Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are being clinically tested in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints. Preclinical data indicate that targeting of histone-lysine N-methyltransferase EZH2, a regulator of chromatin remodelling implicated in acquired therapeutic resistance, might augment and prolong chemotherapy responses. High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs has been linked to expression of Achaetescute homologue 1 (ASCL1; also known as ASH-1), a key transcription factor driving SCLC oncogenesis; encouraging preclinical and clinical activity has been demonstrated for an anti-DLL3-antibody–drug conjugate. The immune microenvironment of SCLC seems to be distinct from that of other solid tumours, with few tumour-infiltrating lymphocytes and low levels of the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1). Nonetheless, immunotherapy with immune-checkpoint inhibitors holds promise for patients with this disease, independent of PD-L1 status. Herein, we review the progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients.

SUMMARYThe effect of cardiac contraction on coronary arterial flow has been described in terms of an intramyocardiaJ pump, which displaces blood backward and forward during systole and diastole, respectively. Normally, the mean forward flow exceeds, and consequently conceals, this backflow. The main left coronary artery of six anesthetized open-chest dogs was perfused with a Gregg cannula from a constant pressure source via a pcrfusion line containing an adjustable stenosis. At mean left main arterial pressures, P^, of 65, 90, 125, and 155 mm Hg, the hearts were perfused via different grades of stenosis, while a constant mean perfusion pressure (Pu,) distal to the stenosis was maintained. Mean coronary flow was then independent of stenosis grade. However, with increasing stenosis grade, the systolic-diastolic coronary flow difference decreased, whereas the dlastolic-systolic coronary pressure difference increased. By varying the stenosis grade at constant P^ linear relationships between diastolic-systolic pressure difference and flow difference were obtained and were interpreted as being a result of an electrical analog potential-source equivalent. From the potential-source equivalent, the diastolic-systolic pressure changes of the intramyocadial pump, pi_, can be determined as well as the coronary resistance, R., impeding the flow variations originated by p^. We found p^ = 53.1 ± 7.02 (SD) nun Hg, and independent of P^. R. was correlated with the resistance to coronary flow, Re, via R. = 0.63 x R,. -12.9 mm Hg»s/ml (r -0.939, n -25). R* was defined as (Pic -14 nun Hg)/mean coronary flow. The waterfall model extended to allow for autoregulation to achieve an equal division of mean flow over the myocardium could not explain these results. From a decay curve of coronary arterial pressure following clamping of the perfusion line, intramyocardial coronary capacitance was estimated to be approximately 0.07 ml/mm rig/100 g LV. This value is in agreement with published volume pressure relationships of the intramyocardial blood compartment. The phasic coronary blood flow component requires intramyocardial arterial volume. We conclude that systolic-diastolic variations in coronary blood flow are not due to varying resistances but are caused by an active intramyocardial pump. Circ Res 49.-SS4-593, 1981THREE centuries have elapsed since Scaramucci (Porter, 1898) first speculated on the phasic nature of coronary blood flow. In modern physiological thinking, two more or less parallel lines of reasoning developed: Sabiston and Gregg (1957) held that contraction of the heart impedes coronary arterial flow, whereas Wiggers (1954) believed that systole and diastole were inseparable. In the second volume of Circulation Research, Wiggers states, "The volume of blood that can enter intramural vessels during diastole must depend to some extent on the degree to which they are emptied during preceding systole," supporting this opinion with the observation that systole enhances coronary venous outflow.From the Department of Physiology ...

Phosphoprotein driven cellular signaling events represent most of the new molecular targets for cancer treatment. Application of reverse-phase protein microarray technology for the study of ongoing signaling activity within breast tumor specimens holds great potential for elucidating and profiling signaling activity in real-time for patient-tailored therapy. Analysis of laser capture microdissection primary human breast tumors and metastatic lesions reveals pathway specific profiles and a new way to classify cancer based on functional signaling portraits. Moreover, the data demonstrate the requirement of laser capture microdissection for analysis and reveal the metastasis-specific changes that occur within a new microenvironment. Analysis of biopsy material from clinical trials for targeted therapeutics demonstrates the feasibility and utility of comprehensive signal pathway activation profiling for molecular analysis.

