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PurposeDespite the intra- and intertumoral heterogeneity seen in glioblastoma multiforme (GBM), there is little definitive data on the underlying cause of the differences in patient survivals. Serial imaging assessment of tumor growth allows quantification of tumor growth kinetics (TGK) measured in terms of changes in the velocity of radial expansion seen on imaging. Because a systematic study of this entire TGK phenotype—growth before treatment and during each treatment to recurrence —has never been coordinately studied in GBMs, we sought to identify whether patients cluster into discrete groups on the basis of their TGK.Patients and MethodsFrom our multi-institutional database, we identified 48 patients who underwent maximally safe resection followed by radiotherapy with imaging follow-up through the time of recurrence. The patients were then clustered into two groups through a k-means algorithm taking as input only the TGK before and during treatment.ResultsThere was a significant survival difference between the clusters ( P = .003). Paradoxically, patients among the long-lived cluster had significantly larger tumors at diagnosis ( P = .027) and faster growth before treatment ( P = .003) but demonstrated a better response to adjuvant chemotherapy ( P = .048). A predictive model was built to identify which cluster patients would likely fall into on the basis of information that would be available to clinicians immediately after radiotherapy (accuracy, 90.3%).ConclusionDichotomizing the heterogeneity of GBMs into two populations—one faster growing yet more responsive with increased survival and one slower growing yet less responsive with shorter survival—suggests that many patients who receive standard-of-care treatments may get better benefit from select alternative treatments.

Abstract BACKGROUND Neck remnants are not uncommon after endovascular treatment of cerebral aneurysms. Critics of endovascular treatments for cerebral aneurysms cite neck remnants as evidence in favor of microsurgical clipping. However, studies have failed to evaluate the true clinical significance of aneurysm neck remnants following endovascular therapies. OBJECTIVE To assess the clinical significance of residual aneurysm necks and to determine the rate of subsequent rupture following coiling or stent-assisted coiling of cerebral aneurysms. METHODS We retrospectively reviewed the records of 1292 aneurysm cases that underwent endovascular treatment at 4 institutions. Aneurysms treated by primary coiling or stent-assisted coiling were included in the study; those treated by flow diversion were excluded Aneurysms with residual filling (i.e., Raymond–Roy Occlusion Classification II, neck remnant; or III, residual aneurysm filling) were assessed for their risk of subsequent rupture. RESULTS A total of 626 aneurysms were identified as having residual filling immediately posttreatment. Of these, 13 aneurysms (2.1%) ruptured during the follow-up period (mean 7.3 mo; range 1-84 mo). Eleven of the 13 (84.6%) were ruptured at presentation. Rupture at presentation, the size of the aneurysm, and the increasing age of the patient were predictive of posttreatment rupture. CONCLUSION We found that unruptured aneurysms with residual necks following endovascular treatment posed a very low risk of rupture (0.6%). However, patients presenting with ruptured aneurysms had a higher risk of rerupture from a neck remnant (3.4%). These results highlight the importance of achieving complete angiographic occlusion of ruptured aneurysms.

ABSTRACT Bacteria that produce heat‐stable enterotoxins (STs), a leading cause of secretory diarrhea, are a major cause of morbidity and mortality worldwide. ST stimulates guanylyl cyclase C (GCC) and accumulation of intracellular cyclic GMP ([cGMP] i ), which opens the cystic fibrosis transmembrane conductance regulator (CFTR)‐related chloride channel, triggering intestinal secretion. Although the signaling cascade mediating ST‐induced diarrhea is well characterized, antisecretory therapy targeting this pathway has not been developed. 2‐ChloroATP (2ClATP) and its cell‐permeant precursor, 2‐chloroadenosine (2ClAdo), disrupt ST‐dependent signaling in intestinal cells. However, whether the ability to disrupt guanylyl cyclase signaling translates into effective antisecretory therapy remains untested. In this study, the efficacy of 2ClAdo to prevent ST‐induced water secretion by human intestinal cells was examined. In Caco‐2 human intestinal cells, ST increased [cGMP] i , induced a chloride current, and stimulated net basolateral‐to‐apical water secretion. This effect on chloride current and water secretion was mimicked by the cell‐permeant analog of cGMP, 8‐bromo‐cGMP. Treatment of Caco‐2 cells with 2ClAdo prevented ST‐induced increases in [cGMP] i , chloride current and water secretion. Inhibition of the downstream consequences of ST‐GCC interaction reflects proximal disruption of cGMP production because 8‐bromo‐cGMP stimulated chloride current and water secretion in 2ClAdo‐treated cells. Thus, this study demonstrates that disruption of guanylyl cyclase signaling is an effective strategy for antisecretory therapy and provides the basis for developing mechanism‐based treatments for enterotoxigenic diarrhea.—Zhang, W., Mannan, I., Schulz, S., Parkinson, S. J., Alekseev, A. E., Gomez, L. A., Terzic, A., Waldman, S. A. Interruption of transmembrane signaling as a novel antisecretory strategy to treat enterotoxigenic diarrhea. FASEB J. 13, 913–922 (1999)