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Abstract Objectives Functional problems, including nasal flow problems, are associated with specific skeletal and dental features. Further, maxillary expansion has been associated with nasal airway resistance alterations. This study aimed to investigate whether there is a correlation between skeletal features and nasal airflow‐ and olfaction‐related problems. Materials and methods This prospective study included 68 patients (30 boys, 38 girls; mean age 9 ± 2 years) examined at the Ohu University Hospital. We classified patients into three skeletal Classes (Class I, II, and III) based on the ANB angle. Olfactory disorder history was collected from the guardians. Maxillofacial measurements, nasal airflow assessments, and olfactory tests were performed using cephalometric analysis, rhinomanometry, and T&T olfactometer, respectively. Results Malocclusion, resulting from skeletal mandibular protrusion and smaller maxilla, was associated with reduced olfaction in children. The detection and recognition thresholds of skeletal Class III were significantly higher than those of Classes I (p = .01) and II (p = .01). Significant correlations were observed between SNA and the detection threshold (r = −.50) as well as between nasion perpendicular‐point A and the recognition threshold (r = −.53). The detection and recognition thresholds were significantly higher in Class III than in Classes I (r = .3) and II (r = −.1). Conclusions Maxillary growth and development may be associated with olfaction in children. Changing the maxillofacial morphology may improve olfactory function. In the future, we will investigate how malocclusion treatment affects olfactory function.

Summary: Initial studies of cancer metabolism in the early 1920s found that cancer cells were phenotypically characterized by aerobic glycolysis, in that these cells favor glucose uptake and lactate production, even in the presence of oxygen. This property, called the Warburg effect, is considered a hallmark of cancer. The mechanism by which these cells acquire aerobic glycolysis has been uncovered. Acidic extracellular fluid, secreted by cancer cells, induces a malignant phenotype, including invasion and metastasis. Cancer cells survival depends on a critical balance of redox status, which is regulated by amino acid metabolism. Glutamine is extremely important for oxidative phosphorylation and redox regulation. Cells highly dependent on glutamine and that cannot survive with glutamine are called glutamine-addicted cells. Metabolic reprogramming has been observed in cancer stem cells, which have the property of self-renewal and are resistant to chemotherapy and radiotherapy. These findings suggest that studies of cancer metabolism can reveal methods of preventing cancer recurrence and metastasis. Keywords: Glycolysis, Warburg effect, Glutamine metabolism, Acidic extracellular pH

Maxillary sinus floor elevation (sinus lift) is a widely recognized dental-surgical approach for dental implant placement. However, for an otorhinolaryngological high-risk patient with severe anatomic-structural impairments of the maxillary sinus drainage pathway, surgical intervention is recommended before sinus lift to avoid postsinus lift maxillary sinusitis. Here, we show a case that postsinus lift maxillary sinusitis in such a high-risk patient was noninvasively prevented by the collaboration of otorhinolaryngologist and dentist. A 48-year-old Japanese male intended to undergo a sinus lift for dental implant placement by periodontist. Otorhinolaryngologist found septal deviation, concha bullosa, the presence of Haller cell, and nasal mucosal swelling by the nasal allergy, while no sinusitis and diagnosed him as a “high-risk case” for postsinus lift maxillary sinusitis. The patient was administered preoperative topical steroid and leukotriene receptor antagonist in addition to perioperative antibiotic prophylaxis so that his complication was noninvasively prevented. Thus, this case suggested that consultation from dentist to otorhinolaryngologist provides benefit to the patients who have been diagnosed as “high-risk case” for postsinus lift maxillary sinusitis.

