Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.

BACKGROUND: The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. METHODS: We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines. RESULTS: In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]≥250). There was significant association between FGF14 (GAA)≥250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA)≥250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein. CONCLUSIONS: A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).

Enhanced recovery after surgery after radical gastrectomy: Improved compliance over time is associated with a shorter postoperative hospital stay.

BACKGROUND: Changing adherence over time to enhanced recovery after surgery (ERAS) protocols following radical gastrectomy and the impact this has on length of stay (LoS) is not well described. This study aimed to explore the changes in adherence to core ERAS elements over time and the relationship between compliance and LoS. METHODS: A retrospective, single center cohort study was performed between 01/2016-12/2021. An ad hoc analysis revealed the point at which a significant difference in the number of patients being discharge on postoperative day (PoD) 3 was noted allowing allocation of patients to Group A (01/2016-12/2019) or B (01/2020-12/2021). Compliance with core ERAS elements was compared and the relationship between compliance and discharge by (PoD) 3 assessed. Variables significant on univariate analysis were assessed using binary multivariate regression. RESULTS: Of the 268 patients identified, 187 met the inclusion criteria (Group A 112 and Group B 75). More patients in Group B mobilized on PoD 1 (60.0 vs. 31.3%, p = <0.001), tolerated postgastrectomy diet by PoD 3 (84.6 vs. 62.5%, p = 0.049), and were discharged by PoD 3 (34.7 vs. 20.5%, p = 0.002). Protocol compliance of >75% was associated with discharge on PoD 3 (area under the curve, 0.726). Active mobilization on PoD 1 (OR 3.5, p = 0.009), compliance ≥75% (OR 3.3, p = 0.036), and preoperative nutritional consult (OR 0.2, p = 0.002) were independently associated with discharge on PoD 3. Discharge on PoD 3 did not increase readmission or representation to hospital. CONCLUSION: Early mobilization, protocol compliance >75%, and preoperative nutritional consult were associated with discharge on PoD 3 after radical gastrectomy.

Impact of bulky loco-regional lymphadenopathy in esophageal adenocarcinoma on survival: a retrospective single center analysis.

The relationship between 'bulky' locoregional lymphadenopathy and survival has not been investigated in the setting of esophageal adenocarcinoma (EAC). This study aimed to explore whether bulky regional lymphadenopathy at diagnosis affected survival outcomes in patients with EAC treated with neoadjuvant chemotherapy and en bloc resection. A single-center retrospective review of a prospectively maintained upper GI cancer surgical database was performed between January 2012 and December 2019. Patients with locally advanced EAC (cT2-3, N+, M0) treated with neoadjuvant docetaxel-based chemotherapy and transthoracic en bloc esophagogastrectomy were identified. Computed tomography scans from before the initiation of treatment were reviewed, and patients were stratified according to whether bulky loco-regional lymph nodes were present. This was defined as lymphadenopathy >2 cm in any axis. Overall survival was compared, and a Cox multivariate regression model was calculated. Two hundred twenty-five of the eight hundred seventy patients identified met the inclusion criteria. Forty-eight (21%) had bulky lymphadenopathy, leaving 177 allocated to the control group. More patients with bulky lymphadenopathy had ypN3 disease (18/48, 38% vs. 39/177, 20%, P = 0.025). Among patients with bulky lymphadenopathy, overall survival was generally worse (32.6 vs. 59.1 months, P = 0.012). However, among the 9/48 (19%) patients with bulky lymphadenopathy who achieved ypN- status survival outcomes were similar to those with non-bulky lymphadenopathy who also achieved lymph node sterilization. Poor differentiation (HR 1.8, 95% CI 1.0-2.9, P = 0.034), ypN+ (HR 1.9, 95% CI 1.1-3.6, P = 0.032), and bulky lymphadenopathy were independently associated with an increased risk of death (HR 1.7, 1.0-2.9, P = 0.048). Bulky regional lymphadenopathy is associated with a poor prognosis. Efforts to identify the ideal treatment regimen for these patients are urgently required.

ERAS following Gastrectomy for Octo- and Nonagenarians: A Single-Center Retrospective Analysis.

