Does radical trachelectomy (RT) during pregnancy have higher obstetrical and oncological risks than RT before pregnancy?

PURPOSE: Radical trachelectomy (RT) with pelvic lymphadenectomy has become a new treatment option for young patients with uterine cervical cancer stages 1A2-1B1 who desire the preservation of their fertility. However, the application of RT for pregnant patients is still controversial. We comparatively studied both obstetrical and oncological outcomes of pregnant patients who underwent vaginal RT during pregnancy and those who underwent vaginal RT before pregnancy. METHODS: Both obstetrical and oncological results of eight patients who underwent vaginal RT with pelvic lymphadenectomy during pregnancy in our institute between 2010 and 2020 (Group A), and ten pregnant patients who underwent vaginal RT with pelvic lymphadenectomy before pregnancy during the same period (Group B) were reviewed based on their medical charts. RESULTS: There were neither significant differences in blood loss, surgical time, or surgical completeness between Group A and Group B, nor were there significant differences in obstetrical outcomes between the two groups. However, two of the eight patients in Group A had recurrence of the cancer. None of the patients in Group B has shown any signs of recurrence thus far. CONCLUSION: Vaginal RT during pregnancy does not affect the obstetrical prognoses of patients with early invasive uterine cervical cancer, and it might be a tolerable treatment modality for them. However, oncologically, it should be performed carefully as there is a risk of recurrence.

A new large-caliber trocar for percutaneous endoscopic gastrostomy by the introducer technique in head and neck cancer patients.

BACKGROUND AND STUDY AIMS: In many patients, percutaneous endoscopic gastrostomy (PEG) can be limited by digestive tract stenosis. PEG placement using an introducer is the safest alternative for this group of patients, but the available devices are difficult to implement and require smaller-caliber tubes. The aim of this study was to evaluate the modification of an introducer technique device for PEG placement with regard to the following: procedure feasibility, possibility of using a 20-Fr balloon gastrostomy tube, tube-related function and problems, complications, procedure safety, and mortality. PATIENTS AND METHODS: Between March 2007 and February 2008, 30 consecutive patients with head and neck malignancies underwent introducer PEG placement with the modified device and gastropexy. Each patient was evaluated for 60 days after the procedure for the success of the procedure, infection, pain, complications, mortality, and problems with the procedure. RESULTS: The procedure was successful in all cases with no perioperative complications. No signs of stomal infection were observed using the combined infection score. The majority of patients experienced mild-to-moderate pain both in the immediate postoperative period and at 72 hours. One major early complication (3.3%) and two minor complications (6.7%) were observed. No procedure-related deaths occurred during the first 60 days after the procedure. CONCLUSION: The device modification for PEG using the introducer technique is feasible, safe, and efficient in outpatients with obstructive head and neck cancer. In this series, it allowed the use of a larger-caliber tube with low complication rates and no procedure-related mortality.

An evaluation of gastric scintigraphy pre- and postpyloroduodenal peptic stenosis dilation.

