjuvant therapy for early breast cancer.

BACKGROUND: Peritumoral vascular invasion (PVI) may assist in assigning optimal adjuvant systemic therapy for women with early breast cancer. PATIENTS AND METHODS: Patients participated in two International Breast Cancer Study Group randomized trials testing chemoendocrine adjuvant therapies in premenopausal (trial VIII) or postmenopausal (trial IX) node-negative breast cancer. PVI was assessed by institutional pathologists and/or central review on hematoxylin-eosin-stained slides in 99% of patients (analysis cohort 2754 patients, median follow-up >9 years). RESULTS: PVI, present in 23% of the tumors, was associated with higher grade tumors and larger tumor size (trial IX only). Presence of PVI increased locoregional and distant recurrence and was significantly associated with poorer disease-free survival. The adverse prognostic impact of PVI in trial VIII was limited to premenopausal patients with endocrine-responsive tumors randomized to therapies not containing goserelin, and conversely the beneficial effect of goserelin was limited to patients whose tumors showed PVI. In trial IX, all patients received tamoxifen: the adverse prognostic impact of PVI was limited to patients with receptor-negative tumors regardless of chemotherapy. CONCLUSION: Adequate endocrine adjuvant therapy appears to abrogate the adverse impact of PVI in node-negative disease, while PVI may identify patients who will benefit particularly from adjuvant therapy.

Enhancement of fibroblast proliferation, collagen biosynthesis and production of growth factors as a result of combining sodium hyaluronate and aminoacids.

Fibroblasts play a key role in tissue healing by producing the majority of extracellular matrix components, favouring granulation tissue formation, and stimulating re-epithelialization. Hyaluronan is a component of ECM and its anti-inflammatory effects and properties in enhancing wound closure are well known. In this study, we examined the effects of Aminogam gel, a new pharmacological preparation suggested to improve wound healing, composed of hyaluronic acid, proline, lysine, glycine and leucine, on human fibroblasts. Results show that fibroblasts treated with hyaluronic acid plus aminoacid solution increased their proliferative activity, collagen I and III, and fibronectin synthesis. Moreover, HA plus aminoacid solution increased the expression of transforming growth factor beta, connective tissue growth factor, interleukin-6 and -8, assayed by RT-PCR. These results suggested that Aminogam gel, involved in several stages of wound healing, as fibroblast proliferation, granulation tissue formation, ECM component deposition, and production of cytokines, may be a useful device to favour and accelerate wound closure.

Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaws: an analysis of 31 cases with confocal laser scanning microscopy.

INTRODUCTION: Patients undergoing bisphosphonate therapies may develop jaw lesions, mainly consisting in bone necrosis. No effective treatment has been proposed so far for such lesions, nor is there a uniform concept on the possible pathogenesis of this entity. METHODS: The study population included 31 patients with bisphosphonate-related osteonecrosis of the jaws and 10 healthy donors. All patients underwent to jaw bone biopsy and the tissue samples were divided into two parts, one of which was fixed, decalcified and routinely processed. The second part was fixed, embedded in methylmetacrylate, cut and stained with methylene blue and basic fuchsine. All samples were subjected to light and confocal microscopic examination and to histomorphometric analyses to evaluate differences in bone structure between the two samples groups. RESULTS: Three main histological patterns were identified in ONJ patients: 1 - Areas with active acute inflammation, characterized by predominance of soft tissues, inflammatory infiltrate, acellular necrotic debris, thin-walled and dilated blood vessel, intensely basophilic bone spiculae with scalloped borders showing prominent bone resorption. 2 - Areas characterized by predominance of bony structures showing wide acellular necrotic sequestra and large, scalloped Haversian canals containing inflammatory cells. 3 - Non-necrotic areas contained larger amounts of bone, showing increased trabecular thickness, inter-osteonic bone deposition and smaller and fewer Haversian canals. These differences were more evident after comparing the histomorphometrical data of samples from ONJ patients with controls. Also, lamellar bone from treated patients was composed of bigger osteones containing larger osteocytes. Two different types of newly-formed woven bone, mainly showing centrifugal spatial orientation, were easily detectable in these areas. Osteoclast-like cells detected in inflammatory areas from treated patients were small and contained few nuclei, but they were rare to absent in non-necrotic bone from the same patients. CONCLUSIONS: These features point at a peculiar process of bone remodeling in patients undergoing bisphosphonate therapy, which showed scarce osteoclastic activity and subsequent deposition of newly-formed bone. The latter would be made up of thicker bone structures supplied by fewer blood vessels. Consequently, in case of increased metabolic requests, this modified bone would not be supported by adequate blood supply, thus leading to necrosis and superinfection.