Background: The safety and efficacy of enhanced recovery after surgery (ERAS) following elective gastrectomy for gastric cancer in patients >80 years of age are not well described. The aim of this study was to explore whether an ERAS protocol following gastrectomy in this age group can be safely implemented and reduce postoperative length of stay. Methods: A retrospective, single-center analysis was performed. All patients >80 years of age with gastric cancer undergoing elective subtotal and total gastrectomy between January 2010 and December 2021 were identified. With the implementation of an ERAS protocol in January 2016, patients treated beforehand were allocated to Group A (pre-ERAS) and Group B (ERAS). The length of stay, incidence of postoperative complications and representation/readmission to the hospital were compared between the groups. Results: Of the 221 patients identified, 56 met the inclusion criteria with 22 patients (39.3%) allocated to Group A and 34 patients (60.7%) to Group B. There were no differences with regard to the type of resection and surgical approach. Length of stay was shorter in Group B (5 days, range 2-27 versus 10 days, 3-109, P = .040). A trend toward more discharges by postoperative day 3 was noted among patients in Group B (7/34, 20.6% versus 2/22, 9.1%, P = .253). There were no differences in the incidence of postoperative complications or readmission hospital between the groups. Conclusion: Among patients >80 years of age, ERAS following gastrectomy for cancer is associated with a reduced length of stay and can be safely implemented.

Survival in esophageal cancer with nonregional lymphadenopathy: a propensity score-matched analysis.

BACKGROUND: Survival among patients with esophageal cancer with stage IV nonregional lymphadenopathy treated with neoadjuvant therapy and surgical resection is not well described. This study aimed to compare the survival outcomes of patients with nonregional lymphadenopathy with a propensity-matched cohort of patients with locoregional disease. METHODS: This was a retrospective cohort analysis of a prospectively maintained database from a regional upper gastrointestinal cancer network in Quebec, Canada. From January 2010 to December 2022, patients with radiologically suspicious nonregional retroperitoneal or supraclavicular lymphadenopathy were identified. Using 1:1 propensity score matching, a control group without nonregional disease was created. RESULTS: Of the 1235 patients identified, 39 met the inclusion criteria and were allocated to the study group of whom 35 of 39 (89%) had adenocarcinoma. Retroperitoneal and supraclavicular lymphadenopathy occurred in 26 of 39 patients (67%) and 13 of 39 patients (33%). Of the 39 patients, 34 (87%) received neoadjuvant chemotherapy, and 5 (13%) received chemoradiotherapy. After resection, ypN0 of nonregional lymph node stations occurred in 21 of 39 patients (54%). When comparing the study group with a matched non-stage IV control group, the median overall survival was similar in patients with retroperitoneal lymphadenopathy (21.0 months [95% CI, 8.0-21.0] vs 27.0 months [95% CI, 13.0-41.0]; P = .262) but not with supraclavicular disease (13.0 months; 95% CI, 8.0-18.0; P = .039). The median follow-up intervals were 40.1 months (95% CI, 1.0-83.0) for the study group and 70.0 (95% CI, 33.0-106.0) for the control groups. CONCLUSION: Compared with a matched cohort of patients with similar disease burden but not stage IV disease, retroperitoneal lymphadenopathy did not negatively affect survival outcomes. Multimodal curative intent therapy may be appropriate in select cases.

Neuroradiological findings in GAA-FGF14 ataxia (SCA27B): more than cerebellar atrophy.

Background: GAA-FGF14 ataxia (SCA27B) is a recently reported late-onset ataxia caused by a GAA repeat expansion in intron 1 of the FGF14 gene. Initial studies revealed cerebellar atrophy in 74-97% of patients. A more detailed brain imaging characterization of GAA-FGF14 ataxia is now needed to provide supportive diagnostic features and earlier disease recognition. Methods: We performed a retrospective review of the brain MRIs of 35 patients (median age at MRI 63 years; range 28-88 years) from Quebec (n=27), Nancy (n=3), Perth (n=3) and Bengaluru (n=2) to assess the presence of atrophy in vermis, cerebellar hemispheres, brainstem, cerebral hemispheres, and corpus callosum, as well as white matter involvement. Following the identification of the superior cerebellar peduncles (SCPs) involvement, we verified its presence in 54 GAA-FGF14 ataxia patients from four independent cohorts (Tübingen n=29; Donostia n=12; Innsbruck n=7; Cantabria n=6). To assess lobular atrophy, we performed quantitative cerebellar segmentation in 5 affected subjects with available 3D T1-weighted images and matched controls. Results: Cerebellar atrophy was documented in 33 subjects (94.3%). We observed SCP involvement in 22 subjects (62.8%) and confirmed this finding in 30/54 (55.6%) subjects from the validation cohorts. Cerebellar segmentation showed reduced mean volumes of lobules X and IV in the 5 affected individuals. Conclusions: Cerebellar atrophy is a key feature of GAA-FGF14 ataxia. The frequent SCP involvement observed in different cohorts may facilitate the diagnosis. The predominant involvement of lobule X correlates with the frequently observed downbeat nystagmus.