Whoops-Resections – how can we improve?

Soft tissue sarcomas (STS) are a rare and heterogeneous group of malignant tumors of mesenchymal origin that comprise less than 1 percent of all adult malignancies and approximately 12 percent of pediatric cancers. The age-standardized incidence rate in Switzerland is 4.43 per 100,000 person-years for STS. Sarcomas occur at all anatomic body sites, but the majority are in the extremities (Fig.1) (1). Due to their rarity, STSs are often not considered in the differential diagnosis. Often, STS presents as a slowly enlarging, superficial, soft-tissue lesion, sometimes following a history of trauma. Given the much higher frequency of benign soft-tissue lesions, STSs are often treated surgically as unplanned excisions (UE). Hence, excision is performed without previous imaging and biopsy, without adherence to a proper diagnostic pathway and therapeutic plan. As both the surgeon and the patient are astonished to note the pathological finding of a supposedly benign lesion as "malignant", the surgery performed is referred to as a "Whoops resection". Consecutively, micro- or even macroscopically residual tumor might persist in the surgical situs, potentially requiring second and maybe more extensive surgery (including amputation). As a result, UE might lead to increased functional disabilities and therefore reduced quality of life with a relevant impact on daily living. Importantly, UE might be associated with increased local recurrence rates and decreased survival (2). The rates of whoops resections reported in the literature vary from approximately 11.3% to over half of STS resections (3). While there appears to be no association with patient residence and insurance status, UE rates are lower in tertiary centers than in non-tertiary hospitals. Notably, these rates highly depend on the country-specific structure and collaboration within sarcoma networks and referral patterns. According to current guidelines, biopsy-proven STS requires a wide surgical resection as an essential treatment for virtually all patients. Depending on patient and tumor characteristics, perioperative radiation- and/or chemotherapy should be considered in order to improve patient outcome. This review aims to raise awareness for this clinically relevant topic, discuss the impact of UE on patient quality of life and treatment outcomes, and provide guidance for future improvement

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

International audienceAbstract Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements