| 1. |
- Cashin, Peter H, 1984-
(författare)
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Cytoreductive Surgery and Intraperitoneal Chemotherapy in Patients with Peritoneal Metastases from Colorectal Cancer : Aspects of loco-regional treatment outcome, patient selection, and chemo-sensitivity
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Previously, peritoneal metastases(PM) from colorectal cancer(CRC) have been considered a terminal and generalised form of cancer. A new treatment strategy combining cytoreductive surgery(CRS) and intraperitoneal chemotherapy(IPC) has recently shown promising results. The aim of this thesis was to investigate different aspects of this treatment in order to optimise the treatment and to clarify its potential as a new treatment option. Treatment outcome, patient selection, method of IPC (hyperthermic intraperitoneal chemotherapy-HIPEC vs. sequential postoperative intraperitoneal chemotherapy-SPIC) and choice of drugs for IPC were the aspects covered in this thesis.The treatment outcome of CRS and IPC according to the median overall survival ranged from 24 to 34 months with 5-year overall survival ranging from 20 to 40% depending on the IPC treatment administered. Furthermore, the 5-year disease-free survival was impressive at 32% for patients receiving HIPEC. This establishes the curative potential of this treatment. Due to current inadequacies of radiological imaging, a score (Corep score) was developed for patient selection purposes. This score had a sensitivity of 80% and specificity of 100% in identifying patients with short cancer-specific survival after the treatment (<12 months). Further studies are needed to elucidate the clinical usefulness of the Corep score. HIPEC was associated with better survival than the SPIC method at similar morbidity and mortality rates, suggesting that HIPEC be the method of preference. Concerning the choice of drugs, the last study investigated the chemo-sensitivity of different PM tumour-types with a special focus on CRC. While CRC samples were generally more resistant, the ratio of the in vivo concentration compared to the ex vivo concentration giving a 50% tumour cell death showed that oxaliplatin had the best profile across all PM tumour types as well as for CRC. This needs further confirmation in a clinical trial.
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| 2. |
- Collin, Åsa
(författare)
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Colorectal cancer : Aspects of staging, treatment, recurrence and survival
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer is the third most common malignancy in the world, and major breakthroughs have been made regarding both surgical and oncological treatment. Still, postoperative complications, such as perineal infections after abdominoperineal resection (APR), are a major cause of morbidity, and distant recurrence rate is nearly 20%. In this thesis, means to improve postoperative infection rates, nodal staging in rectal cancer (and resulting overtreatment through (chemo)radiotherapy), cancer recurrence rates and survival, were investigated. In Paper I, the effects on complication rates, recurrence rates and survival of antibiotics applied locally after an APR, by means of a gentamicin-collagen sponge in the perineal wound, were analysed in a randomized setting. No difference was seen regarding any of the endpoints. The results suggest that local antibiotics can safely be omitted in APRs. Paper II investigated the effects of mechanical bowel preparation (MBP) on cancer recurrence and survival, among colon cancer patients undergoing a colon resection. Data from the Swedish randomized MBP trial were used. After follow-up, no improvement in recurrence rates or overall survival was seen, but cancer-specific survival was improved in the MBP group. In conclusion, MBP might be a prognostic favourable factor for outcome in colon cancer patients. In Paper III, the effect of new national guideline criteria for MRI nodal staging in rectal cancer was assessed, regarding the proportion of clinically positive nodes and staging accuracy, and resulting effects on preoperative (chemo)radiotherapy use. Comparing the two years prior to guideline implementation with the two years after implementation revealed a significant decrease in the proportion clinically positive nodes, but staging accuracy remained low, and (chemo)radiotherapy rates decreased with seemingly no correlation to guidelines. Thus, new guidelines decreased the rate of clinically positive nodes, but nodal accuracy remained poor and nodal staging should perhaps not be a criterion in preoperative treatment decisions. Paper IV investigated the impact of the total mesorectal excision quality, by means of the three Quirke grades, mesorectal (best quality), intramesorectal and muscularis propria (worst quality), on recurrence and survival, and assessed risk factors for intramesorectal or muscularis propria resection. Muscularis propria grade was associated with a higher local recurrence rate, but not with distant recurrence or survival. Several factors were associated with intramesorectal and muscularis propria grade, and more caution is warranted in these patients. In conclusion, this thesis provides insight into treatment choice, and the association of day-to-day treatment details with postoperative complications, recurrence and survival rates, as well as the challenges of nodal staging.