BACKGROUND: The usual treatment of pyloroduodenal peptic stenosis has been mainly surgical, through pyloroplasty or gastric resection, with or without vagotomy. Since the first description of treatment for this peptic complication by endoscopic balloon dilation perfomed by Benjamin in 1982 [2], this procedure has become a therapeutic option in association with the medical treatment of peptic disease. The aim of this study is to evaluate the results involving clinical, endoscopic, and gastric emptying scintigraphy parameters. METHODS: Between August 1998 and February 2000, 20 patients with pyloroduodenal stenosis refractory to conservative treatment were treated at the Gastrointestinal Endoscopy Unit of the University of São Paulo Medical School. All patients who presented clinical manifestations of pyloroduodenal stenosis underwent upper gastrointestinal endoscopy to confirm peptic stenosis. Biopsy of the narrowing for the confirmation of a benign disease and gastric biopsy for Helicobacter pylori detection were performed. The treatment consisted of dilation of the stenosis with type TTS (Through The Scope) hydrostatic balloon under endoscopic control, treatment of Helicobacter pylori infection, and gastric acid suppression with oral administration of proton pump inhibitor. All patients, except one who was excluded from this study, were submitted to a clinical endoscopic assessment and gastric emptying evaluation by ingestion of (99m)Tc before and after the treatment. Endoscopic evaluation considered the diameter of the stenotic area before and after treatment. A scintigraphic study compared the time of gastric emptying before and after balloon dilation. RESULTS: Nineteen patients completed treatment by hydrostatic balloon dilation. Clinical symptoms such as bloating (p < 0.0001), epigastric pain (p = 0.0159), gastric stasis (p < 0.0001), and weight gain (p = 0.036) showed significant improvement. The diameter of the stenotic area increased significantly (p < 0.01) after the dilation treatment as well as a better gastric emptying of (99m)Tc (p < 0.0001). CONCLUSION: The dilation of the peptic pyloroduodenal stenosis using a hydrostatic balloon is a safe and effective procedure. The evaluation with gastric scintigraphy by ingestion of (99m)Tc is an effective method of assessment for the improvement of gastric function, because its results corresponded to the clinical improvement after endoscopic treatment.

Telomerase activity in small-cell and non-small-cell lung cancers.

BACKGROUND: Telomerase is an enzyme that adds hexameric TTAGGG nucleotide repeats onto the ends of vertebrate chromosomal DNAs (i.e., telomeres) to compensate for losses that occur with each round of DNA replication. Somatic cells do not have telomerase activity and stop dividing when the telomeric ends of at least some chromosomes have been shortened to a critical length. It has been suggested that immortalized cells (including some, but probably not all, cancer cells) continue to proliferate indefinitely because they express telomerase. PURPOSE: To investigate whether expression of telomerase is a prerequisite for the development of naturally occurring human cancers, we assayed the levels of telomerase activity in specimens of human lung tumor and adjacent normal tissue. METHODS: Using a polymerase chain reaction-based assay, we examined telomerase activity in 136 primary lung cancer tissues and 68 adjacent noncancerous tissues obtained by surgical resection. We also studied telomerase activity in four primary and 23 metastatic lesions obtained through biopsy, (two patients) or autopsy (10 patients). Relative telomerase activity levels were estimated by serial dilutions of extracts prepared from the specimens. Telomerase activity was also assayed in extracts of cells present in pleural fluids from three patients with adenocarcinoma of the lung. RESULTS: Among surgically resected samples, telomerase activity was detected in 109 (80.1%) of 136 primary lung cancer tissues and in three (4.4%) of 68 normal adjacent tissues. All 11 surgically resected specimens of primary small-cell lung cancer (from 11 patients) revealed high levels of telomerase activity, whereas the activity ranged from undetectable to high levels in the 125 surgically resected specimens of primary non-small-cell lung cancer tissue (from 125 patients). Generally, high levels of telomerase activity were observed in metastatic lesions and tumors with altered telomere length. A few primary and, surprisingly, some metastatic tumors did not appear to have detectable telomerase activity. Telomerase activity was, however, detected in cells present in all tested pleural fluids obtained (from three patients with adenocarcinoma of the lung). CONCLUSION: The subset of non-small-cell lung cancers that exhibits only low or undetectable levels of telomerase activity may contain primarily mortal cancer cells. Cancers that exhibit high levels of telomerase activity, such as all of the small-cell lung cancers examined in this study, are likely to consist mainly of immortal cells. IMPLICATIONS: Telomerase activity may be useful both as a diagnostic marker to detect the existence of immortal lung cancer cells in clinical materials and as a target for therapeutic intervention.

Alterations in telomeric repeat length in lung cancer are associated with loss of heterozygosity in p53 and Rb.