Mineral trioxide aggregate (MTA) has been recommended for various uses in endodontics. To understand the effects of MTA on alveolar bone, we examined whether MTA induces osteoblastic differentiation using MC3T3-E1 cells. MTA enhanced mineralization concomitant with alkaline phosphatase activity in a dose- and time-dependent manner. MTA increased production of collagens (Type I and Type III) and matrix metalloproteinases (MMP-9 and MMP-13), suggesting that MTA affects bone matrix remodeling. MTA also induced Bglap (osteocalcin) but not Bmp2 (bone morphogenetic protein-2) mRNA expression. We observed induction of Atf6 (activating transcription factor 6, an endoplasmic reticulum (ER) stress response transcription factor) mRNA expression and activation of Atf6 by MTA treatment. Forced expression of p50Atf6 (active form of Atf6) markedly enhanced Bglap mRNA expression. Chromatin immunoprecipitation assay was performed to investigate the increase in p50Atf6 binding to the Bglap promoter region by MTA treatment. Furthermore, knockdown of Atf6 gene expression by introduction of Tet-on Atf6 shRNA expression vector abrogated MTA-induced mineralization. These results suggest that MTA induces in vitro osteoblastogenesis through the Atf6–osteocalcin axis as ER stress signaling. Therefore, MTA in endodontic treatment may affect alveolar bone healing in the resorbed region caused by pulpal infection.

Laryngeal carcinoma and laryngeal papilloma are the most commonly encountered tumorous lesions in the larynx. Herein, we report a case of the mass arising from the left vocal cord in a 49-year-old Japanese man. Endoscopic examination suggested that the mass is a tumor such as carcinoma and papilloma. Pathological examination showed that the specimen demonstrated actinomycosis in the left vocal cord. Although vocal cord actinomycosis is extremely rare, the otolaryngologist should recognize this condition during the inspection of the larynx.

Exostosis, osteoma, and adenoma are the most commonly encountered benign lesions in the external auditory canal. Herein, we report a case of the mass arising from the external auditory canal in a 24-year-old Japanese man. CT revealed the soft tissue mass without bony erosion, and MRI revealed that the mass showed a homogenous, iso signal intensity on a both T1- and T2-weighted image, suggesting that the mass is a benign tumor such as adenoma. Pathological examination showed that the specimen demonstrated xanthogranuloma in the external auditory canal. Although xanthogranuloma of the external auditory canal is extremely rare, otolaryngologists should recognize this condition during the inspection of the external auditory canal.

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of β2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Purpose: Approximately 7% of patients with newly diagnosed prostate cancer (PCa) in the US will have have metastatic disease. The dogma that there is no role for surgery in this population has been questioned recently. Here we report long-term outcomes of a phase 1 clinical trial on cytoreductive radical prostatectomy., Materials and Methods: This is a multicenter phase 1 trial. The major inclusion criterion was biopsy proven N1M0 or NxM1a/b PCa. Primary end point was the Clavien-Dindo-based major complication rate. Secondary outcomes were biochemical progression and overall survival. RNA-seq correlative study was conducted in nine select cases as a pilot study., Results: Final accrual was 32 patients of which 25 and 7 were cNxM1 and cN1M0, respectively. With the median follow-up of 46 months (interquartile range 31.7 - 52.7 months), 25 out of the 32 patients (75%) were alive at the time of last contact. There were three disparate groups based on the oncologic outcome: favorable, intermediate, and poor. In seven men with favorable response, androgen deprivation therapy was switched to intermittent approach and five remain free of any evidence of disease after more than two years off all systemic therapy with the normalization of serum testosterone. Of these five patients, three had M1 disease. Long-term use of one pad or less per day was 80%. RNA-seq analysis revealed an enriched downregulation of tumor necrosis factor (TNF)-α signature in the favorable group., Conclusion: Overall long-term oncologic outcome of cytoreductive radical prostatectomy was significantly higher than historical results. Importantly, the combination of surgery with systemic therapy may result in a long durable response in a minority of men who present with metastatic PCa., Competing Interests: All authors have no significant conflict of interest., (© 2022 Asian Pacific Prostate Society. Publishing services by Elsevier B.V.)