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| 3. |
- Danielson, Johan, 1975-
(författare)
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Anorectal Malformations : Long-term outcome and aspects of secondary treatment
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Faecal incontinence (FI) is defined as the inability to control bowel movements. The causes of FI are many and diverse. One of the more uncommon reasons for FI is Anorectal Malformations (ARMs). An ARM is a congenital anomaly that affects somewhere between 1/2500 and 1/5000 live born babies. Many ARM patients have persistent FI. Several different procedures have been utilised to address this issue. This thesis aims to evaluate (1) the long-term outcome in adulthood of ARMs in relation to the modern Krickenbeck classification, and (2) scope for treating FI with transanal injection with dextranomer in non-animal stabilised hyaluronic acid (NASHA/Dx), in patients both with and without ARMs.All patients treated for ARMs in Uppsala up to 1993 were invited to participate in a questionnaire study of quality of life and function. The study included 136 patients and compared them with 136 age- and sex-matched controls. The Krickenbeck classification was found to predict functional outcome, and ARM patients had more problems with incontinence and obstipation, as well as inferior Quality of Life (QoL), compared with controls. Thirty-six patients with FI, owing to causes other than ARMs, were treated with transanal submucous injection of NASHA/Dx. The patients were monitored for two years after treatment. Significant reductions in both their incontinence score and the number of their incontinence episodes were achieved. A significant improvement in QoL was observed in patients who had at least a 75% reduction in incontinence episodes. No serious complications occurred.A prospective study of transanal injection of NASHA/Dx was conducted on seven patients with persistent FI after ARMs. After six months a significant reduction in the number of incontinence episodes was obtained. A significant improvement in QoL was also found. No serious complications occurred.In conclusion, adult patients with ARMs have inferior outcome of anorectal function and QoL compared with controls. NASHA/Dx is effective and appears to be safe in treating FI in general. This effect seems to be the same in selected patients with persistent FI after ARMs.
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| 4. |
- Dranichnikov, Paul, MD, PhD Candidate, 1980-
(författare)
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HIPECology : Aspects of Postoperative Morbidity Following the HIPEC Procedure
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Peritoneal surface malignancy (PM), regardless of the dissemination site, was once considered a terminal condition. However, the introduction of a surgical approach with cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) with or without early intraperitoneal chemotherapy (EPIC) shifted the attitude from managing the symptoms of PM to disease treatment with curative intent. The magnitude of this combined therapy leaves the patients at risk for a diverse range of postoperative morbidities. Moreover, some small cohort studies argued that combining HIPEC with EPIC is associated with a higher risk of postoperative complications compared to HIPEC alone. The overall aim of the thesis was to investigate postoperative morbidity following the management of PM with CRS and HIPEC ± EPIC.We investigated readmission morbidity within 6 months after CRS and HIPEC, using a national population-based register. The results of this study showed that morbidity causing HIPEC-related readmission was higher than expected, with almost half of the interventions occurring outside the HIPEC centre. Gastric resection and advanced age are independent predictors of morbidity and readmission. We analyzed postoperative coagulopathy and the risk for venous thromboembolic events (VTE) in a prospective study. Results revealed that significant postoperative changes in coagulation biomarkers occur with dynamic changes over 10 days postoperatively. The incidence of symptomatic VTE was low. Residual tumor at completion of surgery, and elevated D-dimer on day 2, were independent risk factors for postoperative VTE. Postoperative morbidity following HIPEC + EPIC was compared to morbidity following HIPEC alone in our propensity score matched study. Results showed that HIPEC + EPIC is associated with a prolonged hospital stay (LOS), but there was no statistically significant relevant increase in postoperative morbidity, reoperation rate or incidence of readmission. Finally, we also analyzed the impact of different strategies of intraoperative fluid management during CRS and HIPEC on postoperative outcomes. Goal-directed therapy (GDT) is associated with significantly improved LOS despite an increase in morbidity in some patients. GDT management does not affect the postoperative risk for hemorrhage, although the choice of an oxaliplatin-based HIPEC does. Personalized GDT based on patients’ characteristics and surgery should be utilized during the management of CRS and HIPEC patients.
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| 5. |
- Enblad, Malin
(författare)
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Colorectal and appendiceal peritoneal metastases : From population studies to genetics
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Peritoneal dissemination of colorectal and appendiceal origin was previously considered the end-stage of malignant disease. Today, treatment with cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) has prolonged survival and cured some patients with peritoneal metastases (PM). Unfortunately, a majority of patients still have fatal outcomes. In this thesis, colorectal and appendiceal PM were studied from a wide population-based perspective down to the detailed perspectives of histopathology and genetics, with the aim of further contributing to prolonged survival.In Paper I, the heterogeneous histopathology of PM was investigated and a substantial proportion of patients undergoing CRS and HIPEC were found to have surgical specimens lacking neoplastic epithelium. These patients had a favourable prognosis and the results illustrate the importance of thorough analysing and reporting of histopathology for understanding differences in survival outcomes and for improving patient selection. In Paper II, the role of inflammation in colorectal and appendiceal carcinogenesis was investigated at a population-based level. Patients with non-surgical treatment of appendicitis had an increased incidence of cancer (especially of appendiceal and right-sided colon cancer) compared to the general population. This should be taken into consideration in the discussion of optimal management of patients with appendicitis. In Paper III, risk factors for PM were studied with the aim of aiding in the detection of PM at earlier stages. Appendiceal and right-sided colon cancer, advanced tumour and node stages, mucinous histopathology and vascular invasion were identified as high risk features for developing PM, and should increase awareness of potential PM. In Paper IV, genome-wide chromosomal copy number alterations of PM were explored and associated with prognosis after CRS and HIPEC. Colorectal PM exhibited a wide range of alterations of which copy number gain on parts of chromosome 1p and 15q were significantly associated with poor prognosis and have the potential to be used as prognostic molecular markers in the future.In conclusion, this thesis provides new insights into the field of colorectal and appendiceal cancer and PM to be used for improved patient selection, early detection and prevention, ultimately contributing to improved survival.
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| 6. |
- Franck-Larsson, Karin
(författare)
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Gastrointestinal Manifestations and Pathophysiological Mechanisms in Systemic Sclerosis
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic sclerosis (SSc) is a rare systemic, autoimmune disease characterized by vascular changes and fibrosis of the skin and internal organs. Patients with SSc more frequently than healthy controls reported upper gastrointestinal (GI) symptoms, which was more abundant in the diffuse cutaneous form (dcSSc) of the disease than in the limited (lcSSc). One-third of a population-based cohort of 79 SSc patients reported faecal incontinence, compared to 11% in 158 healthy matched controls (p<0.001), and this symptom negatively influenced general well-being and social life. Impaired rectal sensibility, rectal bleeding, irritable bowel syndrome-like symptoms, abdominal pain, the need for manual assistance at defecation, and the use of oral laxatives were more common in patients than in controls. SSc patients reported lower scores in both physical and mental scales of the SF-36 questionnaire than controls, indicating worse health-related quality of life. Gastric emptying was slower in patients than in controls, and a higher prevalence of delayed gastric emptying in patients with dcSSc indicated more severe GI tract involvement than in lcSSc. Electrogastrographic recordings did not correlate to gastric emptying results, indicating factors other than defective myoelectric signals contributed to disturbed gastric function. SSc patients with faecal incontinence had lower anal squeeze pressures than patients without this symptom. Only patients with faecal incontinence had ultrasonographic abnormalities in the internal and external anal sphincters, and absence of the rectoanal inhibitory reflex. Thus, faecal incontinence in SSc patients may depend on both neurogenic and structural mechanisms. A discrete increase in fibre density observed in a majority of SSc patients might have implications from a disease mechanistic perspective. Sera from 47% of 70 SSc patients had the capacity to induce interferon (IFN)-α, production which correlated to the presence of anti-RNP and anti-SSA autoantibodies. Increased serum levels of IFN-inducible protein were associated with vascular manifestations, and increased serum levels of IFN-α with digital ulcers. Increased serum levels of monocyte chemoattractant protein-1 or IFN-α were associated with lung fibrosis. An activated type I IFN system previously observed in several other systemic autoimmune diseases is also present in SSc and may contribute to vascular pathology and the pro-fibrotic process.