In the two-stage model of controlling cellular senescence in cultured human fibroblasts, retinoblastoma (Rb) and p53 proteins may be key factors regulating the mortality stage 1 mechanism. In addition, the critical loss of telomeric DNA due to the end-replication problem may result in the mortality stage 2 mechanism. Cells which acquire telomerase activity can overcome the M2 mechanism by stabilizing telomere length and thus become immortal (telomere hypothesis). At present it is known whether cellular immortality is a prerequisite for all human cancers. To investigate this question and the applicability of the two-stage model to human cancers, we analysed the relationship between alterations of telomere length and other genetic changes in lung cancer. Among 60 primary lung cancer tissues, telomere length alterations were observed in 16 tumors (26.7%) including 14 with short and two with elongated telomeres. Ten of them revealed allelic loss of both p53 and Rb genes, and remaining six showed no abnormalities in both genes. We propose that inactivation of both p53 and Rb genes may promote cell divisions causing telomere shortening in lung cancer as in the two-stage model, while there may be another pathway to overcome both M1 and M2 mechanisms, especially for adenocarcinoma.

p53 gene mutations are associated with shortened survival in patients with advanced non-small cell lung cancer: an analysis of medically managed patients.

Mutations in the p53 gene are common in many cancers. Nevertheless, the relationship between mutations of this tumor suppressor gene and patient survival in non-small cell lung cancer (NSCLC) remains unclear. Interpretation of prior studies of patient outcomes are complicated by the inclusion of both surgical and nonsurgical patients. To better isolate the potential effects of p53 gene mutations per se on tumor progression, we chose to examine patients with advanced disease in whom surgery was not performed (stages IIIA, IIIB, and IV). We have used PCR-denaturing gradient gel electrophoresis, a sensitive and specific method for the detection of a variety of p53 mutations in cytology or biopsy specimens, to evaluate the prognostic significance of p53 gene mutations in nonsurgical patients with advanced NSCLC. In 70 consecutive medical patients, p53 mutations were found in 29 cases (41%) at the time of initial diagnosis. Followed prospectively, patients with p53 mutations had a significantly reduced survival time after diagnosis than those without mutations (median survival, 17 versus 39 weeks; P = 0.0003) independent of other clinical factors. This abbreviated survival occurred in both patients who received chemotherapy (n = 39, P = 0.002) or best supportive care (n = 31, P = 0.018). These results indicate that mutations of the p53 gene in patients with NSCLC who do not undergo surgical resection portends a significantly worse prognosis.

Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese.

Polymorphisms at three loci in the thiopurine methyltransferase (TPMT) gene are known to be responsible for azathioprine and 6-mercaptopurine (6MP) toxicity. Among them, only TPMT*3C variant allele with A719G mutation was found in 15/522 (2.9%; 17/1044 alleles; 1.6%) Japanese individuals including two homozygotes. The allele frequency was different from that in Caucasians, and investigation of TPMT polymorphisms with consideration of ethnic differences before administration of azathioprine or 6MP may provide clinically useful information.

Whole-blood incubation method to study neutrophil cytoskeletal dynamics.

To reduce artifactual effects in the study of filamentous (F)-actin dynamics in neutrophils, we have developed a whole-blood incubation method. Neutrophils in whole blood contained significantly less basal F-actin than did separated neutrophils. Although the peak relative F-actin content of neutrophils in whole blood after formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation was significantly higher than that of separated neutrophils at 10(-9) to 10(-6) M fMLP concentrations (p < 0.05), there was no significant difference in increase in mean fluorescence intensity and the EC50 (concentration of stimulant giving a half-maximum response). On the other hand, the EC50 of platelet-activating factor (PAF) between separated neutrophils and whole-blood-incubated neutrophils differed significantly (1.6 +/- 1.1 x 10(-9) M in separated neutrophils and 2.0 +/- 0.7 x 10(-8) M in whole-blood-incubated neutrophils, p < 0.05). The whole-blood incubation method described presently reduces the sample volume, cost and time needed to separate neutrophils, prevents neutrophil activation during separation, and reserves all blood components that may affect neutrophil function. For these reasons, the conditions adopted in the present method are thought to simulate well neutrophils circulating in vivo and the method would be preferable to other neutrophil function tests performed to study actin dynamics.

Suppressed antidonor MLC responses in renal transplant candidates conditioned with donor-specific transfusions that carry the recipient's noninherited maternal HLA haplotype.

