PMC9185004_01
(a) H&E, PD-L1 expression, and T-cell populations in the 2014 tumor
biopsy. H&E shows a low-grade glioma, PD-L1 negative, T-CD4 negative and
with scant perivascular T CD8+ cells. (b) Pedigree depicting the cancer
history of the patient's family, reflecting an autosomal dominant pattern of
inheritance. (c) Mismatch-repair protein IHC shows preserved expression of
MSH2 and MSH6, partial PMS2 expression and complete lack of expression of
MLH1. (d) Sanger sequence of the patient's peripheral blood lymphocytes
demonstrating a pathogenic MLH1 mutation [c.1865 T > A
(p.L622 H)].. CRC, colorectal cancer; HGD, high-grade dysplasia; LGG, low-grade glioma;
(+), mutation carrier; (-), noncarrier.
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The patient underwent germline genetic testing that confirmed the carrier status of the pathogenic hMLH1 mutation previously detected in his paternal uncle (Figure 1).
MRI tumor evolution from initial diagnosis until the end of therapy.. Upper row: A large nonenhancing glioma in the left temporal lobe is seen in
the MRI from December 2012. A biopsy informed of a grade-II IDH wild-type
astrocytoma (according to WHO 2007 4th edition that corresponds to an IDH
wild-type GB according to WHO 2021 5th edition classification of CNS tumors)
and treatment with single-agent temozolomide was administered for 12 months
until PD occurred in January 2014. A partial tumor resection was made
followed by adjuvant RT between April and May 2014. A W&S strategy
started until February 2015 when due to PD, treatment with FTM was
administered between February and May 2015, suffering PD.. Treatment with Bevacizumab 10 mg/kg/q2wk was started in June 2015,
experiencing a rapid and complete/near-complete tumor response after only
four cycles that was maintained until February 2017, when a W&S strategy
was began until April 2018, when PD occurred. Yellow arrows indicate the
tumor in cases of PD. The yellow box indicates the post-contrast MRI from
May 2015 where the tumor progression was observed. Although radionecrosis
was also present, the very high perfusion values (VSRr) indicate a
predominant tumor component. The blue box indicates the post-contrast MRI
from July 2015, where a major tumor response after bevacizumab can be
seen.. Lower row: The patient started a rechallenge with bevacizumab 10 mg/kg/q2wk
in April 2018, showing progressive disease as the best response in June 2018
but without clinical deterioration until November 2018, when therapy was
stopped and treatment with nivolumab 3 mg/kg/q2wk started. After four
cycles, MRI in February 2019 showed progressive disease. Due to concerns of
a potential PsPD due to an immune-mediated response, a tumor biopsy was
performed that was reported as GB with a very scant T-cell infiltrate (not
shown). Given the clinical stability, it was decided to continue nivolumab
beyond progression. In May 2019, MRI showed an overt radiologic progression
with clinical deterioration (worsening aphasia and gait instability).
Treatment with reduced-dose irinotecan (125 mg/m2/q2wk) combined with
bevacizumab (10 mg/kg/q2wk) was started with significant toxicity (G2
diarrhea, G3 asthenia) after the first cycle, and the patient and his family
decided to definitively stop treatment, being transferred to a
palliative-care facility.. BEV, bevacizumab; CNS, central nervous system; CPT-11, irinotecan; CR,
complete response; FTM, progressive disease; IDH, isocitrate dehydrogenase;
MRI, magnetic resonance imaging; Nivo, nivolumab; PD, progressive disease;
PsPD, pseudoprogression; RT, radiotherapy; SD, stable disease; T1 PC,
post-contrast T1 image; TMZ, temozolomide; VSRr x 8, perfusion value
equivalent to eight times that of the normal-appearing contralateral white
matter; W&S, wait and see.
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Due to toxicity (grade III asthenia, and grade II diarrhea), however, treatment was permanently discontinued after one single cycle administered in June 2019, and the patient was transferred to hospice for end-of-life care where he died 3 months later (Figure 2).