Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.

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.

Correction of segmental tracheal stenosis in children.

Segmental tracheal stenosis in children may be either acquired or congenital in nature. Acquired injuries usually involve a previous tracheostomy site or an area just superior to the carina. Congenital stenosis may occur in any location and often is associated with pulmonary agenesis. Surgical correction may be undertaken relatively safely in children of any age by segmental resection. We report three patients ranging in age from 4 weeks to 3 years who were corrected successfully. The use of cardiopulmonary bypass may be indicated, especially in young infants, to facilitate resection.

Thyroglossal duct remnants in infants and children: reevaluation of histopathology and methods for resection.

Established principles for the management of thyroglossal duct remnants have been accepted widely since Sistrunk's description of the operative procedure in 1928. Nevertheless, inadequate excisions and troublesome recurrences still are encountered. We have reviewed 90 infants and children treated at The Children's Hospital in Boston over a 25-year period. Ten patients referred to our institution after an average of 2.4 prior operations per patient elsewhere suffered a recurrence rate of 30% after very wide reexcision. The remaining 80 patients who underwent primary excision at our institution had a 6.3% recurrence rate. All recurrences were managed successfully by further, wider excision. Histologic review demonstrated variability in patterns of drainage of the tract into the oropharynx, with accessory tracts and alveolar outpouchings off the main duct being present in 7.8% of specimens. This study demonstrates that the greatest opportunity for curative resection is at initial presentation, and that previous inadequate or unsuccessful excision is a major risk factor for further recurrence. The variability in microscopic anatomy of thyroglossal duct remnants can account for recurrent disease after lesser procedures, and underscores the importance of wide dissection above the hyoid bone. Our operative methods are illustrated.

Long-term evaluation of esophageal and pulmonary function in patients with repaired esophageal atresia and tracheoesophageal fistula.

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.

Esophageal atresia and ante-thoracic skin tube esophageal conduits: squamous cell carcinoma in the conduit 44 years following surgery.

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.

Bronchial atresia associated with a bronchogenic cyst. Evidence of early appearance of atretic segments.

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.

Empyema in children: clinical course and long-term follow-up.

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.

Management of pneumothorax in cystic fibrosis.

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.

Testicular autotransplantation in children.

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.

Course and prognosis after colectomy and ileostomy for inflammatory bowel disease in childhood and adolescence.

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.

Botryoid rhabdomyosarcoma of the biliary tract.

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.

An analysis of ultrasound scanning as a guide in determination of "high" or "low" imperforate anus.

The classic upside-down abdominal roentgenogram and the use of pelvic reference points have frequently been inaccurate in assessing the level of the distal pouch in patients with imperforate anus. The ultrasonic study described is different from that previously reported and allows more precise localization of the distal rectal pouch. A review of our experience allows us to make certain definitive statements about this diagnostic modality.

Hemolytic-uremic syndrome: a diagnostic and therapeutic dilemma for the surgeon.

The hemolytic-uremic syndrome consists of microangiopathic hemolytic anemia, acute renal failure, and thrombocytopenia following a prodromal illness of gastroenteritis or upper respiratory infection. The syndrome can present in dramatic fashion with severe abdominal pain and signs of peritonitis suggesting an acute surgical crisis. In a series of 25 patients, 40% had abdominal pain, 25% had abdominal tenderness, and 20% had peritoneal signs. Clues to diagnosis in the early stages of the acute illness were mild to moderate hypertension, abnormal peripheral blood smear, anemia despite dehydration, and proteinuria. Significant abdominal pain and x-ray evidence of colitis may occur before development of typical laboratory findings, and these were evident in at least one case. Three patients underwent laparotomy for suspected bowel perforation. Colitis without perforation was found in all cases. In the absence of documented perforation, toxic megacolon, or intussusception, the decision to perform laparotomy in patients with hemolytic-uremic syndrome who have signs of peritonitis must be individualized. Failure to recognize the underlying renal problem can lead to serious errors in fluid and electrolyte management and delay of appropriate therapy.

Bronchial atresia: a recognizable entity in the pediatric age group.

Bronchial atresia, a congenital lesion that develops after the 16th wk of fetal life, may be more common than previously believed, and this probably explains some cases of so-called congenital lobar emphysema. It may produce symptoms of pulmonary infection, wheezing, and respiratory distress severe enough to justify elective resection of that part of the lung distal to the atresia. The roentgenographic features that make this a recognizable entity are the following: (1) There is localized hyperinflation of lung in a segmental or lobar distribution, with a circular or oval parahilar radiodensity. Bronchography will demonstrate that there is no filling of the bronchus supplying this part of the lung. (2) The occasional neonate with this condition may present with an intrathoracic mass suggesting retained fetal lung fluid in lobar distribution. Bronchography will demonstrate that there is no filling of the bronchus to that part of the lung. (3) A plug of desquamated tissue and mucus in the cyst-like bronchus just distal to the point of atresia appears to be an unvarying component of the syndrome. It most commonly presents as a round or oval density, but in some cases it may be shaped like a rod or tree and rarely contains an air-fluid level.

Management of large skin defects in newborn children with myelodysplasia: a new method.

A method successfully used in closing a large skin defect in each of three children with myelodysplasia is described in detail. Full thickness skin closure was achieved in 7--10 days without skin grafts or rotation flaps.

Management of major hemoptysis in patients with cystic fibrosis.

Although bronchoscopy remains the best definitive method for localization of the site of hemorrhage in patients who have massive hemopytsis, angiography remains an important adjunct to this localization. When combined with embolization of the bleeding bronchial artery, it is an effective method of therapy for the management of massive hemoptysis in patients with cystic fibrosis.

The management of portal hypertension in cystic fibrosis.

We have found that with proper selection and preoperative preparation, a major portosystemic shunt can be done with considerable safety in a majority of cystic fibrosis patients and thus provide them with significant palliation and improved quality of life.

The lung following repair of congenital diaphragmatic hernia.

To determine the effects of the pulmonary hypoplasia present at birth in infants with congenital diaphragmatic hernia upon subsequent development of the lung, 19 patients who had undergone surgical repair before the age of one year were studied at ages 6 to 18 years. Total lung capacity and vital capacity averaged 99% of predicted value. Diffusing capacity for carbon monoxide was normal. Forced expiratory volume in one second averaged 89% of predicted value and 80% of vital capacity. Total respiratory system conductance and maximum expiratory flow volume curves obtained during air and helium-oxygen breathing were normal. Xenon 133 radiospirometry performed in nine patients revealed equal distribution of lung volumes on the two sides. Ventilation to the hernia side was reduced in only two patients. Blood flow to the hernia side was reduced in all nine patients. Chest radiographs supported the physiologic observations. These findings are consistent with the persistence of a reduction in the number of branches or generations of pulmonary arteries and bronchi on the side of the hernia. Since a substantial part of the vascular resistance resides in peripheral vessels, this developmental abnormality influences the distribution of pulmonary blood flow, although it has little effect on tests reflecting airway resistance or the distribution of ventilation.