New chitin complexes and their anti-aging activity from inside out.

BACKGROUND: Nutritional and topical antioxidants and immuno-modulant compounds play a key role in maintaining healthy skin. However, little is known about the combined effects antioxidant cosmeceuticals and nutricosmetics can have on the appearance of aging skin. OBJECTIVE: The clinical trial was designed to study the combined effects on skin hydration, superficial lipids, elasticity, peroxidation and global clinical appearance, of melatonin, Vit. E and Betaglucan (MEB) complexed with chitin nano-crystals administered both topically and orally. Clinical examinations were conducted by dermatologists. DESIGN: By a randomized placebo-controlled, 12 week multicenter study on 70 healthy subjects, affected with skin photo-aging, the anti-aging efficacy and tolerability of the combined activity of topical emulsion and oral hard capsules, containing MEB complexed with chitin nano-crystals (CN) was evaluated clinically and by biophysical non-invasive measurements at week 4,8 and 12. RESULTS: The effects of MEB intake resulted significantly higher (p<0.005) than placebo for all the parameters evaluated by biophysical and clinical measurements. The values resulted higher when the active ingredients MEB were complexed with CN, whether used topically, orally or a combination of both (p<0.05). The positive results, observed since week 4, were accompanied by no side-effects throughout the entire study. CONCLUSION: The combined topical and oral use of MEB was associated with reduced wrinkling, better skin appearance and general overall wellness. When MEB were complexed with CN, the obtained results were statistically more positive (p<0.05) for all the biophysical and clinical parameters considered.

Outcome of special types of luminal breast cancer.

BACKGROUND: The identification of special types of breast cancer might be of value in assessing prognosis and predicting response to therapy. METHODS: A total of 7372 consecutive patients with immunohistochemically defined luminal invasive breast cancer operated at the European Institute of Oncology between 1997 and 2005 were included. We then explored patterns of recurrence by histological type. Median follow-up was 5.8 years. RESULTS: Tumors from 5707 patients were classified as invasive ductal cancer (IDC) not otherwise specified (NOS), 851 lobular, 338 mixed ductal and lobular, 250 cribriform, 143 mucinous and 83 tubular carcinomas. Compared with IDC NOS disease-free survival (DFS) was significantly longer in patients with cribriform tumors [5-year DFS 97.9% versus 87.4%; hazard ratio (HR) = 0.48; P = 0.015) and in pooled cribriform plus tubular carcinomas (5-year DFS 98.7% versus 87.4%; HR = 0.45; P = 0.005). Mucinous tumors presented similar DFS if compared with IDC (5-year DFS 93 % versus 87.4%; HR = 1.03; P = 0.91). Conversely, DFS was poorer for patients with lobular carcinoma (5-year DFS 86.8% versus 87.4%; HR = 1.27; P = 0.01). CONCLUSIONS: The diagnosis of tubular, cribriform and lobular carcinomas carry distinct prognostic implications. The identification of these special types has a significant utility in luminal breast cancer and should be considered in therapeutic algorithms.

Prognosis in women with small (T1mic,T1a,T1b) node-negative operable breast cancer by immunohistochemically selected subtypes.

Knowledge is limited about prognostic significance of breast cancer subtypes among women with small invasive node-negative breast tumours. We explored patterns of recurrence in 1691 women with pT1mic/T1a/T1b, pN0 and M0 breast cancer according to four immunohistochemically defined tumour subtypes: (i) Luminal A (ER-positive, PgR-positive, HER2-negative and Ki-67 < 14%); (ii) Luminal B (ER-positive and/or PgR-positive, HER2-positive and/or Ki-67 ≥ 14%); (iii) HER2-positive, both endocrine receptors absent; and (iv) Triple Negative. At multivariate analysis, women with the Triple Negative breast cancer subtype had an increased risk of loco-regional relapse (LRR) (Hazards Ratio (HR) 3.58; 95%CI: 1.40-9.13) and breast cancer related events (HR 2.18; 95%CI: 1.04-4.57). Overall, Luminal B subtype was not associated with a statistically significant increased risk of recurrence compared with Luminal A, while patients with Luminal B subtype tumours overexpressing HER2 had a 2 fold risk of reduced breast cancer related survival (BCS), but not an increased risk of LRR and distant metastases. Women with HER2 breast cancer subtype had a statistically significant increased risk of LRR (HR 4.53; 95%CI: 1.56-13.1), distant metastases and reduced BCS (HR 3.22; 95%CI: 1.44-7.18) and overall survival (HR 2.87; 95%CI: 1.05-7.89) when compared with the Luminal A subtype, at multivariate analysis. In conclusion, women with small size, node-negative, breast cancer are at higher risk of relapse if with HER2-positive endocrine receptor absent or Triple Negative disease.