As the US transitions from volume- to value-based cancer care, many cancer centers and community groups have joined to share resources to deliver measurable, high-quality cancer care and clinical research with the associated high patient satisfaction, provider satisfaction, and practice health at optimal costs that are the hallmarks of value-based care. Multidisciplinary oncology care pathways are essential components of value-based care and their payment metrics. Oncology pathways are evidence-based, standardized but personalizable care plans to guide cancer care. Pathways have been developed and studied for the major medical, surgical, radiation, and supportive oncology disciplines to support decision-making, streamline care, and optimize outcomes. Implementing multidisciplinary oncology pathways can facilitate comprehensive care plans for each cancer patient throughout their cancer journey and across large multisite delivery systems. Outcomes from the delivered pathway-based care can then be evaluated against individual and population benchmarks. The complexity of adoption, implementation, and assessment of multidisciplinary oncology pathways, however, presents many challenges. We review the development and components of value-based cancer care and detail City of Hope's (COH) academic and community-team-based approaches for implementing multidisciplinary pathways. We also describe supportive components with available results towards enterprise-wide value-based care delivery.

There is a significant controversy on whether race should be a factor in considering active surveillance for low-risk prostate cancer. To address this question, we analyzed a multi-institution database to assess racial disparity between African-American and White-American men with low risk prostate cancer who were eligible for active surveillance but underwent radical prostatectomy. A retrospective analysis of prospectively collected clinical, pathologic and oncologic outcomes of men with low-risk prostate cancer from seven tertiary care institutions that underwent radical prostatectomy from 2003-2014 were used to assess potential racial disparity. Of the 333 (14.8%) African-American and 1923 (85.2%) White-American men meeting active surveillance criteria, African-American men were found to be slightly younger (57.5 vs 58.5 years old; p = 0.01) and have higher BMI (29.3 v 27.9; p < 0.01), pre-op PSA (5.2 v 4.7; p < 0.01), and maximum percentage cancer on biopsy (15.1% v 13.6%; p < 0.01) compared to White-American men. Univariate and multivariate analysis demonstrated similar rates of upgrading, upstaging, positive surgical margin, and biochemical recurrence between races. These results suggest that single institution studies recommending more stringent AS enrollment criteria for AA men with a low-risk prostate cancer may not capture the complete oncologic landscape due to institutional variability in cancer outcomes. Since all seven institutions demonstrated no significant racial disparity, current active surveillance eligibility should not be modified based upon race until a prospective study has been completed., Competing Interests: CONFLICTS OF INTEREST None.

Emerging evidence has suggested that cytoreductive prostatectomy (CRP) allows superior oncologic control when compared to current standard of care androgen deprivation therapy alone. However, the safety and benefit of cytoreduction in metastatic prostate cancer (mPCa) has not been proven. Therefore, we evaluated the incidence of complications following CRP in men newly diagnosed with mPCa. A total of 68 patients who underwent CRP from 2006 to 2014 at four tertiary surgical centers were compared to 598 men who underwent radical prostatectomy for clinically localized prostate cancer (PCa). Urinary incontinence was defined as the use of any pad. CRP had longer operative times (200 min vs 140 min, P < 0.0001) and higher estimated blood loss (250 ml vs 125 ml, P < 0.0001) compared to the control group. However, both overall (8.82% vs 5.85%) and major complication rates (4.41% vs 2.17%) were comparable between the two groups. Importantly, urinary incontinence rate at 1-year after surgery was significantly higher in the CRP group (57.4% vs 90.8%, P < 0.0001). Univariate logistic analysis showed that the estimated blood loss was the only independent predictor of perioperative complications both in the unadjusted model (OR: 1.18; 95% CI: 1.02-1.37; P = 0.025) and surgery type-adjusted model (OR: 1.17; 95% CI: 1.01-1.36; P = 0.034). In conclusion, CRP is more challenging than radical prostatectomy and associated with a notably higher incidence of urinary incontinence. Nevertheless, CRP is a technically feasible and safe surgery for selecting PCa patients who present with node-positive or bony metastasis when performed by experienced surgeons. A prospective, multi-institutional clinical trial is currently underway to verify this concept.

