Meta-Analysis on Induction Chemotherapy in Locally Advanced Nasopharyngeal Carcinoma.

PURPOSE: Concurrent chemo radiotherapy (CCRT) has been the standard of care in locally advanced nasopharyngeal carcinoma (LA-NPC) for many years. The role of induction chemotherapy (ICT) has always been controversial. This systematic review and meta-analysis investigates the value of adding ICT to CCRT in LA-NPC. MATERIALS AND METHODS: Two reviewers independently assessed the eligibility of randomized controlled trials (RCTs) comparing ICT followed by CCRT versus CCRT alone, including treatment-naive adult patients with histologically proven nonmetastatic LA-NPC. RESULTS: Eight RCTs with in total 2,384 randomized patients, of whom 69% had N2-N3 disease, were selected. ICT was the allocated treatment in 1,200 patients, of whom 1,161 actually received this. Treatment compliance varied, with a median rate of 92% (range, 86%-100%) of patients receiving all cycles of ICT. The percentage of patients completing radiotherapy was 96% and 95% [(Combined Risk difference(CRD)= 0.004; 95% Confidence Interval (CI) -0.001-0.01; p = 0.14)] in the ICT group and CCRT group, respectively, whereas chemotherapy during radiotherapy could be completed in only 28% of the ICT group versus 61% in the CCRT group (CRD, -0.243; 95% CI, -0.403 to -0.083; p = .003). Grade 3-4 acute toxicity was mostly hematologic during the ICT phase (496 events vs. 191 nonhematologic) and was predominant in the ICT group (1,596 events vs. 1,073 in the CCRT alone group) during the CCRT. Adding ICT to CCRT provided a significant benefit in overall survival (hazard ratio [HR], 0.680; 95% CI, 0.511-0.905; p = .001) and progression-free survival (HR, 0.657; 95% CI, 0.568-0.760; p < .001). CONCLUSION: Although ICT followed by CCRT is associated with more acute toxicity and a lower compliance of the chemotherapy during the CCRT phase, this association resulted in a clinically meaningful survival benefit. ICT should be considered as a standard option in patients with LA-NPC, but further study on optimal patient selection for this treatment is warranted. IMPLICATIONS FOR PRACTICE: Locally advanced nasopharyngeal carcinoma (LA-NPC) is a relatively common disease in some parts of the world, with a rather poor prognosis due to its high metastatic potential. The role of induction chemotherapy (ICT) has always been controversial. This meta-analysis found that ICT followed by concurrent chemoradiotherapy (CCRT) in LA-NPC is associated with a significant clinical improvement in both overall survival and progression-free survival compared with CCRT alone. ICT should be considered as a standard option in patients with LA-NPC.

Patterns of practice in palliative radiotherapy in Africa - case revisited.

AIMS: To investigate patterns of practice in palliative radiotherapy in Africa. MATERIALS AND METHODS: Fifteen centres in Africa provided detailed information about radiotherapy in both metastatic and locally advanced disease via a questionnaire. Information included general information (institution status, equipment, staff, patient number), radiotherapy and other treatment characteristics in bone metastasis, brain metastasis, metastatic spinal cord compression, lung and liver metastasis, as well as locally advanced tumours. RESULTS: The number of patients annually seen/treated ranged from 285 to 5000. Breast, cervix, head and neck, gastrointestinal and prostate cancer were the top five cancers overall. Eight (53%) institutions were without linear accelerators, four (27%) had a single one, whereas one institution each had two, three and four linear accelerators. The number of cobalt machines ranged from 0 to 2 (median 1). Most centres still prefer to use fractionated radiotherapy regimens over single-fraction regimens in bone metastasis, although most centres are now using single-fraction radiotherapy in retreatments. Radiotherapy in brain metastasis and metastatic spinal cord compression mostly conform to worldwide standards. Lung and liver metastases are rarely irradiated, largely as a consequence of the lack of modern radiotherapy technology. Locally advanced disease in various tumour sites was mostly palliated, in agreement with current evidence-based practices. CONCLUSIONS: African countries still lack adequate staffing and equipment to adequately address their clinical burden, being palliative in most cases. Emphasis should also be made on more rationally using existing capacities by using more of the single-fraction radiotherapy regimens, especially in bone metastasis.

