The recombinant chimeric human parainfluenza virus type 1 vaccine candidate, rHPIV3-1cp45, is attenuated, immunogenic, and protective in African green monkeys

A recombinant live-attenuated chimeric human parainfluenza virus type 1 (HPIV1) candidate vaccine was previously generated by replacing the fusion (F) and hemagglutinin-neuraminidase (HN) glycoprotein open reading frames (ORFs) of the HPIV3 candidate vaccine, rHPIV3cp45, with those of wild-type HPIV1. Previously, this recombinant chimeric virus, designated rHPIV3-1cp45, exhibited a greater level of the temperature sensitivity of replication in vitro and a greater level of attenuation of replication in the respiratory tract of immunized hamsters when compared to its HPIV3cp45 parent virus. In the present study, rHPIV3-1cp45 was evaluated for its level of attenuation and efficacy in African green monkeys (Cercopithecus aethiops), a primate in which both HPIV1 and HPIV3 wild-type viruses replicate efficiently. The rHPIV3-1cp45 candidate vaccine was as restricted in replication in the upper and lower respiratory tract as its thoroughly characterized rHPIV3cp45 parent indicating that the attenuating mutations present in the rHPIV3cp45 backbone specified an appropriate level of attenuation of rHPIV3-1cp45 for primates. The level to which rHPIV3-1cp45 replicated in the respiratory tract of African green monkeys was also sufficient to induce a strong immune response to HPIV1 and provided protection against challenge with wild-type HPIV1. These results provide a basis for further evaluation of this HPIV1 candidate vaccine in humans.     

One hundred and eleven cases of breast conservation treatment with simultaneous reconstruction at the European Institute of Oncology (Milan)

AIMS AND BACKGROUND: Breast conserving treatment (BCT) should provide similar quality of local control as mastectomy and avoid psychological distress due to mutilation. Randomized trials have demonstrated the value of conservative surgery for small tumors. Several publications have indicated the possibility of improving the cosmetic result when quadrantectomy is combined with plastic surgery. These papers focused on two techniques involving reduction mammaplasty and latissimus dorsi flap procedures. At the European Institute of Oncology (EIO) we use various plastic procedures to reshape the breast and to improve symmetry. The choice of these techniques depends on tumor size and location, as well as on breast volume. METHODS AND STUDY DESIGN: In two years (1995 and 1996) 111 patients were treated at the EIO with quadrantectomy and concomitant plastic surgery. Preoperative tumor staging was as follows: T1 57.5%, T2 29%, T3 4.5%, Tis 8%, and sarcoma 1%. The tumor locations were upper quadrant 50%, lower quadrant 40%, and central quadrant 10%. The plastic surgery techniques used included local glandular flaps, areola transposition, mastopexy or classical reduction mastoplasty procedures, the round block technique, prosthesis insertion, and distal musculocutaneous flaps. Cosmetic evaluation on the basis of predefined cosmetic criteria was carried out on photographs after a mean follow-up of 21 months. In 48 cases the patients' own rating of breast cosmesis was asked. RESULTS: The global results were good in 77.5%, fair in 17%, and poor in 5.5% of the patients. No statistical difference was observed between different tumor locations, although the percentage of good cosmetic results, which was similar in the upper and lower quadrantectomy groups, was slightly lower for centrally located tumors. With regard to the different techniques, we obtained 100% good results with the round block technique and the Grisotti flap, 87% good results with the inferior pedicle, 74% good results with the Lejour and superior pedicle techniques, 67% good results with the latissimus dorsi flap, and 58% good results with prosthetic implants. The outcome was less satisfactory when no contralateral mastoplasty was performed (14 of the 111 cases): 72% good, 14% fair, and 14% poor results. These differences were not statistically significant. The median weight of the specimens was 157 g, which is almost three-fold the usual weight in regular tumorectomies. Six carcinomas were found in contralateral breasts (4 DCIS and 2 infiltrating). CONCLUSIONS: The double-team approach (plastic surgeons and oncologists) to BCT may improve the final cosmetic result following large tumor excisions. It can also extend the indications for breast preserving surgery. Moreover, it allows surgical and histological exploration of the contralateral breast when a surgical procedure for symmetry is required.     