Minimal axillary lymph node involvement in breast cancer has different prognostic implications according to the staging procedure.

It is still controversial whether the identification of micrometastases and isolated tumor cells in the axillary lymph nodes of patients with breast cancer has any prognostic value. We evaluated the prognostic role of isolated tumor cells and micrometastases in the axillary lymph nodes in 3,158 consecutive patients pT1-2 pN0-N1mi (with a single involved lymph node) and M0, referred to the Division of Medical Oncology after surgery performed at the European Institute of Oncology from April 1997 to December 2002. Median follow-up was 6.3 years (range 0.1-11 years). Sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) were performed in 2,087 and 1,071 patients, respectively. A worse metastasis-free survival was observed for patients with micrometastatic disease compared to node-negative patients, if staged with ALND (log-rank P < .0001; HR: 3.17; 95% CI 1.72-5.83 at multivariate analysis), but not for patients who underwent SLNB (log-rank P = 0.36). The presence of a single micrometastatic lymph node is associated with a higher risk of distant recurrence as compared to node-negative disease only for patients undergoing ALND for staging purposes. Treatment recommendations for systemic therapy should not take into account the presence of a single micrometastatic lymph node identified during complete serial sectioning of sentinel node(s).

Preoperative bevacizumab combined with letrozole and chemotherapy in locally advanced ER- and/or PgR-positive breast cancer: clinical and biological activity.

The antiangiogenic agent bevacizumab showed synergistic effects when combined with chemotherapy in advanced breast cancer. We presently investigated the activity of bevacizumab in combination with chemotherapy, including capecitabine and vinorelbine, and endocrine therapy, including letrozole (+triptorelin in premenopausal women), as primary therapy for patients with ER and/or PgR > or =10% T2-T4a-c, N0-N2, M0 breast cancer. Biological end point included the proliferative activity (Ki67), whereas clinical end points were clinical response rate, pathological complete response (pCR) and tolerability. Circulating endothelial cells (CECs) and their progenitors, as surrogate markers of antiangiogenic activity, were measured at baseline and at surgery.Thirty-six women are evaluable. A clinical response rate of 86% (95% CI, 70-95) and no pCR were observed; Ki67 was significantly decreased by 71% (interquartile range, -82%, -62%). Toxicity was manageable: two grade 3 hypertension, four grade 3 deep venous thrombosis and no grade >2 proteinuria were observed. Treatment significantly decreased the percentage of viable CECs and prevented the chemotherapy-induced mobilisation of circulating progenitors. Basal circulating progenitors were positively associated with clinical response. In conclusion, bevacizumab is feasible and active in association with primary chemoendocrine therapy for ER-positive tumours in terms of proliferation inhibition, clinical response and antiangiogenic activity.

Factors that predict early treatment failure for patients with locally advanced (T4) breast cancer.

Locally advanced breast cancer (LABC) is associated with dire prognosis despite progress in multimodal treatments. We evaluated several clinical and pathological features of patients with either noninflammatory (NIBC, cT4a-c) or inflammatory (IBC, cT4d) breast cancer to identify subset groups of patients with high risk of early treatment failure. Clinical and pathological features of 248 patients with LABC, who were treated with multimodality treatments including neoadjuvant chemotherapy followed by radical surgery and radiotherapy were reassessed. Tumour samples obtained at surgery were evaluated using standard immunohistochemical methods. Overall, 141 patients (57%) presented with NIBC (cT4a-c, N0-2, M0) and 107 patients (43%) with IBC (cT4d, N0-2, M0). Median follow-up time was 27.5 months (range: 1.6-87.8). No significant difference in terms of recurrence-free survival (RFS) (P=0.72), disease-free survival (DFS) (P=0.98) and overall survival (OS) (P=0.35) was observed between NIBC and IBC. At the multivariate analysis, patients with ER- and PgR-negative diseases had a significantly worse RFS than patients with ER- and/or PgR-positive diseases (hazard ratio: 2.47, 95% CI: 1.33-4.59 for overall). The worst RFS was observed for the subgroup of patients with endocrine nonresponsive and HER2-negative breast cancer (2-year RFS: 57% in NIBC and 57% in IBC) A high Ki-67 labelling index (>20% of the invasive tumour cells) and the presence of peritumoral vascular invasion (PVI) significantly correlated with poorer RFS in overall (HR 2.69, 95% CI: 1.61-4.50 for Ki-67>20% and HR 2.27, 95% CI: 1.42-3.62 for PVI). Patients with endocrine nonresponsive LABC had the most dire treatment outcome. High degree of Ki-67 staining and presence of PVI were also indicators of higher risk of early relapse. These factors should be considered in therapeutic algorithms for LABC.

