Case report: Squamous carcinoma in an oesophageal foregut cyst

Cysts within the oesophageal wall may represent inclusion cysts, retention cysts or developmental cysts. Foregut duplications are developmental anomalies, which occur as a result of abnormal canalization of the foregut during intrauterine life. Malignant transformation is an extremely rare event occurring within oesophageal cysts, adenocarcinoma being the most common histology. We report a case of squamous cell carcinoma arising within an oesophageal cyst affecting the upper third of the oesophagus. The malignant cyst was not amenable to primary surgical resection and hence was treated using chemo-radiotherapy. The treatment gave good disease control, at the expense of a high oesophageal stricture. Chemo-radiotherapy is an alternative treatment modality to achieve long-term disease control in squamous cell carcinoma complicating oesophageal foregut cyst when primary surgical resection is not possible.     

Outcome and pattern of failure in pathologic stage I-II papillary serous carcinoma of the endometrium: implications for adjuvant radiation therapy

PURPOSE: To evaluate the outcome and patterns of failure in women with pathologic Stage I-II papillary serous carcinoma of the uterus and to discuss the implications for adjuvant radiation therapy (RT). METHODS: Twenty-three pathologic Stage I-II uterine papillary serous carcinoma patients were treated at our institution between 1980 and 2001. All underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy and assessment of peritoneal cytology. Pelvic and para-aortic lymph node sampling was performed in 12 and 8 patients, respectively. FIGO stages were as follows: IA = 3, IB = 8, IC = 6, IIA = 5, and IIB = 1. Adjuvant therapies included the following: 9 none, 10 RT (6 pelvic, 1 vaginal brachytherapy, 3 both), 4 chemotherapy, and 1 hormonal therapy. No patient received whole abdominal radiation therapy or para-aortic RT. Disease-free survival, pelvic recurrence-free survival, and cause-specific survival were estimated using the method of Kaplan-Meier, and prognostic factors were analyzed by the log-rank test. Median follow-up was 38.7 months (range: 3-109 months). RESULTS: The 5-year actuarial disease-free survival and cause-specific survival for the entire group was 41% and 73.6%, respectively. Nine patients developed recurrent disease. Five failed in the pelvis, of which 4 relapsed in the vagina. No pelvic failures occurred in women treated with adjuvant RT. Patients treated with adjuvant RT had a better 5-year actuarial pelvic recurrence-free survival (100% vs. 57.5%, p = 0.06) than patients treated with surgery alone. Two patients failed in the abdomen. However, neither developed an isolated abdominal recurrence. Six patients failed in distant sites, primarily the lungs and bone. CONCLUSION: Although patients with pathologic Stage I-II uterine papillary serous carcinomas have organ-confined disease, recurrence is common, particularly in the pelvis and distant sites. Our results suggest that adjuvant RT reduces the risk of pelvic failure. Contrary to traditional assumptions, however, abdominal recurrence was uncommon in our patients, despite the lack of whole abdominal radiation therapy. Our results support the use of pelvic RT in these patients. Future studies should investigate the role of adjuvant chemotherapy.     

Local delivery of IL-1 alpha polymeric microspheres for the immunotherapy of an experimental fibrosarcoma

The immunotherapeutic effects of interleukin-1 alpha (IL-1 alpha) encapsulated within 1-5 microns-diameter poly (D, L-lactide) microspheres and delivered intratumorally into fibrosarcoma-bearing mice were investigated. Such microspheres are avidly taken up by macrophages, and directing IL-1 alpha into these cells may activate them to participate in antitumor responses in vivo. Treating of tumor-bearing mice with IL-1 alpha microspheres has increased their survival rate, as compared with control mice, untreated or treated with microspheres containing bovine serum albumin (BSA). In 20% of the IL-1 alpha-treated mice, a complete tumor regression was observed. The timing of treatment with IL-1 alpha microspheres was crucial; optimal survival and regression rates were observed in mice treated 24 hr postinjection of the tumor cells. Administration of three doses of IL-1 alpha microspheres on days 1, 8, and 15 postinjection of tumor cells resulted in longer survival rates. Histopathology studies on regressed tumors revealed extensive areas of tumor cell degeneration and necrotic tissue surrounded by a large number of inflammatory cells. A similar picture was observed when IL-1 alpha microspheres were administered into the footpad of control mice, whereas the tissue reaction to BSA microspheres was much milder. Thus, it appears that tumor regression is mainly due to the antitumor effects of IL-1 alpha. Further studies are being aimed at increasing the immunotherapeutic efficiency of microspheric IL-1 alpha, used as a single treatment or in combination with other treatment modalities.     