Forty-seven patients with end-stage renal disease were entered into a donor-specific transfusion protocol consisting of three infusions of whole blood every two weeks prior to transplantation. Fourteen of the patients became sensitized following transfusion and were not transplanted. Thirty-one patients received a transplant from the DST donor and have an estimated two-year graft survival of 97%, three-year survival of 88%, and four-year survival of 69%. Cells of eleven of the 36 recipients tested in one-way MLC before and two weeks after completion of DST exhibited a significantly decreased antidonor MLC response. Deletion of CD8+ positive lymphocytes from suppressed MLCs resulted in restoration of antidonor MLC reactivity in four of six patients. An analysis of the family HLA profile in patients exhibiting a decreased donor-directed MLC response revealed a significant (P less than 0.02) association between decreased MLC reactivity following DST and the expression of noninherited maternal HLA antigens by cells of the transfusion donor. These alterations in cellular immune responses noted in some patients following DST are consistent with the appearance of specific antidonor T suppressor cells as a result of donor-specific transfusion.

Telomerase activity in malignant ovarian tumors with deregulation of cell cycle regulatory proteins.

Using a semiquantitative telomeric repeat amplification protocol assay, telomerase-positive frequencies and enzyme levels were measured. Out of 95% of 49 human ovarian tumors, the highest level of telomerase activity was observed in malignant tumors. Furthermore, by immunohistochemical staining of cell cycle regulatory proteins (pRB, p16, cyclin D1, cyclin E and p53) at the G1 checkpoint, we evaluated the relation between each protein alterations and the levels of telomerase activity. We could not demonstrate a clear relation with each molecule except for cyclin E, but suggesting that aberrant accumulation of these proteins was considered as a reason for telomerase deregulation, which may play an essential role in the pathway of telomerase regulation.

Glutathione S-transferase-pi gene expression and platinum drug exposure in human lung cancer.

We examined the association between the gene expression levels of glutathione S-transferase-pi (GST-pi) and platinum drug exposure in human lung cancer. First we monitored GST-pi gene expression levels in two lung cancer cell lines and in peripheral mononuclear cells of ten previously untreated lung cancer patients after platinum drug exposure. Next we examined GST-pi gene expression levels in 40 lung cancer autopsy specimens. The GST-pi gene expression levels were assessed by the quantitative reverse transcription-polymerase chain reaction or Northern blot analysis. The GST-pi gene expression was not induced by platinum drugs either in vitro and in vivo within 24 h of exposure. In contrast, GST-pi gene expression levels in lung cancer tissues of patients who had been exposed to platinum drugs at least 1 month before death were significantly higher than that in those of patients who had not been exposed. These results suggest that GST-pi gene expression is associated with chronic exposure to platinum drugs in lung cancer and/or the stress response to xenobiotics.

Former poison gas workers and cancer: incidence and inhibition of tumor formation by treatment with biological response modifier N-CWS.

Mustard gas is known to have mutagenic and carcinogenic effects on animal and human cells. In this report, 1,632 male Japanese who worked in poison gas factories at some time between the years 1927 and 1945 were studied to determine comparative risk for development of cancer, the reference population being data on Japanese males overall. The standardized mortality ratio (SMR) for lung cancer in workers directly and indirectly involved in the production of mustard gas was significantly elevated. In addition, SMR for lung cancer in worker who had worked for more than 5 years was also significantly elevated. Thus, poison gas workers who had engaged in the production of mustard gas or related work for more than 5 years are a high-risk group for lung cancer. Under the cancer preventive program, Nocardia rubra cell-wall skeleton (N-CWS) was administered to 146 former poison gas workers. During a 4.5 year observation period, development of cancers was found in 7 treated workers and 17 untreated controls. After elimination of the influence of smoking level, a significant suppression of development of cancers was noted in the N-CWS-treated workers as compared to the untreated controls. Although the molecular mechanisms of carcinogenesis in former poison gas workers remains unclear, our study proposes the possible effect of biological response modifiers in the prevention of cancer development in high-risk human subjects.

Alternative splicing, but not allelic loss, of the FHIT gene increases with development of lung cancer.