Expression of ER, PgR, HER1, HER2, and response: a study of preoperative chemotherapy.

PURPOSE: To identify the role of estrogen (ER), progesterone (PgR), epidermal growth factor 1 (HER1), and HER2 receptors in predicting response to preoperative chemotherapy. MATERIALS AND METHODS: We reviewed the pretreatment biopsies of 485 patients with locally advanced breast cancer (cT2-T4, N0-2, M0) treated with preoperative chemotherapy. The incidence of pathological complete remission (pCR) and outcome were assessed with respect to clinical and pathological findings including ER/PgR status (absent versus expressed), HER1 (absent versus expressed) and HER2 (overexpressed versus none) expression. RESULTS: Patients with ER/PgR-absent tumors were 12.0 times [95% confidence interval (CI) 4.93-29.28] more likely to achieve a pCR (P < 0.0001). Predictors of disease-free survival (DFS) at the univariate analysis included HER1 [hazards ratio (HR) 1.6, 95% CI 1.04-2.32, P = 0.03] and HER2 (HR 1.6, 95% CI 1.08-2.38, P = 0.02) expression. A statistically significant difference in DFS was confirmed at the multivariate analysis for patients with ER/PgR-absent disease (HR 2.1, 95% CI 1.41-2.99, P = 0.0002). CONCLUSIONS: The pCR rate is higher and outcome worse for patients with ER/PgR-absent tumors. HER1 and HER2 expression may have a prognostic role in locally advanced breast cancer and warrant further studies.

Adjuvant treatment for young women with early breast cancer.

Breast cancer rarely occurs in young women (<35 years). Several data indicate that diagnosis is associated with a worse prognosis, due to a more aggressive presentation. Although the effect of chemotherapy for premenopausal women is substantial, recent evidence suggested that patients with age <35 years with endocrine responsive tumors had a significant higher risk of recurrence than older premenopausal patients with such biological characteristics. Whereas premenopausal patients with endocrine nonresponsive disease presented similar outcome. Information from different studies of three major researching cooperative groups on breast cancer patients treated with chemotherapy alone, showed a similar interaction between the age and endocrine receptor status. Innovative treatment strategies needed and the combination of ovarian function suppression with endocrine agents (such as tamoxifen) in adjuvant therapy for endocrine receptor positive tumors could be considered. Moreover, more investigation on chemotherapy, its timing, duration, and intensity are required in the adjuvant care for endocrine nonresponsive disease. A strong emotional involvement is required to those patients approaching to adjuvant therapy, which may complicate the phase of treatment decision making. There is an urgent need for tailored clinical trials on young women with breast cancer diagnosis, to allow significant progress on adjuvant treatment of these population.

A phase II study of primary dose-dense sequential doxorubicin plus cyclophosphamide and docetaxel in cT4 breast cancer.

BACKGROUND: Dose-dense chemotherapy with anthracyclines and taxanes has improved either disease free survival or overall survival in high risk patients with early breast cancer. PATIENTS AND METHODS: The activity and safety of a dose-dense schedule (q14 days) of adriamycin 60 mg/sqm and cyclophosphamide 600 mg/sqm (AC) x 4 cycles followed by docetaxel 75 mg/sqm for 4 cycles with hematopoietic support in patients with stage IIIB breast cancer was explored. Patients with ER > or =10% tumors received concomitant endocrine therapy with 3-month triptorelin and letrozole. RESULTS: Fifteen patients with histologically proven cT4b (three patients) and cT4d (twelve patients) M0 breast cancer were enrolled. Median age was 48 years (range 25-66). Eight clinical responses including one pathological complete remission (pCR), three stable disease (including minor responses) and four progression of disease, one during AC and three during taxotere, were observed. Four patients had grade 3-4 non hematological toxicities and all except one discontinued treatment. CONCLUSION: Due to the high rate of progressive disease, this schedule should not represent a standard option in cT4 breast cancer.