Risk factors for multiple oral premalignant lesions

Oral leukoplakia, oral submucous fibrosis and erythroplakia are 3 major types of oral premalignant lesions. Multiple oral premalignant lesions may possibly develop due to field cancerization, where carcinogenic exposures can cause simultaneous genetic defects to the upper aerodigestive tract epithelium, putting the epithelium at high risk for development of premalignant lesions at different stages of carcinogenesis. There have been no epidemiological studies on risk or protective factors of the disease. A case-control study was conducted with data from the baseline screening of a randomized oral cancer screening trial in Kerala, India. A total of 115 subjects with multiple oral premalignant lesions (8-10% of oral premalignant lesions in our case series) were included: 64 subjects with oral leukoplakia and oral submucous fibrosis, 19 subjects with oral leukoplakia and erythroplakia, 22 subjects with oral submucous fibrosis and erythroplakia and 10 subjects with all 3 lesions. Individuals without oral lesions were considered controls (n=47,773). The odds ratio (OR) for ever tobacco chewers was 37.8 (95% confidence interval (CI)=16.2-88.1) when adjusted for age, sex, education, BMI, smoking, drinking and fruit/vegetable intake. Dose-response relationships were seen for the frequency (p<0.0001) and duration of tobacco chewing (p<0.0001) with the risk of multiple oral premalignant lesions. Whereas alcohol drinking may possibly be a risk factor for multiple oral premalignant lesions, smoking was not associated with the risk of multiple oral premalignant lesions (OR=0.9, 95%CI=0.5-1.7). The results suggest that tobacco chewing was the most important risk factor for multiple oral premalignant lesions and may be a major source of field cancerization on the oral epithelium in the Indian population.     

Estimation of an optimal radiotherapy utilization rate for breast carcinoma: a review of the evidence

BACKGROUND: Radiotherapy utilization rates for breast carcinoma vary widely, both within and between countries. Current estimates of the proportion of patients with carcinoma who optimally should receive radiotherapy are based either on expert opinion or on the measurement of actual utilization rates, and not on the best scientific evidence. METHODS: To develop an evidence-based benchmark for radiotherapy utilization in patients with breast carcinoma, the authors undertook a systematic review of treatment guidelines on the use of radiotherapy for breast carcinoma. A decision tree was constructed, and the proportions of patients with clinical features that lead to a decision for radiotherapy were obtained from epidemiological data. This ideal utilization rate was compared with the utilization rates of radiotherapy over the last decade for breast carcinoma in Australia and internationally. RESULTS: The proportion of patients with breast carcinoma in whom radiotherapy would be recommended according to the best available evidence was calculated at 83% (95% confidence interval, 82-85%) of all patients with breast carcinoma. A review of actual radiotherapy utilization rates for breast carcinoma revealed that, in clinical practice, actual utilization rates varied between 24% and 71%. CONCLUSIONS: A substantial difference was found between the recommended optimal utilization of radiotherapy based on evidence and the actual rates reported in clinical practice. The reasons for these differences need to be examined, and a plan for addressing the suboptimal use of radiotherapy needs to be implemented. Cancer 2003.     

Effect of retinoic acid on ferritin H expression during brain development and neuronal differentiation

We have previously shown that brain ferritin H expression, which has been associated with iron utilization, is developmentally regulated. Because retinoic acid (RA) regulates gene expression and is involved in cellular differentiation, we tested the hypothesis that RA regulates ferritin H during brain development and neuronal differentiation. RA, administered to rats on postnatal day 1, produced a 4-fold increase in brain ferritin H mRNA (p < 0.01) after 24 h. To examine whether RA-stimulated neuronal differentiation contributed to this up-regulation, ferritin and ferritin H mRNA were measured in human neuronal precursor cells (NTera-2, NT2) before and after 4-weeks of RA-stimulated differentiation into post-mitotic neurons. Differentiation resulted in a 2-fold increase in both ferritin and ferritin H mRNA (p < 0.05). Immunocytochemistry and Northern analysis showed significant elevations in ferritin expression that began as early as 24 h after RA treatment. While there was also a significant increase in the labile iron pool after RA treatment, this did not occur until 72 h. These data show that RA regulates ferritin H expression during rat brain development and neuronal differentiation and suggests a new role for RA in brain iron metabolism.     