The FHIT gene is considered to be a tumor suppressor gene, its role and inactivation mechanism remain unclear. We analyzed FHIT gene aberrations in 64 lung cancer tissues and found that the appearance of the aberrant FHIT transcripts depends on the condition of RT-PCR and high telomerase activity, shortened telomere length, and advanced pathological stage were likely associated with the prevalence of aberrant FHIT transcripts, but not with allelic loss of the FHIT gene. These observations would indicate that an additional unknown gene may exist, which is more responsible for the allelic loss around the FHIT gene locus.

Analyses of bronchoalveolar lavage fluid (BALF) in MRL-lpr/lpr mice.

We performed bronchoalveolar lavage (BAL) in MRL-lpr/lpr (MRL/l) and MRL- +/+ (MRL/n) mice and evaluated various cellular and humoral components of the bronchoalveolar lavage fluid (BALF) to clarify the pathogenic mechanism of pulmonary fibrosis in MRL/l mouse. The numbers of macrophages, neutrophils and lymphocytes, N-Acetyl-beta-glucosaminidase (beta-NAG), and fibronectin increased in the BALF from MRL/l mice than that from MRL/n mice, but no significant differences were observed in total protein, beta-glucuronidase, acid phosphatase, or phospholipid level. Increased fibronectin level in the BALF from MRL/l mice may be related with pathogenesis of pulmonary fibrosis.

Activation of platelets in bronchial asthma.

STUDY OBJECTIVES: To investigate whether platelets are activated in asthmatics with increased release of preformed mediators and to investigate the influence of oral administration of theophylline on them. DESIGN: Comparison of the intracellular free calcium concentration ([Ca2+]i) in platelets as an indicator of platelet activation, CD62P expression on platelets, and the chemokine regulated upon activation in normal T cells expressed and presumably secreted (RANTES) level in platelet-rich buffer supernatants between asthmatics and normal subjects. SETTING: The respiratory outpatient clinics, Hiroshima University, Japan. PARTICIPANTS: Twenty-five normal volunteers, 19 asthmatics taking no oral drugs associated with asthma treatment (group A), and 18 asthmatics taking oral theophylline (group B). MEASUREMENTS AND RESULTS: While the resting [Ca2+]is in platelets were similar among the three groups, the [Ca2+]is in group A were significantly higher than those in normal subjects (p<0.05) and group B (p<0.01) after thrombin or 9,11-epithia-11,12-methano-thromboxane A2 (STA2) stimulation in the absence of external Ca2+. The CD62P expression level and RANTES level in group A after STA2 stimulation were significantly higher than those in normal subjects and group B (p<0.05). CONCLUSIONS: We conclude that agonist-mediated activation of platelets is augmented in asthmatics resulting in enhanced release of chemokine such as RANTES, which could be suppressed by oral administration of theophylline.

Anti-Kveim monoclonal antibody. New monoclonal antibody reacting to epithelioid cells in sarcoid granulomas.

A monoclonal antibody to the sarcoid granulomagenic agent contained in Kveim suspension was prepared by immunizing mice with Kveim suspension. One monoclonal antibody (IHY-1) that reacted with the epithelioid cells in sarcoid granulomas on immunoperoxidase technique was selected. The immunoperoxidase technique was used to compare this monoclonal antibody's binding to sarcoidosis- or tuberculosis-affected lymph nodes. IHY-1 is a monoclonal antibody of IgM class. This antibody did not react to erythrocytes, lymphocytes, monocytes, alveolar macrophages, or the macrophage-derived cell lines such as U-973 and KG-1. It reacted to granuloma epithelioid cells of sarcoidosis-affected lymph nodes. The monoclonal antibody also reacted positively to epithelioid cells in tuberculous granulomas although the reaction was not as strong. Since IHY-1 was found to bind to both types of granulomas, this suggests that the epithelioid cells in sarcoidosis have antigenicity common to the epithelioid cells in tuberculosis.

Increased expression of platelet-derived growth factor A and insulin-like growth factor-I in BAL cells during the development of bleomycin-induced pulmonary fibrosis in mice.