Purpose: There are limited long-term data on patients treated with image guided intensity modulated radiation therapy (IG-IMRT) for prostate cancer recurrence or high-risk disease features after radical prostatectomy. We report single-institution results for patients treated with IG-IMRT and identify variables associated with outcome., Methods and Materials: This is a retrospective chart review consisting of 313 consecutive patients who were treated with adjuvant or salvage IG-IMRT from 2004 to 2013. Cox proportional hazards analysis was used to identify factors related to survival and toxicity. Toxicity was graded using the Common Terminology Criteria for Adverse Events Version 4.0., Results: The median follow-up was 55 months (range, 6-131 months). The median pre-radiation therapy (RT) prostate-specific antigen (PSA) was 0.3 ng/mL (range, <0.01-55.4). The vast majority of patients (87%) received elective pelvic nodal irradiation (median dose: 45 Gy). Androgen deprivation therapy (ADT) was given to 39% of patients for a median of 9 months. Five-year biochemical progression-free survival and distant metastasis-free survival were 59% (95% confidence interval, 53%-66%) and 89% (95% confidence interval, 85%-93%), respectively. On multivariate analysis, higher pre-RT PSA (>0.2 ng/mL), biopsy Gleason score (≥7 [4+3]), and duration of ADT (>6 months) were significantly associated ( P < .05) with biochemical progression-free survival. Actuarial late grade 3 genitourinary and gastrointestinal toxicities at 5 years were 10% and 2%, respectively., Conclusion: Our results suggest that lower pre-RT PSA level and longer duration of ADT are associated with improved biochemical control. The incidence of late grade 3 gastrointestinal toxicity was low, but late grade 3 genitourinary toxicity was higher than anticipated.

Bladder neck preservation (BNP) during radical prostatectomy (RP) may improve postoperative urinary continence, although its overall effectiveness remains controversial. We systematically searched PubMed, Ovid Medline, Embase, CBM and the Cochrane Library to identify studies published before February 2016 that assessed associations between BNP and post-RP urinary continence. Thirteen trials (1130 cases and 1154 controls) assessing BNP versus noBNP (or with bladder neck reconstruction, BNR) were considered suitable for meta-analysis, including two randomized controlled trials (RCT), six prospective and five retrospective studies. Meta-analysis demonstrated that BNP improved early urinary continence rates (6 mo, OR = 1.66; 95% CI, 1.21-2.27; P = 0.001) and long-term urinary continence outcomes (>12 mo, OR = 3.99; 95% CI, 1.94-8.21; P = 0.0002). Patients with BNP also had lower bladder neck stricture frequencies (OR = 0.49; 95% CI, 0.29-0.81; P = 0.006). Anastomotic leak rates, positive surgical margins and biochemical failure rates were comparable between the two groups (P>0.05). There were no differences in baseline characteristics except for a smaller average prostate volume (WMD = -2.24 ml; 95% CI, -4.27 to -0.22; P = 0.03) in BNP patients. Our analyses indicated that BNP during RP improved early recovery and overall long-term (1 year) urinary continence and decreased bladder neck stricture rates without compromising oncologic control.

Background: The purpose of this study is to evaluate and report the feasibility, safety, and initial outcomes of patients with limited localized prostate cancer treated using a trans-rectal magnetic resonance image-guided focused ultrasound (MRGFUS) device. Attempts to focally treat only the index lesion for prostate cancer have been explored to reduce side effects while maintaining oncologic control. MRGFUS allows for precise targeting of thermal ablative therapy with real-time thermometry., Methods: Three patients underwent multiparametric 3T MRI and TRUS-guided 16-sector mapping biopsies of the prostate. The patients were eligible if they had Gleason 6 or 7 (3 + 4) disease, no MRI-visible tumor ≥15 mm, no extracapsular extension, and no more than two discrete cancerous lesions ≤10 mm in length. Acoustic power was adjusted to achieve temperatures of 65 to 85 °C., Results: Age ranged from 60 to 64 years. The number of biopsy-positive sectors treated ranged from 2 to 4. Post therapy, 16-sector biopsies at 6 months were negative in two patients with one patient still with Gleason 6 cancer (10 %, 2 mm) in one core. 16-sector biopsy in the first patient remains negative at 24 months. PSA continues to remain stable in all patients. IPSS in all patients either remained stable or decreased then stabilized. Erectile function according to the International Index of Erectile Function (IIEF) was excellent for all patients and demonstrated no decline up to the time of last follow-up at 12-24 months., Conclusions: MRGFUS is a feasible alternative for focal therapy in a select subset of patients with prostate cancer. The treatment is well tolerated with no evidence of decline in functional outcomes. Initial post-therapy biopsy results are promising. Long-term treatment efficacy requires further study.