Chimiotherapie des cancers du col de l'uterus au stade IV a vesical a l'Institut Curie de Dakar

Les cancers du col de l'uterus au stade IV ne relevent plus de la combinaison standard radio-chirurgicale. Aussi dans notre contexte marque par les difficultes de tous ordres pour correctement appliquer la chimiotherapie; nous avons pense opportun de retracer notre experience dans l'utilisation de moyen therapeutique dans les cancers du col uterin classes IVa vesical a Dakar. Sur 91 dossiers retenus; 80 ont concerne la mise en oeuvre de la combinaison chimiotherapie et radio-therapie selon diverses modalites. Les resultats enregistres dans la pratique de cette modalite nous poussent a proposer la procedure chimiotherapie neoadjuvante suivie de radiochimiotherapie dans notre contexte en l'absence de curietherapie pour ameliorer la survie

Primary testicular lymphoma.

Primary testicular lymphoma (PTL) is a rare disease accounting for 1% of non-Hodgkin's lymphoma. PTL occurs more frequently in older patients and is a potentially fatal disease. In the early stages (I and II), the treatment consists of orchidectomy followed by chemotherapy (CT) and prophylactic scrotal radiotherapy (RT) with/or without iliac and/or paraaortic lymph node RT. In the advanced stages (III and IV), CT is the treatment of choice whereas the place of scrotal RT is controverted. In both early and advanced disease intrathecal CT is warranted to prevent CNS relapse. New molecular approaches and/or more aggressive treatments are being explored.

Palliative radiation therapy practice for advanced esophageal carcinoma in Africa.

While numerous surveys of pattern of practices of palliative radiotherapy (RT) in advanced esophageal cancers have been published in developed countries, there is no such survey in African countries. During and after a regional training course by the International Atomic Energy Agency (IAEA) in palliative cancer care, a questionnaire was distributed to African RT centers to gather information about infrastructure and human resources available, and the pattern of practice of palliative RT for esophageal cancers. Twenty-four of the 35 centers (60%) completed the questionnaire. Twenty out of 23 (87%) centers treat patients with esophageal cancer presenting with dysphagia using external beam RT (16 centers external beam RT alone and 4 centers also use brachytherapy as a boost). Twelve (60%) centers prescribe RT doses of 30 Gy in 10 fractions and 2 centers 20 Gy in 5 fractions. Eighteen centers (78%) have low dose rate (LDR) brachytherapy, and 9 (39%) centers have high dose rate (HDR) brachytherapy. One center only used HDR brachytherapy alone to a dose of 16 Gy in 2 fractions over 8 days. RT remains a major component of treatment of patients with esophageal cancers in African countries. Still, there is a great variety among centers in both indications for RT and its characteristics for a treatment indication.

Radiochemotherapy for lung cancer in developing countries.

Radiochemotherapy has become a standard approach in locally advanced non-small cell lung cancer and limited disease small cell lung cancer. Most of the data supporting this observation come from the developed world and only extremely rarely have good-quality clinical trials been carried out in developing countries. It is therefore of paramount importance to put the experience of the developed world into the context of the limited resources and other health care problems of developing countries. In this overview, the problems with the implementation of such data are discussed. The necessity of carrying out clinical trials specifically designed to address the needs of developing countries is emphasised. The research on cheaper ways of radiochemotherapy combination should be encouraged. The specific national guidelines for local needs should be created and followed. The availability of radiotherapy equipment is of major importance, as radiotherapy has a pivotal role in non-surgical treatment of lung cancer, especially in the developing world.

Cerebellous metastases in patients with uterine cervical cancer. Two cases reports and review of the literature.

Brain metastases from cervical cancer are extremely rare. We report on two patients who developed cerebellous metastases following uterine cervical cancer. The interval between diagnosis of the primary cancer and diagnosis of brain metastasis was 8 months. The main complaint was symptoms of increased intracranial pressure and cerebellous syndrome. Surgical excision of the brain lesion followed by radiation therapy was performed in the first case. The second patient received palliative radiation therapy. The first patient died 8 months after diagnosis. The second patient is alive 2 months after diagnosis.

Prolactin gene expression in ovine and caprine mammary gland.

The presence of prolactin (PRL) mRNA in the mammary gland of lactating goats and sheep was demonstrated by Northern analysis and RT-PCR. This provides evidence that the PRL gene is transcribed in this tissue. This ectopic expression is not restricted to the lactational period, as PRL transcripts were also found during the last third of pregnancy. Comparison of mammary and pituitary PRL mRNAs showed that they are similar in size but less abundant in mammary gland. In addition, an 847-bp cDNA fragment amplified from mammary retrotranscripts, containing the entire coding region and the major part of the 5' and 3' untranslated regions (UTRs), was found to be identical in sequence to its pituitary counterpart. Primer extension analysis, performed to obtain further information on the structure of the mammary PRL mRNA, has shown that the 5' UTR is 56 nucleotides (nt) long for both species. This is comparable with the size (53 nt) found using the caprine pituitary RNA as template. These results strongly suggest that the PRL gene is not transcribed from a different promoter in mammary gland, as has been demonstrated for placental and lymphocyte cells, but is more likely transcribed from the pituitary-specific promoter. Finally, the presence of PRL mRNA in polysomal fractions suggests that PRL is synthesized in mammary cells.