Transplant surgeon formation: vocation, incentives, between old and new surgeon generations.

The training of the transplant surgeon is one of the most difficult paths in medicine. The transplant surgeon must be trained as a general and a vascular surgeon; he has to be skilled and upgraded in transplant surgical technique; he has to decide the suitability of the donor and of the organs as well as the immunosuppressive therapy for each recipient; he must know the intensive care unit, hepatology, and nephrology. The transplant surgeon has to deal with surgical, infectious, and metabolic complications after organ transplantation. Thus, clinical formation of the transplant surgeon is multifactorial and always upgraded. However, transplants never happen in the morning; retrivals are more likely to be in the night (especially the holidays ones). "Weekend" is a word not frequently used by transplant surgeons. Moreover, when the transplant procedure happens, the normal activity of the ward and of the outpatient clinic were have to be done. The transplant surgeon must have a sort of "vocation" for such a job. Organ harvesting setting is a good proof of adaptability, always during nighttime, often in small hospitals with operating room nurses unfamiliar with the procedure, sometimes waiting for some colleagues or delaying the surgery. This vocation is enhanced by enthusiasm, but incentives are necessary to feed this love. Incentives should be professional and economic; transplant surgeons should be allowed to make clinical decisions, to choose the surgical technique of transplantation, to control the decision process. Lastly, due to the "total on call," the surgeon should profit from a right salary avoiding extramural activities.

Role of endocrine responsiveness and adjuvant therapy in very young women (below 35 years) with operable breast cancer and node negative disease.

BACKGROUND: There is limited knowledge about prognosis, and treatment effects in young women with node-negative disease. PATIENTS AND METHODS: We evaluated biological features, treatment recommendations and prognosis for 841 premenopausal patients with pT1-3, pN0 and M0, operated from 1997 to 2001. RESULTS: Patients below 35 years (101, 12%) were more likely to have tumors > 2 cm (35.6% versus 24.2%, P = 0.002), grade 3 (48.5% versus 31.9%, P = 0.009) and with elevated Ki-67 expression (62.4% versus 50.7%, P = 0.002). At the multivariate analysis a statistically significant difference in disease-free survival (DFS, HR 4.44; 95% CI 2.53 to 7.78, P < 0.0001), risk of distant metastases (DDFS) (HR 3.23; 95% CI 1.32 to 7.94, P = 0.011) and overall survival (OS) (HR 2.89; 95% CI 1.06 to 7.87, P = 0.038) was observed for younger versus older patients and in the subgroup with endocrine responsive tumors (DFS, HR 5.17, 95% CI 2.72-9.83, P = < 0.0001; DDFS, 3.76, 95% CI 1.33-10.6, P = 0.013; OS, 4.71, 95% CI 1.09-20.4, P = 0.039 ). CONCLUSIONS: Compared with less young, very young patients with endocrine responsive and node-negative breast cancer have a worse prognosis. Tailored treatments should be explored in this cohort of patients.

Breast cancer vaccines: a clinical reality or fairy tale?

The characterization of tumor antigens recognized by immune effector cells has opened the perspective of developing therapeutic vaccines in the field of breast cancer. The potential advantages of the vaccines are: (i) the induction of a robust immune response against tumors that are spontaneously weekly immunogenic; (ii) the tumor specificity for some antigens; (iii) the good tolerance and safety profile and (iv) the long-term immune memory, critical to prevent efficiently tumor recurrence. Most trials evaluating breast cancer vaccines have been carried out in patients with extended metastatic breast cancer, characterized by aggressive tumors, resistant to standard cytotoxic treatments, so that clinical efficacy was difficult to achieve. However, some significant immune responses against tumor antigens induced upon vaccinations were recorded. The aim of this review is to analyze the activity of vaccination strategies in current clinical trials. Data of clinical activity have been observed by using vaccines targeting HER2/neu protein, human telomerase reverse transcriptase, carcinoembryonic antigen and carbohydrate antigen given after stem cell rescue. The review discusses possible future directions for vaccine development and applications in the adjuvant setting.

