PIK3CA Mutations are Common in Many Tumor Types and are Often Associated With Other Driver Mutations.

OBJECTIVES: Genotyping clinical cancer specimens determines a fuller spectrum of mutations that an individual tumor harbors, and thus provides better insight into its molecular pathogenesis. Using genotyping data collected during routine clinical care our objective was to better determine the genomic landscape associated with PIK3CA mutations since much interest has been placed on PIK3CA targeted therapy. METHODS: We performed multiplexed tumor genotyping within our CLIA-certified clinical laboratory on all consenting cancer patients who presented to the Brigham and Women's Hospital/Dana-Farber Cancer Center, regardless of histologic subtype. A total of 3252 cancers were genotyped for 471 mutations in 41 cancer-associated genes (including 23 mutations in PIK3CA), using a PCR-mass spectrometry assay. RESULTS: A total of 288 (9%) samples contained a mutation in PIK3CA, involving 25 different primary sites. In 117 (41%) cases, the PIK3CA mutation was found with at least 1 other mutation, many known oncogenic drivers, while only 7% of the non-PIK3CA mutated cases, when comparing like tumor types, had >1 mutation (P<0.0001). Breast cancers had the highest rate of PIK3CA mutations (34%), which correlated with estrogen receptor + status (P=0.0002). CONCLUSIONS: These findings suggest that PIK3CA mutations may be a relatively late event and may function primarily in a supporting/modifying role, and not as a primary driver of oncogenesis. Although further studies are needed, our observations during clinical tumor genotyping suggest that when other pro-oncogenic pathways are mutated along with PIK3CA, then, PIK3CA inhibition alone may not be effective and combination therapy may be warranted.

A Cluster of CNS Infections Due to B. cereus in the Setting of Acute Myeloid Leukemia: Neuropathology in 5 Patients.

Bacillus cereus typically causes a self-limited foodborne gastrointestinal (GI) illness. Severe invasive infection occurs rarely, mainly among immunocompromised hosts. We describe a cluster of B. cereus infections among 5 patients with acute myeloid leukemia and chemotherapy-induced neutropenia. The initial case presented with occipital lobe abscess and was found on biopsy to have organisms consistent with Bacillus species. Within 1 week, a second patient died of fulminant brain swelling and hemorrhage. Neuropathologic autopsy and culture revealed B. cereus; hospital infection control and public health officials were notified. Three more patients died within the subsequent 9 months (2 patients had rapid massive hemorrhage and many bacilli reminiscent of Bacillus anthracis infection, and 1 patient had sparse bacilli, petechial hemorrhages, and border zone infarcts). Blood cultures yielded positive results in 3 of 5 cases. A possible route of infection was hematogenous dissemination via GI mucosal breaches (GI symptoms occurred in 3 of 5 cases, and postmortem GI ulceration was found in 3 of 4 cases). Bacilli were seen in 2 of 3 GI ulcerations. Epidemiologic work-up, including a site visit conducted by the Centers for Disease Control and Prevention, did not identify a clear common source but suggested the possibility of bananas as a food source. Bacillus cereus causes a rapidly progressive, hemorrhagic meningoencephalitis with high mortality among patients with neutropenia. Neuropathologists can play a key role in the detection of outbreaks.