BACKGROUND:Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity.PATIENTS AND METHODS:This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy.RESULTS:A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107).CONCLUSION:Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits.CLINICAL TRAIL NUMBER:NCT02499770.

OBJECTIVE:Upper-extremity ovarian autologous transplantation was first used for girls undergoing abdominal/pelvic radiation therapy; long-term follow-up is provided.DESIGN:A case series.SETTING:Tertiary pediatric medical center.PATIENTS:Girls with Wilms tumor with planned abdominal/pelvic radiation therapy.INTERVENTIONS:Subjects 1, 2, and 3 (ages 5, 2, and 1 year) presented with a Wilms tumor and underwent surgical resection. Each patient underwent ovarian autotransplantation to move ovarian tissue out of the radiation field. Subjects 1 and 2 had thin slices from 1 ovary placed in the arm. Subject 3 had a free transfer of the entire ovary into an axilla. Follow-up was obtained for the subsequent 20-25 years for all 3 subjects.OUTCOME MEASURES:Pubertal, menarcheal, and menstrual history, and hormonal serum levels.RESULTS:All subjects survived and experienced spontaneous pubertal development and menarche. Data were available for follow-up for 20-25 years. Subjects 1 and 2 showed spontaneous follicular development of the autotransplanted ovarian tissue. They had fluctuating gonadotropin and estradiol levels until age 29 and 26, respectively; spontaneous menses until age 29 and 26; and cessation of spontaneous menses with elevated gonadotropins and low estradiol levels at age 30 and 26. Subject 3 had severe monthly axillary pain, and the ovary was transferred back to the pelvis. She then had ovarian dysfunction with intermittent spontaneous ovarian activity until age 25.CONCLUSIONS:Ovarian autotransplantation to the upper extremity resulted in long-term sex steroid production for spontaneous puberty, menarche, follicular development, and menses with fluctuating gonadotropin and ovarian sex steroid levels and follicular activity that lasted for 13-15 years.

Patients who have undergone repair of esophageal atresia and tracehoesophageal fistula as infants have been noted to have residual esophageal dysmotility and pulmonary dysfunction during their childhood years. However, limited information is available about the long-term follow-up of these patients. In this study we performed esophageal and pulmonary function studies on 12 adults who had required surgical repair of these defects in the first week of life. Most patients had symptoms of dysphagia and heartburn at time of evaluation. Pathologic gastroesophageal reflux was documented in 67% of patients and esophagitis was noted in 34%. All patients had esophageal motility abnormalities characterized by low-amplitude nonperistaltic waves throughout most of the esophagus. In addition, although most patients had no respiratory symptoms, mild restrictive lung volumes were noted in many patients. However, airflow obstruction and airway hyperreactivity were not present. These data demonstrate that clinical symptoms and abnormal esophageal manometry and pulmonary function persist well into the third and beginning of the fourth decade after repair of esophageal atresia and tracheoesophageal fistula in infancy.

Prior to 1941, a small group of patients born with esophageal atresia had esophageal continuity reestablished by creation of an ante-thoracic skin tube conduit. This conduit was constructed in stages using tubed bipedicle grafts of thoracic skin. William E. Ladd reported on seven such patients. M.H., a 45-year-old married female, was the first patient to undergo this procedure and had maintained a normal existence until 6 months prior to admission to this hospital in 1985. She was a nonsmoker and nondrinker who had married and borne 2 children and had maintained adequate nutrition. Six months prior to admission, the patient noticed increasing dysphagia and the presence of a firm area in the upper third of the subcutaneous esophagus. Esophagoscopy demonstrated two polypoid lesions within the conduit. Multiple biopsies did not show any evidence of malignancy. Despite this, it was felt that the subcutaneous skin tube should be removed. A substernal colonic esophageal conduit was established and the subcutaneous skin tube removed. Histologic examination revealed extensive areas of benign pseudoepitheliomatous hyperplasia with foci of well-differentiated microinvasive squamous cell carcinoma within the wall of the tube. Ultimately, excision of overlying skin, subcutaneous tissue, and muscle under the skin tube site was done. This area was covered with a skin graft. The therapeutic approach as well as the implications concerning the long-term use of skin in heterotopic locations was discussed.

We report a case of congenital lobar emphysema in an adult due to bronchial atresia and presenting characteristically with a solitary pulmonary nodule due to a mucous plug. In the same patient the presence of a bronchogenic cyst leads to a hypothesis that the atretic segment is the result of an insult occurring during the 5th or 6th week of intrauterine life rather than one occurring after airway development is complete. We report a case of congenital lobar emphysema in an adult due to bronchial atresia and presenting characteristically with a solitary pulmonary nodule due to a mucous plug. In the same patient the presence of a bronchogenic cyst leads to a hypothesis that the atretic segment is the result of an insult occurring during the 5th or 6th week of intrauterine life rather than one occurring after airway development is complete.