Use of mycophenolate mofetil in liver transplantation: a literature review.

Mycophenolate mofetil (MMF) is an immunosuppressive drug, exhibiting its effect through inhibition of proliferation of T and B lymphocytes. Standard primary immunosuppressive therapy after orthotopic liver transplantation (OLT) is based on a calcineurin-inhibitor (CNI): cyclosporine or tacrolimus. Renal failure with arterial hypertension, due to CNI side-effects, is a major cause of morbidity and mortality after OLT. Several studies have shown the efficacy of MMF to improve CNI-induced nephrotoxicity, blood pressure, and uric acid concentration in liver transplant patients with concomitant reduction or withdrawal of CNI. Predose plasma mycophenolic acid concentrations (MPA) are related to adverse events, drug dose, and clinical status. Blood level values outside the suggested MPA therapeutic range are associated with acute rejection episodes and side effects, which have been described in about half of the patients treated with MMF. Most authors have described gastrointestinal and hematological side-effects, whereas these appear usually dose related, responding quickly to reduction. MMF is potent and safe immunosuppressive agent, and replacement of CNI by MMF in liver transplant patients with renal dysfunction may improve not only kidney function but also other CNI-associated side-effects, such as hypertension and hyperuricemia, with a low risk of rejection.

Interposition of the right colic angle between the liver and thoracic wall: an unusual cause of massive rectal bleeding following percutaneous biopsy in a liver transplant recipient.

A 37-year-old male liver transplant recipient developed hemorrhagic shock from massive rectal bleeding a few hours after a protocol liver biopsy. Conservative treatment was not possible and the patient underwent a radiological investigation of the celiac and mesenteric arterial trunks, which showed active bleeding from a branch of the middle colic artery. Embolization with Tabotamp (Ethicon, Neuchatel, CH Switzerland) particles led to successful hemostasis. We thus discuss the possible mechanisms of injury. To our knowledge, no other cases of major rectal bleeding following percutaneous liver biopsy have been reported in the literature. We emphasize the need for Doppler ultrasound assistance, in terms of either preoperative examination with or without marking or guidance. The latter is the safest and most reliable technique, given the low risk of puncture of other organs and the low probability of obtaining an inadequate sample.

A novel method for monitoring response to chemotherapy based on the detection of circulating cancer cells: a case report.

We describe a novel method for detecting micrometastasis in the blood stream of cancer patients based on RT-PCR amplification of tumor-associated carcinoembryonic antigen (CEA) mRNA. To increase sensitivity and specificity of RT-PCR, CEA transcript was selectively up-regulated in cancer cells by exposure of peripheral blood to non-toxic concentrations of staurosporine (ST). Thereafter, polyA(+) RNA was extracted from tumor cells captured by means of magnetic beads coated with a monoclonal antibody against a common human epithelial antigen. Finally, RNA was subjected to RT-PCR analysis of CEA transcript. Using this approach, we demonstrated an ST-mediated increase in CEA transcript in blood specimens collected from a patient with metastatic colon cancer before receiving treatment with 5-fluorouracil/leucovorin. After a few cycles of chemotherapy, CEA-positive tumor cells were no longer detected. Clinical follow-up of this patient indicated that treatment with chemotherapy induced a dramatic reduction in liver metastasis. Therefore, it can be hypothesized that lack of CEA transcript detection might be consistent with disappearance or at least marked reduction of circulating tumor cells.

Role of topical and nutritional supplement to modify the oxidative stress.