Cloning and structural analysis of four genes encoding interferon-omega in rabbit.

By using an ovine interferon-tau (IFN-tau) cDNA probe, four recombinant phages were isolated from a rabbit genomic library and sequenced from nucleotides -450 to 1,300 relative to the CAP site. Each of the four rabbit genes contains an open reading frame of 595 nucleotides and code for proteins that exhibit structural characteristics of the interferon-omega (IFN-omega) family. They display more than 98% identity in their coding regions. The deduced amino acid sequences share > 96% sequence similarity. In contrast, the 5' and 3' noncoding regions have diverged considerably (approximately 50% identity). Amino acid comparisons of rabbit IFN-omega with IFN-omega of other species reveal the highest degree of identity with human (72%), followed by porcine (68%) IFN-omega. Rabbit IFN-omega displays only 57% sequence similarity with ovine IFN-tau. The coding regions of the four genes subcloned in a cytomegalovirus eukaryotic expression vector and transfected in monkey COS-7 cells direct the production of proteins that protect bovine and rabbit cells against vesicular stomatitis virus infection, thus demonstrating that these genes encode fully active IFN proteins. The expression of these genes was studied in Sendai-induced rabbit leukocytes. A single band of poly(A)+RNA hybridized with a rabbit IFN-omega probe under stringent conditions, whereas no IFN-omega transcript was detected with RNA isolated from uninduced leukocytes. Southern blot analysis suggest the existence of at least eight IFN-omega genes or pseudogenes in the rabbit genome.

Addition of a dipeptide spacer significantly improves secretion of ovine trophoblast interferon in yeast.

Yeast has been analysed for its potential to secrete an ovine member of the type-I interferon (IFN) family, trophoblastin (oTP-1). The processing potential of the yeast KEX2 gene product (KEX2p) was evaluated using gene oTP-1 fused to the pre-pro sequence encoding the pre-pro peptide of the yeast alpha-factor precursor. High-level accumulation of nonprocessed (unmatured) recombinant oTP-1 (re-oTP-1) was observed in the medium. In order to short-circuit the limiting activity of KEX2p and to obtain a fully matured re-oTP-1, secretion was directed using a pre::oTP-1 fusion, relying only on signal peptidase-dependent processing. However, secretion of oTP-1 was impaired. High-level secretion was restored when the gene product contained a peptide spacer between oTP-1 and the signal peptidase cleavage site. The oTP-1 variant was shown to have an extended N terminus. An N-extended form was examined further and shown to have the correct size. Surprisingly, the variant retained its in vitro and in vivo biological activities. This system is likely to represent a general method for high-level secretion of type-I IFNs.

Multiple mRNA species code for two non-allelic forms of ovine alpha s2-casein.

The two non-allelic forms of alpha s2-casein, occurring in ovine milk, differ by an internal deletion of nine amino acid residues, including both cysteine residues at positions 34 and 42 in the mature chain. Sequencing of several alpha s2-casein cDNA, isolated from the mammary cDNA library of a single lactating ewe, showed three new types which differed from that previously studied. In addition to the expected deletion of codons +34 to +42 affecting 30-40% of mRNA, another structural difference involving an internal stretch of 44 nucleotides in the 5' untranslated region, was found. S1-nuclease protection assays confirmed the existence of several types of the relevant mRNA and sequencing of in-vitro-amplified genomic DNA demonstrated the presence of the 44-nucleotide stretch in the alpha s2-casein transcriptional unit, thus ruling out the possibility of a cloning artefact. The different alpha s2-casein mRNA, four in terms of deletion and two in terms of nucleotide substitutions for a given ewe, can be readily explained by partial exon skipping and allelic differences, respectively. This assumption is well supported by the following observations: 5' and 3' ends of both deleted DNA fragments are similar to those of exons; sequences neighbouring the 44-nucleotide stretch of the genomic DNA perfectly match consensus sequences described for 3' and 5' ends of introns; the rather simple patterns observed on Southern blots of different enzymatic digests of genomic DNA strongly suggest the occurrence of only 1 copy alpha s2-casein gene/haploid genome. During the course of evolution, the alpha s2-casein-encoding gene has undergone many mutations and some of them might have occurred in regions corresponding to consensus splicing regions of the pre-mRNA. Thus, complete skipping of some exons might be responsible for the shorter sizes of rat and mouse alpha s2-casein mRNA. If so, the overall organization of the alpha s2-casein gene in the different species might be more similar than expected from structural comparisons of the cognate mRNA or caseins.