Background: Second-line therapy is frequently utilized for metastatic urothelial carcinoma, but there are limited data to guide this approach. While an assessment of overall survival based on registry data may not capture the impact of second- and third-line therapies on clinical outcome, this may be reflected in relative conditional survival (RCS)., Methods: Patients with stage IV urothelial carcinoma diagnosed from 1990-2010 were identified from the Surveillance, Epidemiology and End Results (SEER) dataset. The association of clinicopathologic variables with disease specific survival (DSS) was explored through univariate and multivariate analyses. DSS in subgroups divided by time period (1990-2000 v 2001-2010) was compared using the Kaplan-Meier method and log-rank test. One-year RCS at annual landmarks up to 5 years was compared in subgroups divided by time period., Results: Of 261,987 patients diagnosed with urothelial carcinoma from 1990-2010, 3,110 patients met criteria for the current analysis. Characteristics of patients diagnosed between 1990 and 2000 (n = 810) and 2001 to 2010 (n = 2,300) were similar and there was no significant difference in DSS between the two groups. On multivariate analysis, older age (age ≥ 80) was associated with shorter DSS (HR 1.79, 95%CI 1.48-2.15), but no association was found between time period of diagnosis and outcome. One-year RCS improved substantially through successive annual landmarks up to 5 years, but no differences were seen in subgroups divided by time of diagnosis., Conclusions: No difference in RCS was observed amongst patients with stage IV urothelial carcinoma diagnosed from 1990-2000 and 2001-2010. A lack of difference in RCS (more so than cumulative DSS) may reflect a lack of progress in salvage therapies for the disease.

Background: The presence of lymph nodes (LN) within the prostatic anterior fat pad (PAFP) has been reported in several recent reports. These PAFP LNs rarely harbor metastatic disease, and the characteristics of patients with PAFP LN metastasis are not well-described in the literature. Our previous study suggested that metastatic disease to the PAFP LN was associated with less severe oncologic outcomes than those that involve the pelvic lymph node (PLN). Therefore, the objective of this study is to assess the oncologic outcome of prostate cancer (PCa) patients with PAFP LN metastasis in a larger patient population., Methods: Data were analyzed on 8800 patients from eleven international centers in three countries. Eighty-eight patients were found to have metastatic disease to the PAFP LNs (PAFP+) and 206 men had isolated metastasis to the pelvic LNs (PLN+). Clinicopathologic features were compared using ANOVA and Chi square tests. The Kaplan-Meier method was used to calculate the time to biochemical recurrence (BCR)., Results: Of the eighty-eight patients with PAFP LN metastasis, sixty-three (71.6%) were up-staged based on the pathologic analysis of PAFP and eight (9.1%) had a low-risk disease. Patients with LNs present in the PAFP had a higher incidence of biopsy Gleason score (GS) 8-10, pathologic N1 disease, and positive surgical margin in prostatectomy specimens than those with no LNs detected in the PAFP. Men who were PAFP+ with or without PLN involvement had more aggressive pathologic features than those with PLN disease only. However, there was no significant difference in BCR-free survival regardless of adjuvant therapy. In 300 patients who underwent PAFP LN mapping, 65 LNs were detected. It was also found that 44 out of 65 (67.7%) nodes were located in the middle portion of the PAFP., Conclusions: There was no significant difference in the rate of BCR between the PAFP LN+ and PLN+ groups. The PAFP likely represents a landing zone that is different from the PLNs for PCa metastasis. Therefore, the removal and pathologic analysis of PAFP should be adopted as a standard procedure in all patients undergoing radical prostatectomy.