Current concepts suggest that macrophages may play a central role in pulmonary fibrosis by virtue of their ability to release a variety of cytokines. In this study, the expression of interleukin (IL)-1 alpha and beta, platelet-derived growth factor (PDGF) A and B, and insulin-like growth factor (IGF) I in BAL cells, which may be involved in fibroblast proliferation, was investigated in murine bleomycin (BLM)-induced pulmonary fibrosis. BAL cells were obtained at 1, 15, and 29 days from Institute for Cancer Research mice after 10 days of intraperitoneal administration of BLM. The relative amounts of cytokine messenger RNA (mRNA) were evaluated by the reverse transcription-polymerase chain reaction method, which simultaneously amplified complementary DNA for cytokines and beta-actin as an internal control. The level of IL-1 beta mRNA in BLM-treated mice was increased 4.5-fold compared with that in saline solution-treated (control) mice 1 day after treatment, while no significant differences were observed between the two groups at 15 and 29 days. The mRNAs of PDGF-A and IGF-I in BLM-treated mice were sustained at levels eightfold and threefold to fourfold, respectively, those of controls over 4 weeks. No significant differences were noted in IL-1 alpha and PDGF-B expression between the two groups. We conclude that IL-1 beta released from macrophages may be important in the early phase of inflammatory responses and that PDGF-A and IGF-I may play important roles in the development of BLM-induced pulmonary fibrosis.

An atypical carcinoid tumor of the lung with mutations in the p53 gene and the retinoblastoma gene.

Molecular analysis of a metastatic lesion of an atypical carcinoid tumor of the lung obtained from a 77-year-old man at autopsy revealed a point mutation in the p53 gene and a deletion in the retinoblastoma (Rb) mRNA. This case suggests that both these antioncogenes may be involved in the progression of atypical carcinoid tumor.

Allelotype and loss of heterozygosity around the L-myc gene locus in primary lung cancers.

L-myc S-allele was reported to be associated with metastasis of lung cancer, indicating the existence of a putative tumor suppressor gene around the L-myc locus, in linkage disequilibrium. The relationship between the S-allele and inactivation of some tumor suppressor gene should be indicated by allelic loss. Therefore, we examined the association between the L-myc S-allele and loss of heterozygosity at 11 loci around the L-myc locus (1p34.3) in primary lesions or other biological characteristics in lung cancer. No associations between the S-allele and allelic loss around the L-myc locus or other characteristics were found. According to the deletion map, three shortest regions of overlap between D1S230 and D1S76 were identified. While loss of heterozygosity at SRO1, between D1S2797 and MYCL1, showed no relationship with the pathological stage, it was more frequently observed in squamous cell carcinoma than adenocarcinoma (P=0.019), and associated with high telomerase activity (P=0.046), an indicator of cellular immortality. In conclusion, we found three shortest regions of overlap (SROs) from D1S2797 to pter, and a tumor suppressor gene, which might be associated with suppression of lung cancer development but not with L-myc S-allele, may exist in SRO1.

Alteration in length of telomeric repeats in lung cancer.

We investigated the relationship between telomere length and various characteristics of tumor cells in 46 lung cancer specimens (40 primary lesions and six metastatic lesions). Three variant patterns of telomere length were observed in 16 cases (34.8%): reduction in 13 cases, elongation in two cases, and convergence in one case. These variant patterns were frequently observed in small cell carcinomas, in metastatic lesions, and in cases which possessed the S-type allele of the L-myc gene. All three cases with telomere elongation or convergence were associated with a poor prognosis. This is compatible with the previous report suggesting that telomerase activity may be an indicator of immortality in vitro. In adenocarcinoma, telomere reduction or elongation was also observed in the early stages with a low percentage of cells in the S-phase, while in cases with other histologic types, these changes were observed only in late stage, in metastatic lesions, or in cancerous tissues with a high percentage of cells in the S-phase. Although the reduction of telomere length in these tissues may be a result of many cell divisions, it may represent another stage of carcinogenesis in early-stage adenocarcinoma.