Expression of a biologically active ovine trophoblastic interferon using a baculovirus expression system.

Ovine trophoblast protein (oTP) an embryonic interferon, which plays a key role in maternal recognition of pregnancy, has been expressed in insect cells using a baculovirus expression system. A cDNA coding for oTP was inserted downstream of the strong polyhedrin promoter. Cells infected with recombinant virus produced biologically active oTP and greater than 90% was secreted into the culture medium during infection. High amount of antiviral activity were produced (up to 5 x 10(5) IU per ml of culture medium). Recombinant oTP (roTP) was purified by immunoaffinity chromatography and found to be identical to authentic oTP with respect to molecular mass and N-terminal amino acid sequence.

The bovine alpha-lactalbumin promoter directs expression of ovine trophoblast interferon in the mammary gland of transgenic mice.

A hybrid construct derived from ovine trophoblastin cDNA and bovine alpha-lactalbumin-encoding gene, was injected into the pronuclei of mouse eggs. In one of the resulting transgenic mouse lines, expression of the hybrid construct was detected and found to be limited to the mammary gland of lactating females which secreted active ovine trophoblastin. This strongly suggests that important cis-acting DNA sequences involved in tissue-specific expression of the bovine gene are located within the second half of the 3' untranslated region, or/and the proximal 5' and 3' regions flanking the transcriptional unit.

Prolactin receptor gene expression in the rabbit: identification, characterization and tissue distribution of several prolactin receptor messenger RNAs encoding a unique precursor.

The expression of the prolactin (PRL) receptor gene was studied in rabbit tissues by Northern blot and S1 mapping analysis of mRNA preparations. Rabbit mammary gland contained three major (10.5, 3.4, and 2.7 kb) and one minor (6.2 kb) prolactin receptor poly(A)+ RNA transcripts all of which contain the entire coding sequence of the long form of PRL receptor. Each of these mammary mRNAs hybridized equally well with cDNA sequences encoding either the NH2 terminal, middle, or COOH terminal part of the rabbit mammary PRL receptor. The four mRNAs differed only in their 5'- and 3'-untranslated regions. The 10.5 kb mammary transcript was further shown to represent a primary transcript of nuclear origin. Among the various rabbit tissues tested, male and female adrenals, mammary gland, ovaries, and jejunum contained the highest level of prolactin receptor mRNA. The prolactin receptor gene was also expressed at moderate to weak abundance in uterus, liver, kidney, pancreas, testis and seminal vesicles. No prolactin receptor mRNA species were detected in adult muscle, lung, total brain, placental cotyledons and spleen, and in thymus from young animals. In all the rabbit tissues examined, the same four PRL receptor poly(A)+ RNA transcripts identified in the mammary gland were expressed and no additional transcript(s) were detected. Variations in the relative proportion of the 10.5 kb transcript and the two smaller transcripts were observed, while the ratio of the 3.4 and 2.7 kb mRNAs remained unchanged. These findings ask for the role of these different transcripts generated in the rabbit, all of which encode the same long form of PRL receptor precursor but have heterogenous 5'- and 3'-untranslated regions. Moreover, they suggest that the various forms of PRL receptor mRNA originate through differential splicing of a single PRL receptor gene.

Cloning and structural analysis of two distinct families of ovine interferon-alpha genes encoding functional class II and trophoblast (oTP) alpha-interferons.

Ovine trophoblast protein (oTP) is a polypeptide secreted by ovine trophectoderm from day 11 to 21, which plays a key role in maternal recognition of pregnancy. Structural analyses established that oTP shares extensive homology with class II alpha-interferon (IFN-alpha II) subfamily. Previous screening of an ovine genomic DNA library probed with an oTP cDNA incidently resulted in the isolation of a functional IFN-alpha II gene and two relevant pseudogenes, as shown by sequence analysis and study of expression in eukaryotic COS cells. The expected oTP gene together with a cognate pseudogene was successfully isolated from the series of clones selected from another genomic library probed with the oTP cDNA, using two specific oligonucleotides, each one complementary to a region of oTP cDNA with little homology with the IFN-alpha II gene and related pseudogenes. Southern blotting of ovine genomic DNA indicated the existence of at least five trophoblast IFN-alpha genes or pseudogenes. Nucleotide sequence comparisons showed that the oTP gene exhibits a higher homology (90%) with bovine trophoblast IFN gene (Stewart et al. (1990) J. Mol. Endocrinol. 4, 275-282) than with oIFN-alpha II gene (70%), thus providing evidence that embryonic IFNs constitute a distinct subfamily of IFN-alpha s.