Carboplatin plus taxol is an effective third-line regimen in recurrent undifferentiated nasopharyngeal carcinoma

BACKGROUND: Recurrent undifferentiated nasopharyngeal carcinoma is a chemosensitive disease. Few third-line treatments have been reported. METHODS: Twelve patients (9 males, 3 females; median age 50 years, range, 20-62) with recurrent undifferentiated nasopharyngeal carcinoma were treated with carboplatin AUC 5.5 + paclitaxel (175 mg/m2, 3-hr infusion) on day 1 every 3 weeks. All patients had been previously treated for recurrent disease with a first-line cisplatin-based chemotherapy and a second-line therapy with low-dose continuous infusion 5-fluorouracil. RESULTS: Overall, 54 courses were given (median, 5; range, 2-6). Three patients (25%) obtained a partial response lasting 6, 10 and 26+ months, 1 (8.3%) a minimal response lasting 6 months, and 3 (25%) no change with a median duration of 5 months. The median survival time was 14 months for patients who had a partial or minimal response or no change, and 5 months for nonresponders. Median overall survival was 9.5 months (3-30+). The treatment was well tolerated, and toxicity was manageable. CONCLUSIONS: The combination has a good palliative role as third-line chemotherapy in recurrent undifferentiated nasopharyngeal cancer.     

Differential expression profiling of head and neck squamous carcinoma: significance in their phenotypic and biological classification

The genetic events associated with the development and progression of head and neck squamous carcinoma (HNSC) are largely unknown. We analysed 12 matched pairs of histologically normal squamous mucosa and tumor specimens from six conventional and six phenotypic variants HNSC to define the differentially expressed genes in these tumors. Parallel expression analysis of 8055 unique genes was performed, and the level of the hybridization signal for each gene was measured after normalization. Hierarchical cluster analysis of the expressed genes showed distinct inter- and intra-tumoral patterns in and between conventional squamous carcinoma and squamous carcinoma variants. We also identified 26 (0.32%) differentially expressed genes that were consistently different between matched pairs of normal and tumor specimens; a selected set of the overexpressed genes was validated using real-time quantitative RT-PCR. The majority of the genes were associated with differentiation and proliferation. Our study defines a set of genes that could form the basis for the construction of limited HNSC targeted expression array and in-depth studies and further highlights gene profile differences that may be useful in pathobiologic classification of HNSC.     

Antigen presenting cells transfected with LMP2a RNA induce CD4+ LMP2a-specific cytotoxic T lymphocytes which kill via a Fas-independent mechanism

Recent reports have demonstrated that EBV can be used as a target of specific CTL-based treatments in severe chronic EBV, immunoblastic B cell lymphoma and Hodgkin's disease (HD). Based upon the promising results form these in vivo studies, it has been suggested that an antigen-specific CTL-based immunotherapy may be of benefit in treating EBV-associated tumors such as HD and nasopharyngeal carcinoma (NPC) which express the potentially immunogenic antigens, LMP1 and LMP2a. Recent work form our group has demonstrated that LMP2a-specific CTLs may be generated in vitro using autologous antigen presenting cells which have been transfected with polyadenylated LMP2a RNA in the presence of a cationic lipid. In this study, we demonstrate that the presence of the lipid enhances dendritic cell (DC) transfection efficiency and appears to protect the intracellular LMP2a RNA from degradation by cellular RNAses. Significantly, these improvements resulted in the transfected DCs having a superior ability to stimulate autologous T cell proliferation. These LMP2a + DCs were used to stimulate LMP2a-specific effector cells which were predominantly a mixture of cytotoxic and helper CD4+ T cells. The molecular mechanisms whereby these CD4+ T cells lyzed their LMP2a-expressing targets was investigated and we show that, although expressing Fas ligand on their surface, LMP2a-specific CD4+ effector cells kill their targets using the Ca2+-dependent perforin/granzyme pathway which is the same mechanism used by CD8+ CTLs.     

Jejunum free flap in hypopharynx reconstruction: Case series

Background

Surgical treatment of hypopharyngeal cancers with extension to the retrocricoid region generally requires a circumferential pharyngolaryngectomy followed by a reconstruction of the removed segment of the upper digestive tract. Historically, many techniques have been used in order to achieve a safe and functional reconstruction. Jejunum interposition is generally considered the best reconstructive technique.