Background and Objectives: Surgical resection of isolated adrenal metastasis in primary lung cancer is associated with improved survival. We report a combined robotic lobectomy and adrenalectomy for resection of a primary lung cancer and metastasis to the adrenal gland., Methods: A 69-year-old male with a significant smoking history and shortness of breath was found to have a 3-cm left upper lobe mass with an enlarged left adrenal gland measuring 1.5cm. The adrenal gland was biopsied confirming metastatic poorly differentiated carcinoma, likely lung cancer. Computed tomography, positron emission tomography, and mediastinoscopy revealed no evidence of disease outside the adrenal gland., Results: Following induction chemotherapy, the patient underwent combination robotic lobectomy, lymphadenectomy, and adrenalectomy while in the same lateral decubitus position. Thoracic and urologic oncology teams performed their respective portions of the operation. Overall operative time was 4 hours, and length of hospital stay was 3 days. Estimated blood loss was 150mL with no narcotic requirements beyond the first postoperative day. Final pathology revealed large cell carcinoma of the lung with metastasis to the adrenal. All surgical margins were negative., Conclusions: Combination robotic lobectomy and adrenalectomy is feasible and can be associated with a short convalescence, minimal pain, and an oncologically sound approach.

Background: The importance of moderate ischemic mitral regurgitation in patients presenting for coronary artery bypass grafting (CABG) is controversial. Therefore, we tracked the course of unrepaired moderate ischemic mitral regurgitation after CABG surgery alone, identified factors associated with worsening postoperative ischemic mitral regurgitation, and assessed the impact of unrepaired moderate ischemic mitral regurgitation on survival., Methods: From 1980 to 2000, 467 patients with moderate ischemic mitral regurgitation underwent CABG alone. The course of unrepaired mitral regurgitation was estimated by a longitudinal analysis of 267 follow-up echocardiograms from 156 patients. The survival impact of moderate ischemic mitral regurgitation was determined among propensity-matched patients with and without ischemic mitral regurgitation., Results: Mitral regurgitation was dynamic early postoperatively. Immediately postoperatively, it was absent or mild in 73% and severe in 6%; by 6 weeks, these figures were 40% and 22%, respectively. The course of postoperative mitral regurgitation was not associated with the preoperative extent of coronary artery disease or left ventricular dysfunction. Five-year survival of matched bypass patients without ischemic mitral regurgitation was 85% compared with 73% for patients with moderate ischemic mitral regurgitation (p = 0.003)., Conclusions: Moderate ischemic mitral regurgitation does not reliably resolve with CABG surgery alone and is associated with reduced survival. Therefore, a mitral valve procedure may be warranted for such patients presenting for CABG. A randomized trial comparing strategies of revascularization with mitral valve repair and revascularization alone is required to determine optimal treatment.

We studied the effects of maternal exposure to endotoxin on pregnancy outcome, stimulation of the hypothalamo-hypophyseal-adrenal axes (HHAA) of ewes and their fetuses, and maternal production of tumor necrosis factor alpha (TNF alpha), a central mediator in the pathogenesis of bacterial endotoxemia. Either endotoxin (lipopolysaccharide, LPS) from Salmonella typhimurium or saline was administered to pregnant sheep (n = 10) at 137.6 +/- 3.5 days gestational age by slow i.v. infusion at 1 microgram.kg-1 total dose over a 3-h period. Fetuses of ewes treated with LPS became hypoxemic by 2.5 h after initiation of LPS infusion. Maternal ACTH increased and peaked during LPS administration to levels approximately 10-fold greater in treated than in control ewes. In contrast, fetal ACTH levels were maximum at 6-12 h. Maternal and fetal cortisol levels were significantly different from control levels by 1 and 12 h, respectively. Maternal plasma TNF alpha peaked (6-7-fold over baseline) at 1-2 h after initiation of LPS administration and steadily declined over the following 48 h. Four of 5 treated ewes either delivered or their fetuses died within 28 h. In summary, infusion of LPS caused fetal hypoxemia and stimulated both fetal and maternal HHAA followed by preterm labor by 28 h after infusion in 4 of 5 ewes. Three of the fetuses died in utero. Maternal plasma TNF alpha rose rapidly, but the specific role it may play in initiation of preterm labor remains to be elucidated.