Co-expression of the proto-oncogene fos (c-fos) and an embryonic interferon (ovine trophoblastin) by sheep conceptuses during implantation.

Expression of the c-fos proto-oncogene by ovine conceptuses was analyzed by Northern and slot blots and indirect immunohistofluorescence in relation to the expression of the embryonic interferon-alpha (oTP) during implantation. c-fos was expressed initially in the trophoblast, and then in the allantois, when this tissue began to develop (day 17). In the embryonic tissues, the c-fos proto-oncogene was weakly expressed up to day 22 and increased thereafter. In the trophoblast, the expression of c-fos proto-oncogene was transient, occurring when the oTP gene was transcribed at a maximal level at the beginning of implantation (days 14-15), and decreased thereafter, following the pattern of oTP gene expression. This decline is due essentially to the arrest of c-fos and oTP gene expression by the trophoblastic cells which established cellular contacts with the uterine epithelium during the implantation process.

Identification and characterization of growth hormone receptor mRNA in the mammary gland.

The present report describes the first characterization of growth hormone (GH) receptor (GH-R) mRNA in the rabbit mammary gland. Northern blot analysis of poly(A)+ RNA isolated from several tissues of rabbit probed with a rabbit liver GH-R cDNA fragment revealed hybridization to only one transcript of 4.2 kb. A specific hybridizing signal appears in the mammary gland mRNA during gestation, when three different probes derived from liver GH-R cDNA and encoding respectively for extracellular, transmembrane and intracellular regions, were used. The signal is lower than in the liver but highly significant. These results indicate that the three regions are present and well conserved in the GH-R transcript found in the mammary gland. By S1 nuclease mapping analysis we demonstrated that the extracellular and transmembrane domains of mammary gland GH-R mRNA are strongly homologous to the liver GH-R mRNA. In addition, mammary gland GH-R mRNA is probably generated by mammary epithelial cells as demonstrated by the hybridization signal obtained using mRNA extracted from purified acini. The increase in the concentration of GH-R mRNA occurs during epithelial cell proliferation associated with a decrease in the proportion of adipocytes and connective cells at late gestation. The 4.2 kb GH-R mRNA species was also detected in ovine and porcine mammary glands during gestation, suggesting a probable expression of the related form of GH-R in these species.

Evidence for extended maintenance of the corpus luteum by uterine infusion of a recombinant trophoblast alpha-interferon (trophoblastin) in sheep.

Ovine trophoblastin (oTP) is a natural interferon of the class-II interferon-alpha subfamily. Recombinant ovine trophoblastin (r.oTP), produced by genetic engineering, was purified by anion-exchange HPLC. The product exhibited a high degree of homogeneity (greater than 98%), and similar immunological cross reaction and antiviral activity to natural oTP. Antiluteolytic activity of r.oTP was established by intrauterine injection in two groups of cyclic recipient ewes. Control group A included 10 ewes which received sterile BSA in saline twice daily for 8 days (from day 10-12 of oestrous cycle). Experimental group B included 17 ewes which received 80 micrograms (4 ewes), 170 micrograms (8 ewes) or 340 micrograms (5 ewes) r.oTP daily for 8 days. Maintenance of functional corpora lutea for 1 month or more was observed in 4 out of 5 ewes which received high doses of r.oTP. These results indicate that oTP alone extends luteal secretory activity.

Cellular localization of an embryonic interferon, ovine trophoblastin and its mRNA in sheep embryos during early pregnancy.

The ovine embryo produces an interferon named ovine Trophoblastin (oTP) which is involved in the maternal recognition of pregnancy and ensures the maintenance of progesterone secretion by the corpus luteum. We have used indirect immunohistofluorescence and in situ hybridization on histological sections to investigate the fate of this protein and its mRNA in ovine embryos from days 3 to 25 of pregnancy. The level of expression was measured by image analysis of the autoradiographs after in situ hybridization. Both techniques clearly demonstrated that oTP and its mRNA were specifically localized in the extra-embryonic trophoblast. Neither the embryonic cells, nor the yolk sac or the amniotic tissues produced the protein or its mRNA. The protein could be detected by d 11 of pregnancy in the elongated blastocyst. Maximum of expression is observed at d 14 and the level decreased by d 16 of pregnancy. The arrest of expression occurred in the regions of trophoblast which have established cellular contacts with the uterine epithelium during the implantation process.