Methods

This study examines the details of the surgical technique, the complications, the oncological and the functional results in a series of 29 consecutive patients submitted to circumferential pharyngoesophageal resection for advanced hypopharyngeal cancer followed by reconstruction with a free flap of jejunum.

Results

Three of the transplants failed because of venous thrombosis. The overall success rate was 90%. There were no general complications. A good swallowing has been preserved in all our patients. All our patients where a phonatory prosthesis was positioned (20/29) were able to achieve speech following speech therapy and all were satisfied with their own capacity to communicate.

Conclusions

The prognosis of hypopharyngeal tumours (18–40% at 5 years) remains poor, but jejunum autografts are being shown to be an excellent choice for the reconstruction of the cervical hypopharyngo-oesophagus offering the patient fast rehabilitation and a reasonable quality of survival. Our experience confirm that this kind of reconstruction is safe with a good results in improving oncologic controls and restoring a good quality of life.     

Expression of cyclin B1 in the metaplasia-dysplasia-carcinoma sequence of Barrett esophagus

BACKGROUND: It is known that proliferation is deregulated progressively during carcinogenesis in Barrett esophagus (BE). Cyclin B1 is a key protein for the regulation of G2-M-phase transition during the cell cycle and is essential for initiation of mitosis. METHODS: Using immunohistochemistry, samples of Barrett metaplastic specialized epithelium (SE; n = 36 samples), low-grade dysplasia (LGD; n = 25 samples), high-grade dysplasia (HGD; n = 25 samples), and invasive adenocarcinoma (CA; n = 46 samples) derived from 50 esophagectomy specimens were investigated for the expression of cyclin B1. The number of cyclin B1 positive cells was determined semiquantitatively. In addition, in SE, LGD, and HGD samples, the pattern of cyclin B1 expression was assessed by determination of the presence of positive cells in four mucosal compartments: the deep glandular zone, the lower crypt zone, the upper crypt zone, and the luminal surface. RESULTS: Cyclin B1 expression was found in all lesions under investigation. Regarding the percentage of positive cells, a marked increase of cyclin B1 positive cells was observed in SE samples compared with LGD samples and in HGD samples compared with CA samples (chi-square test; P < 0.0001), nevertheless showing a broad overlap between the different lesions. Concerning staining patterns, in the majority of SE samples (72.2%), cyclin B1 positive cells were restricted to the glandular zone and the lower crypt zone. In contrast, an expansion of cyclin B1 positive cells to superficially located zones of the mucosa (the upper crypt zone and/or the luminal surface) was observed in the majority of LGD samples (96.0%) and HGD samples (100%; P < 0.0001). CONCLUSIONS: Overexpression of cyclin B1 is a frequent and early finding in the metaplasia-dysplasia-carcinoma sequence in BE. It may contribute to the loss of growth control and, subsequently, to the development of tumors in this location.     

Rationale and definition of the lateral extension of the inguinal lymphadenectomy for vulvar cancer derived from an embryological and anatomical study

BACKGROUND AND OBJECTIVES: The objective of the present study was to define the location of the most lateral superficial inguinal node lying along the inguinal ligament, through an embryological and anatomotopographical study, in order to rationalize the lateral extension of the groin lymphadenectomy in vulvar cancer. METHODS: Sections of the upper portion of the femoral triangle belonging to three human fetuses, whose crown-rump (CR) length ranged from 70 to 310 mm, corresponding to a developmental age of 11 and 35 weeks, were studied. In addition, for an objective topographical evaluation of the disposition of the superficial inguinal lymph nodes, adult cadavers photographs of dissected Scarpa's triangle, reported in anatomical atlases, were analyzed. RESULTS: Both the embryological investigation and the anatomotopographical evaluation on cadavers photographs demonstrate that the most lateral superficial inguinal lymph node does not rise above the medial margin of the sartorius muscle, nor far lateral to the point where the superficial circumflex iliac vessels cross the inguinal ligament. CONCLUSIONS: On the basis of the present study, the authors believe that the superficial circumflex iliac vessels could represent the lateral surgical landmark, easily detectable, at which the inguinal lymphadenectomy should cease. Therefore, there is no need to extend the lateral excision to the anterior superior iliac spine. Finally, leaving the fatty tissue laterally to these vessels, some lymphatic channels could be preserved, decreasing the incidence and the entity of wound seroma and lymphedema.