Plasmablastic lymphoma: a review.

Plasmablastic lymphoma (PBL) has been recently characterised as an aggressive subtype of non-Hodgkin's lymphoma, most frequently arising in the oral cavity of HIV-infected patients. To date, approximately 60 cases fulfilling the clinico-pathological characteristics of PBL have been reported. PBLs are composed of large cells with eccentrically located nuclei and deeply basophilic cytoplasm with a paranuclear hof. The tumour cells are invariably immunoreactive for the plasma cell marker CD138, and show monoclonal rearrangement of the immunoglobulin heavy chain gene (IgH) and/or clonal restriction of the Ig light chain (IgL) gene expression in most of the cases. Similar to other types of AIDS-related lymphomas, there is evidence that Epstein-Barr virus and Kaposi-sarcoma associated Human Herpes Virus 8 may play a relevant role in the pathogenesis of PBL. PBL patients have been treated heterogeneously, with a combination of chemotherapy, radiotherapy and/or surgery, and their prognosis is usually poor, with a death rate of approximately 60% at 1 year.

Effect of gonadectomy on HCC development in HBV transgenic mice.

BACKGROUND AND AIMS: Epidemiological data demonstrate that HCC is prevalent in men compared to women. Herein, we examined the effect of gonadectomy in a murine model that spontaneously develops HCC. ANIMALS AND METHODS: Thirty-two male and 26 female HBV transgenic mice [Tg (Alb-1 HBV) Bri 44] underwent surgical castration or sham operation. At the 18th month, serum samples were collected and all mice were sacrificed. Liver weight and volume were evaluated, each liver was cut into 1.5-mm-thick consecutive slices and nodules were examined on freshly isolated tissue. Consecutive histological sections obtained from each liver slice were evaluated to confirm the diagnosis of HCC. RESULTS: Sham-operated females showed a significantly lower neoplastic growth compared to sham-operated males. This difference disappeared when females underwent gonadectomy. In males, neoplastic growth was not influenced by gonadectomy. Testosterone and estradiol levels were profoundly modified by gonadectomy in both males and females. The testosterone/estradiol ratio in gonadectomized females increased 4.5-fold compared to that in sham-operated females, becoming more similar to the ratio observed in castrated and sham-operated male mice. CONCLUSIONS: HCC growth in our experimental model was not simply influenced by the levels of testosterone or estradiol, taken singularly, but depended on their ratio.

Dysfunctional DC subsets in RCC patients: ex vivo correction to yield an effective anti-cancer vaccine.

Dendritic cells (DCs) are potent antigen-presenting cells responsible for the activation and functional polarization of specific T cells. In patients with renal cell carcinoma (RCC) and other cancers, coordinate DC and T cell defects have been reported. In particular, DC and T cell functional subsets that are not conducive to tumor clearance are hypothesized to predominate in patients with advanced-stage disease. Two major peripheral blood DC subsets have been identified in humans: myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) that are believed to mediate contrasting effects on cancer immunity. Given the lack of information regarding DC subsets in patients with RCC, in the present study we have investigated the comparative frequencies and activation states of mDC and pDC in peripheral blood, cancer tissues and lymph nodes of patients with RCC using flow cytometry and immunohistochemistry. Three monoclonal antibodies (mAbs) reactive against specific DC subsets (BDCA-2 or BDCA-4 for pDC and BDCA-1 and BDCA-3 which represent two distinct subsets of mDC, mDC1 and mDC2, respectively) were employed. We observed a significant reduction of both DC subsets in the peripheral blood of patients as compared to normal donors. Similarly, both mDC and pDC were recruited in large numbers into RCC tumor tissues, where they displayed an immature phenotype (DC-LAMP(-)) and appeared unable to differentiate into mature DC (CD83(+)) that were competent to migrate to draining lymph nodes. However, we were readily able to generate ex vivo mDC from RCC patients. These DC stimulated robust anti-tumor CTL in vitro and would be envisioned for use in DC-based vaccines applied in patients with RCC whose existing immune system is judged dysfunctional, anergic or prone to undergo apoptosis.