Human factor Xa bound amidine inhibitor conformation by double rotational-echo double resonance nuclear magnetic resonance and molecular dynamics simulations

Double rotational-echo double resonance (double REDOR) NMR was used to investigate the conformation of a (13)C-, (15)N-, and (19)F-labeled inhibitor (Berlex Biosciences compound no. ZK-806299) bound to human factor Xa. Conformationally dependent carbon-fluorine dipolar couplings were measured by (13)C[(19)F] REDOR. Natural abundance carbon signals in the full-echo spectra were removed by (13)C[(15)N] REDOR. Major and minor binding modes were suggested by the NMR data, but only the former had adequate signal to noise for distance determinations. Molecular dynamics simulations restrained by double-REDOR-determined intramolecular (13)C-(19)F distances revealed two models for the dominant binding mode that are consistent with the NMR data. We conclude that ZK-806299 binds similarly to both FXa. Moreover, it appears to bind to FXa in a fashion previously demonstrated for ZK-807834, a more selective FXa inhibitor.     

The biological basis of a comprehensive grading system for the adverse effects of cancer treatment

As described in the previous article in this issue by Trotti et al, there have been major changes in the philosophy and scope of the new National Cancer Institute comprehensive grading system for treatment-related toxicities, Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). The most prominent changes are the merging of early and late effects criteria into a single uniform document and the development of criteria that cover all treatment modalities. In this article, we briefly outline the biological support for the new grading system in the context of our current knowledge base. The clinical consequences of radiotherapy in normal tissue have been classically grouped temporally, into early and late effects, using a somewhat arbitrary dividing line, 90 days after commencement of radiotherapy. This definition was developed in an era of standard fractionation used alone or in simple sequential programs involving other modalities. However, most patients are now managed with multiple highly integrated modalities, often augmenting tissue injury and limiting our ability to ascribe any given effect to a particular modality. The use of complex concurrent or hybrid (concurrent/sequential) schedules also undermines the usefulness of a simplistic temporally defined early-late construct. Moreover, there is growing recognition that chemotherapy and surgery produce inherent long-term biologic and clinical effects as well. Our basic understanding of the roles that surgery, chemotherapy, and radiation play in normal tissue response has expanded over the last decade because of vastly improved molecular techniques. The original biologic paradigm viewing acute and late tissue injury as a continuum of response and repair has been strengthened by these additional laboratory investigations. The expression of toxicity over time has been shown to be caused by a variety of cellular, tissue, environmental, and host factors. We continue to elucidate the roles of DNA damage, cytokines, chemokines, and associated inflammation, which lead in some cases to perpetuation of the wound-healing response, progressive tissue fibrosis, and vascular compromise. The continuum model of tissue injury supports the recent changes in the common toxicity grading system. It also provides insights into potential targets and strategies for modulating response, which may in turn lead to effective interventions for altering the therapeutic ratio.     

Complex reconstruction in the management of extremity sarcomas

The concept of limb-sparing surgery for bony sarcomas has evolved over the past 25 years. Today, more than 90% of patients treated by surgeons with expertise in musculoskeletal oncology undergo successful limb-sparing procedures. Many large centers have abandoned osteochondral allografts and resection arthrodesis for the reconstruction of segmental bone and joint defects in favor of metallic endoprostheses. Endoprosthesis survival rates now exceed 85% at 5 years for reconstructions about the knee, which is the most common site for primary bone sarcomas. In the shoulder girdle, the type of resection and soft-tissue reconstruction is probably more important than the type of implant. Extra-articular resection is recommended for most large stage IIB tumors. New expandable prostheses able to be lengthened nonoperatively hold promise for very young children with lower extremity sarcomas. Allograft-prosthetic composites and proximal femoral prostheses provide reliable and stable hip reconstructions. Acetabular components are not required, but attention to capsular reconstruction is necessary to prevent hip dislocation. Techniques of scapula replacement have advanced and provide better upper extremity function after scapula resection than resection alone.