Coming dissertations at MedFak
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Complications after Breast Cancer Surgery and Oncological Outcomes
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-544007
Breast cancer is the most common cancer worldwide for females. A frequent complication following breast cancer surgery is surgical site infection (SSI). Complications can result in diminished quality of life, increased morbidity, elevated healthcare costs, delayed initiation of adjuvant therapy, loss of reconstruction, and potentially adverse oncological outcomes. In Paper I, the primary objective was to investigate the purported association between SSI and breast cancer recurrence. In addition, the study aimed to explore a potential link between any postoperative infection and breast cancer recurrence. This population-based, retrospective cohort study found that neither SSI nor other postoperative infections were associated with worse oncologic outcomes. Paper II investigated risk factors for SSI following breast cancer surgery, as well as risk factors for other wound complications. This research was conducted through a prospectively registered cohort study. Multivariable analysis identified BMI 25-30 and BMI >30 as the only significant risk factors for SSI. Additionally, significant risk factors for any wound complication included mastectomy with or without reconstruction, as well as BMI 25-30 and BMI >30. In Paper III, the primary aim was to evaluate whether SSI increases the risk of systemic breast cancer recurrence. Secondary objectives included assessing the impact of SSI on the risk of locoregional recurrence (LRR), breast cancer-specific survival (BCSS), and overall survival (OS). This analysis utilized high-quality data from national population-based registers, checking for confounding variables such as patient and tumour characteristics. In conclusion, SSI following breast cancer surgery does not significantly increase the risk of systemic recurrence, LRR, overall death, or breast cancer-specific death. Paper IV evaluated the risk of systemic breast cancer recurrence following major systemic postoperative infection or other major event. It also assessed the impact of these exposures on LRR, OS, and BCSS. Utilizing the same cohort as in Paper III, the findings indicated that postoperative major systemic infection was associated with an increased risk of systemic recurrence, overall death and breast cancer-specific death, but not with LRR.
In conclusion, this thesis does not support the hypothesis that SSI is associated with poorer oncological outcomes. However, it demonstrates an association between major systemic infections and worse oncological outcomes.
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To a Radiant Future and Beyond : Improving Radiotherapy of Neuroblastoma
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-544449
Neuroblastoma is a pediatric cancer with a five-year survival rate of merely 50% for high-risk cases. The treatment regimen is aggressive, leading to extensive side effects that significantly impact patients’ quality of life.
Targeted radionuclide therapy (TRT) involves the systemic administration of cancer-specific radioconjugates. This thesis focuses on TRT against the somatostatin receptor 2 (SSTR2) and the antigen CD44v6, two targets that are overexpressed in neuroblastoma,
Radiosensitization renders cells more sensitive to radiation, which can improve the therapeutic efficacy and potentially reduce the radiation dose required to achieve an antitumor effect. This thesis investigates radiosensitization through the stabilization of p53 and the inhibition of heat shock protein 90 (HSP90), two proteins involved in the cellular response to DNA damage.
In papers I and II, we investigated the combination of the SSTR2-targeting radioconjugate 177Lu-DOTATATE with the p53-stabilizing peptide VIP116 for neuroblastoma treatment. The combination therapy demonstrated enhanced antitumor effects in both in vitro and in vivo studies using mice bearing human neuroblastoma xenografts. Notably, the untreated and monotreated controls showed no nephrotoxicity.
In paper III, we demonstrated that combining external beam radiotherapy with the HSP90-inhibitor Onalespib produced additive or synergistic effects in vitro across a panel of neuroblastoma cell lines. Additionally, mice bearing syngeneic neuroblastoma tumor xenografts treated with this combination exhibited significantly improved therapeutic efficacy compared to control groups.
In paper IV, we developed and characterized human anti-CD44v6 antibodies for molecular radiotherapy. This work identified a lead candidate, UU-40, which demonstrated high affinity, strong tumor uptake, and favorable in vivodistribution, making it a promising candidate for future use against CD44v6-expressing cancers.
In conclusion, this thesis demonstrates that radiosensitization enhances the antitumor effects of radiation therapy in preclinical models of neuroblastoma. It is our hope that these discoveries will enable more effective and less harmful treatments for children with neuroblastoma. This thesis also produced an anti-CD44v6 antibody that holds great potential for future use in targeted radionuclide therapy, paving the way for innovative treatments for CD44v6-expressing cancers, including neuroblastoma.
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Peroneus longus to brevis tendon transfer – a feasible procedure?
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-543748
The peroneus (also termed fibularis) longus and brevis muscles stabilize the lateral side of the ankle during gait. Both tendons can be injured through ankle supination trauma. In cases of more extensive damage to the tendons, a direct repair is not possible, and surgery with a peroneus longus to brevis tendon transfer has been suggested with an added lateral ankle ligament reconstruction, and sometimes a calcaneal osteotomy, in the case of hindfoot varus. This thesis explores the outcome after this surgery:
- Sixteen patients (17 feet) had a follow-up 2-6.5 years after surgery, that also included an osteotomy to the first metatarsal. The results showed good patient-reported and clinical outcome, but slight residual hindfoot varus.
- The difference in anatomic structure between the two muscles was studied and sixteen cadaver legs dissected. Both muscles are pennate, but the peroneus longus had longer fibre length and is 1.4-4.6 times larger in volume than peroneus brevis. The good holding power of peroneus brevis is not attributable to muscle anatomy.
- Thirty-two patients filled out the Foot and Ankle Outcome Score (FAOS) and SF-36 and conducted a gait analysis before, and at six and 12 months after surgery. The FAOS improved significantly, and the three physical domains in SF-36 improved. In the gait, the peak pressure under the first metatarsophalangeal joint diminished. Compared to a healthy control group, there was no other significant difference in the gait kinematics. The FAOS had a moderate correlation to the velocity.
Drawing on the evidence presented in this thesis we demonstrate that the peroneus longus to brevis tendon transfer, with a lateral ankle ligament reconstruction and additional calcaneal osteotomy, is a surgical procedure that achieves good outcomes in terms of patient-reported outcome and gait in patients with irreparable tears of the peroneus tendons.