A wide variety of neuroendocrine tumours express somatostatin receptors, and can be visualized by radiolabelled somatostatin analogue scintigraphy. To investigate the value of [111In]-octreotide scintigraphy (Octreoscan), 48 patients (37 with proven carcinoid, pancreatic endocrine and medullary carcinoma of thyroid tumours, 11 with neuroendocrine syndromes multiple endocrine neoplasia (MEN-I) and Zollinger-Ellison syndrome (ZES) were examined with 111In-DTPA-D-Phe1-octreotide. Scintigrams were obtained at 24 and 48 h, and the results were compared with CT and magnetic resonance imaging (MRI). Thirty-five of 48 patients had positive [111In]-octreotide scintigraphy (23/25 (92%) carcinoids, 8/9 (89%) PETs, 4/11 (36%) MEN-I & ZES). Of the 42 lesions located by conventional imaging techniques, 37 (88%) were also identified by Octreoscan. Unexpected lesions (40 sites), not detected by CT or MR imaging were found in 24/48 (50%) patients. [111In]-octreotide scintigraphy has a higher sensitivity for tumour detection, and is superior to MR imaging and CT scanning in the identification of previously unsuspected extraliver and lymph node metastases. It may also be helpful for the localization of clinically suspected tumours in patients with MEN-I and ZES.

Scan-directed unilateral cervical exploration for HPT does not significantly increase the incidence of persistent hypercalcaemia compared with standard bilateral operation.

Thallium-Technetium isotope subtraction scanning was used routinely as a preoperative localization investigation in 90 patients with primary hyperparathyroidism who were submitted to "first-time" cervical exploration from 1985 to 1988. When the scintigram demonstrated a single focus of activity suggesting the site of a solitary parathyroid adenoma, a scan-directed exploration was carried out. If the tumor was found at the location suggested by the scan, it was then removed and the ipsilateral normal parathyroid was biopsied. The contralateral side of the neck was not explored in these patients. A total of 48 patients underwent unilateral cervical exploration while the remaining 42 individuals had a standard bilateral neck operation performed. The difference in operating times for patients who had a solitary adenoma and who underwent unilateral and bilateral neck exploration, respectively, was statistically highly significant (71 minutes versus 97 minutes, p less than 0.001). At mean follow-up of 16.8 months, no patient who had a unilateral neck exploration performed for solitary parathyroid adenoma demonstrated persistent or recurrent hypercalcemia.

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Small cell lung cancer (SCLC) is an aggressive malignancy with a critical need for novel therapies. Our goal was to determine whether PARP inhibition could sensitize SCLC cells to ionizing radiation (IR) and if so, to determine the contribution of PARP trapping to radiosensitization. Short-term viability assays and clonogenic survival assays (CSA) were used to assess radiosensitization in 6 SCLC cell lines. Doses of veliparib and talazoparib with equivalent enzymatic inhibitory activity but differing PARP trapping activity were identified and compared in CSAs. Talazoparib, IR, and their combination were tested in three patient-derived xenograft (PDX) models. Talazoparib radiosensitized 5 of 6 SCLC cell lines in short-term viability assays and confirmed in 3 of 3 cell lines by CSAs. Concentrations of 200 nmol/L talazoparib and 1,600 nmol/L veliparib similarly inhibited PAR polymerization; however, talazoparib exhibited greater PARP trapping activity that was associated with superior radiosensitization. This observation further correlated with an increased number of double-stranded DNA breaks induced by talazoparib as compared with veliparib. Finally, a dose of 0.2 mg/kg talazoparib caused tumor growth inhibition in combination with IR but not as a single agent in 3 SCLC PDX models. PARP inhibition effectively sensitizes SCLC cell lines and PDXs to IR, and PARP trapping activity enhances this effect. PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of radiotherapy in SCLC. .