Sixteen patients, aged 1 month to 15 years, were studied to determine the clinical course and long-term outcome of empyema in previously healthy children. The pathogens responsible were Haemophilus influenzae type b (seven patients), Staphylococcus aureus (five patients), Streptococcus pneumoniae (three patients), and viridans group Streptococcus (one patient). All patients had loculated fluid showing on chest roentgenographs. Chest tube drainage yielded 20 to 1,495 mL (mean 293 mL) during the first three days, accounting for 83% of total drainage. Chest tubes were removed after three to 17 days (mean ten days). Only slight roentgenographic improvement showed during chest tube drainage. Three patients required an open thoracotomy because of an unsatisfactory clinical response. Hospitalization ranged from eight to 77 days (mean 25 days). All patients had residual pleural thickening shown on chest roentgenographs taken at discharge. Thirteen patients were seen 5 to 140 months (mean 66 months) after discharge. Findings from physical examination were normal in 12 of the 13 patients. Pulmonary function tests in ten of the 13 patients revealed (mean percent predicted +/- 1 SD): vital capacity 92 +/- 12, residual volume 85 +/- 31, total lung capacity 92 +/- 13, peak flow rate 96 +/- 17, forced expiratory volume in 1 second 90 +/- 13, and maximal mid-expiratory flow rate 93 +/- 25. In all but one patient, findings on chest roentgenograms were normal or showed slight pleural thickening. Children with loculated empyema can be treated successfully with antibiotics and chest tube drainage. Few patients require open drainage, and further surgery is rarely required. The long-term outcome is excellent.

Presentation of CaseA seven-day-old girl was admitted to the hospital because of an intrathoracic mass.She was born in the 39th week of an uncomplicated third pregnancy to a mother aged 18 years. Delivery was vaginal, with forceps assistance under local anesthesia; the Apgar scores were 9 at one minute and 10 at five minutes. The umbilical cord contained three vessels. The weight was 2.8 kg. Scattered rales were heard on auscultation of the thorax; no other abnormality was found. At the age of three days another examination showed that the lungs were clear, and the child was discharged . . .

The increased longevity of patients with cystic fibrosis has resulted in a concomitant increase in the frequency with which pneumothorax is seen. While several approaches to this problem have been available from both a medical and surgical standpoint, unsettled questions remain regarding the efficacy of various modalities of therapy. A review of our own experience with 170 episodes of pneumothorax has provided a basis for proposing what appears to be a reasoned approach to therapy. During the past 12 years, 65 patients ages 5 to 32 years experienced 170 episodes of pneumothorax. Of the 211 trials of treatment, all yielded a high rate of initial resolution (70% to 100%) but rates of recurrence were high. The recurrence rates were: observation 60%, thoracentesis 79%, trochar thoracotomy 63%, tetracycline sclerosis 86%, and silver nitrate 43%. Quinacrine sclerosis yielded an acceptable recurrence rate of 12.5% and partial pleurectomy had no recurrence. There was no statistical difference in the pulmonary function parameters determined before pneumothorax and after chemical pleurodesis or partial pleurectomy. Based upon the data obtained in this review, we recommend that initial management of the pneumothorax include evacuation of the pneumothorax using a chest tube and then chemical pleurodesis using quinacrine sclerosis. In those cases where this pleurodesis fails, upper-partial pleurectomy with obliteration of pleural blebs via a limited thoracentesis is the treatment of choice. An occasional patient requires a concomitant lobectomy.

A series of 10 microvascular autotransfers of impalpable intraabdominal testes has been reported. The viability rate was 60 percent as determined by growth and size of the transferred testis. Long-term endocrine and fertility studies are needed to determine the function of these gonads. The spermatic vasculature was unpredictable and showed many variations. Indications should be very carefully individualized.

The clinical course of 32 pediatric patients with inflammatory bowel disease (ulcerative colitis--18, Crohn's disease--14) after colectomy and ileostomy was investigated. Specific indications for surgery were: ulcerative colitis (severe colitis--50%, chronic disease--50%); Crohn's disease (fistulae--28%, severe colitis--28%, chronic disease--21%, hemorrhage--14%, growth failure--7%). Proctectomy was performed at the time of colectomy in 72% of patients with ulcerative colitis and in 64% of those with Crohn's disease. Major post-operative complications (stomal dysfunction without documented recurrent disease, obstruction, abscess, bleeding) were observed in 60% of all patients regardless of diagnosis. Histologically documented recurrent disease developed in 42% of the patients with Crohn's disease (mean follow-up: 5 yr) despite removal of all affected bowel. Ileal disease at the time of surgery appeared to be a poor prognostic factor. Sexual activity was either improved or unchanged in sexually active patients. Impotence was not observed in any of the male patients. Despite complications and recurrent disease, the majority (75%) of patients viewed colectomy and ileostomy as improving the quality of their life.