BACKGROUND: Evidence suggests that signs of skin ageing such as wrinkling, ragging and actinic lentigines, may be connected to cumulative oxidative damage incurred throughout our lifetimes. To counteract this oxidative injury, skin is equipped with a network on enzymatic and non-enzymatic antioxidant systems, such as tocopherols, ascorbate polyphenols. All these compounds administered topically by cosmetics or by oral route by diet supplements, have been shown to exert an antioxidant/protective effect in skin or skin cells. OBJECTIVE: The object of this study was to evaluate both in vitro and in vivo the activity performed by different topical antioxidants and nutritional supplements. METHODS: A randomized double-blind placebo-controlled study was carried out for 8 weeks on 30 dry-skinned elderly volunteers, women aged between 48 and 59 years, with moderate xerosis and photoageing. Surface skin lipids, skin hydration and MDA determination were topically detected by 3C System. ROS was evaluated on the blood serum and on IL-3 stimulated human leukocytes by ROS Meter System at 505 nm. All the subjects applied twice a day for 2 months a nanocolloidal gel and/or take a diet supplement by oral route at the quantity of two capsules per day. All the formulations used were antioxidant-enriched (ascorbic acid, tocopherol, alpha-lipoic acid, melatonin, emblica). RESULTS: Oxidative stress and consequently lipids peroxidation decreased from 30 to 40% (P < 0.005) in blood serum of all the subjects treated with antioxidant compounds topically and by oral route. Both free radicals recovered in blood serum and on skin (in vivo) and ROS induced by irradiation of leucocytes with UVB light (in vitro), appear sensibly lower in subjects antioxidant-treated. CONCLUSIONS: From the obtained data, it seems possible to conclude that all the compounds used play interesting role as topical and systemic photoprotectants, thanks to their interesting antioxidant property. Moreover, the antioxidant treatment seems to be a promising therapeutic approach also in reducing the oxidative stress of people affected by photoaging.

Drug-induced modulation of carcinoembryonic antigen (CEA) expression in neoplastic cells from a patient with rectal cancer.

Treatment with 5-fluorouracil (5-FU) or recombinant interferon-gamma (IFN), alone or in combination, was found to increase carcinoembryonic antigen (CEA) expression in several carcinoma cell lines. In this study we examined the in vitro effect of these agents on CEA expression of tumor cells, obtained from a patient operated for rectal cancer. The results showed that exposure of cancer cells to 5-FU or to IFN resulted in increased CEA levels in terms of percentage of CEA-positive cells and mean fluorescence values, as indicated by FACS analysis. However, drug combination did not induce CEA expression higher than that provided by single agents alone. Treatment with 5-FU or with IFN produced a reduction of the total number of viable cells. Moreover, Western blot analysis revealed that exposure of cancer cells to each drug was followed by a substantial increase of the total cellular CEA content. On the contrary, 5-FU in combination with IFN did not increase the expression of the antigen more than that obtained by single agents. Noteworthy, exposure of CEA-negative cells from adjacent normal rectal tissue to both agents alone or in combination, did not result in CEA induction. In conclusion, the present results suggest new approaches aimed at (a) increasing the sensitivity of diagnostic procedures based on detection of CEA-positive tumor cells; (b) facilitating the recognition of CEA-positive cancer cells by immune responses induced by anti-CEA peptide vaccines.

Sequential molecular monitoring of chimerism in chronic myeloid leukemia patients receiving donor lymphocyte transfusion for relapse after bone marrow transplantation.

Recent observations of chimerism in patients relapsed following an allotransplant suggest the persistence of immunotolerance, thus offering a biologic rationale for the use of donor lymphocyte transfusion (DLT). In this study, we have analyzed by PCR amplification of several VNTR regions, sequential bone marrow and peripheral blood DNA samples in four patients who received DLT for CML relapse after bone marrow transplantation. Prior to DLT, all patients showed mixed chimerism in peripheral blood cells while two had mixed chimerism and two no chimerism in the BM. None of these four patients showed evidence of chimerism at the cytogenetic level (all had 100% +ve metaphases). After DLT, a complete hematologic and molecular remission (ie disappearance of the BCR/ABL fusion transcript) was obtained in the two patients who had bone marrow mixed chimerism prior to DLT. The two patients without evidence of marrow chimerism prior to DLT converted to a pattern of mixed chimerism after DLT, but both developed a severe bone marrow aplasia occurring at day 56 and 36, respectively. With regard to the sequential analysis of bone marrow chimerism after DLT we observed that: (1) the disappearance of BCR/ABL +ve cells paralleled the conversion to a pattern of full donor chimerism; and (2) the time interval to achieve CR was inversely correlated with the percentage of donor DNA in bone marrow. In conclusion, we have shown here that the assessment of bone marrow pre-DLT chimerism by PCR analysis might predict the response in patients with favorable characteristics, and also might identify patients at high risk of developing severe myelosuppression.