We reviewed our experience over the past 12 years to determine the best method of management, to determine the morbidity and the physiologic outcome of medical vs surgical treatment of pneumothorax complicating CF, and to assess the influence of age, sex, and Shwachman scores on survival. Sixty-five patients, ages ranging from 5 to 32 years (mean 18 years). Shwachman scores ranging from 25 to 87 (mean 57), and a male-female ratio of 1:1, experienced 170 pneumothoraces, 93 first episodes, and 77 recurrences, requiring 211 trials of management. All methods of management except needle aspiration resulted in a fair rate of resolution (70 to 100%), but recurrence rates were high for observation (60%), needle aspiration (79%), trocar thoracotomy (63%), tetracycline sclerosis (86%), and silver nitrate sclerosis (43%). The recurrence rates were 12.5% for quinacrine sclerosis and 0% for parietal pleurectomy. Quinacrine sclerosis and parietal pleurectomy were the most effective methods of management. There was no significant difference in pulmonary function before pneumothorax and after pleural sclerosis or parietal pleurectomy. Age, sex, and severity of pulmonary disease were all independent variables influencing prognosis. Severity of disease, rather than the occurrence of a pneumothorax, appears to be the major cause of death. We recommend that quinacrine sclerosis should be considered for management of the first pneumothorax, and parietal pleurectomy if it fails.

We report the clinical and pathologic features of five children wih a botyroid rhabdomyosarcoma of the biliary tract. There were three boys and two girls ranging in age from 11/2 to 51/2 years at diagnosis. Obstructive jaundice was the usual presenting sign, often with fever and hepatomegaly. Of four tumors involving the common bile ducts, two extended into porta hepatis and adjacent liver parenchyma; the fifth tumor arose in the wall of the cystic duct. Each had a typical botryoid (grape-like) configuration with a cambium layer of tumor cells beneath biliary epithelium. Rhabdomyoblasts were identified in all cases and confirmed by ultrastructure in one. Our data, along with review of other cases reported in the English literature, indicate a rather guarded prognosis. Although metastases have developed in 40% of cases, death was usually due to the effects of local invasion by tumor. Aggressive adjuvant therapy currently in use for childhood rhabdomyosarcomas may lessen the high mortality associated with this tumor.

Detailed ultrastructural analysis of the respiratory cilia of three male patients with the immotile-cilia syndrome is presented. They all had similar clinical manifestations, namely, situs inversus totalis, repeated respiratory infections, and sinusitis. The respiratory cilia, however, of these patients showed a variety of structural abnormalities some of which are described for the first time. In the cilia of the first patient both the dynein arms were lacking, and, almost 40% of the cilia had one to nine supernumerary microtubules peripheral to the nine outer doublets. The cilia of the second patient showed an absence of inner dynein arms, unusually prominent outer dynein arms, a spoke defect in 46% of cilia examined, and no morphologically detectable nexin links. The cilia of the last patient lacked both dynein arms but, in contrast to the first two patients, showed virtually no microtubular abnormalities. These patients demonstrate that a variety of structural abnormalities in respiratory cilia can result in virtually identical clinical manifestations.

To characterize the outcome of lobectomy in infancy and the low expiratory flows which persist after lobectomy for congenital lobar emphysema, 15 subjects with this history were studied at age 8-30 yr. Total lung capacity was normal in all, but higher values (P < 0.05) were observed in nine subjects with upper lobectomy than in five subjects with right middle lobectomy. Ratio of residual volume to total lung capacity was correlated (P < 0.05) with the amount of lung missing as estimated from normal relative weights of the respective lobes. Xe(133) radiospirometry in eight subjects showed that the operated and unoperated sides had nearly equal volumes at total lung capacity, but that the operated side was larger than the unoperated side at residual volume. Perfusion was equally distributed between the two sides. Similar findings were detected radiographically in four other subjects. Forced expiratory volume in 1 s and maximal midexpiratory flow rate averaged 72 and 45% of predicted, respectively. Low values of specific airway conductance and normal density dependence of maximal flows in 12 subjects suggested that obstruction was not limited to peripheral airways. Pathologic observations at the time of surgery and morphometry of the resected lobes were not correlated with any test of pulmonary function. These data show that lung volume can be completely recovered after lobectomy for congenital lobar emphysema in infancy. The volume increase occurs on the operated side, and probably represents tissue growth rather than simple distension. The response to resection is influenced by the particular lobe resected and may be associated with decreased lung recoil near residual volume. Low expiratory flows in these subjects could be explained by several mechanisms, among which a disproportion between airway and parenchymal growth in infancy (dysanaptic growth) is most compatible with our data.