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| 7. |
- Gustafsson, Ulla-Maria, 1957-
(författare)
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Anal Fistula : Aspects of Aetiology, Diagnosis and Prognosis After Surgical Treatment
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with idiopathic anal fistula (n=85) were compared with 215 control subjects, matched for age and sex, through a 180-item questionnaire. Obesity, smoking, constipation and bowel symptoms associated with IBS were more common in the patients.Endoanal ultrasound (EUS) and magnetic resonance imaging (MRI) were compared in the preoperative evaluation of anal fistula in 23 patients. For classifying the primary tract, EUS and surgical findings agreed in 14 cases, and MRI and surgery for 11: for identifying an internal opening, the corresponding figures were 17 and 10.Healing and sphincter function were studied in 42 patients operated with fistula excision and closure of the internal opening. Twenty-three patients healed primarily and another 10 after one re-operation, whereas nine required further surgery until healed. Anal resting pressure was reduced after three and 12 months, and squeeze pressure after 12 months.Eighty-three patients were randomised to surgery with or without application of gentamicin-collagen underneath the flap: 26/42 of patients randomised to gentamicin-collagen healed primarily compared with 21/41 of patients randomised to surgery only (n.s).Micro perfusion in the flap was studied by laser Doppler flowmetry during surgery in 16 patients. No correlation was seen between change in blood flow during surgery and non-healing/recurrence of the fistula.In conclusion, obesity, functional bowel symptoms and possibly smoking are more common in patients with idiopathic anal fistula than in the general population. Endoanal ultrasound is a useful tool in the preoperative evaluation of anal fistula. Advancement flap repair has a reasonably high primary recurrence rate and healing is not significantly improved by local application of gentamicin-collagen: impaired intraoperative blood perfusion of the flap is an unlikely reason for non-healing. A decrease in continence occurs also after this kind of surgery, probably due to an impaired internal anal sphincter function.
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| 8. |
- Hansson, Johan, 1964-
(författare)
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Loco-regional Treatment of Peritoneal Carcinomatosis: Survival, Morbidity and Quality of Life
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Peritoneal carcinomatosis (PC) is traditionally regarded as a terminal stage of disease with a poor prognosis and systemic chemotherapy is regarded as palliative treatment. In order to improve survival and even to achieve cure for selected patients with PC, cytoreductive surgery and intraperitoneal che-motherapy have been advocated. Despite complete macroscopic removal of tumour, residual microscopic malignant cells might result in recurrence. Intraperitoneal chemotherapy aims to kill residual malignant cells and thereby needs to be distributed in the entire peritoneal cavity. This aggres-sive combined loco-regional treatment has a high risk of morbidity and mor-tality. Whether the increased risks are acceptable to improve survival re-quires investigation and the impact of loco-regional treatment of PC on health-related quality of life (HRQL) needs to bee explored The overall aim of this thesis was to analyse the impact of cytoreductive surgery and intraperitoneal chemotherapy on patients with peritoneal carci-nomatosis. A significant survival improvement (median 32 months) was seen in 18 patients with PC of colorectal origin subjected to loco-regional treatment, in comparison to matched controls treated with systemic chemotherapy (me-dian survival 14 months, Paper I). The results of single-photon emission computer-tomography (SPECT) in 51 patients were correlated to the number of intraperitoneal chemotherapy courses that could be performed without further surgery (Paper II). Postoperative 30-days morbidity and 90-days mortality was investigated in 123 PC-patients after loco-regional treatment. Severe adverse events occurred in 51 (41%) patients. Five patients (4%) had treatment-related mortality. Stoma formation, duration of surgery, periopera-tive blood loss, and extent of PC was associated with morbidity (Paper III). HRQL was investigated in 64 patients. HRQL was negatively affected at 3 months but a partial recovery was seen at 8 months. 30-day morbidity did not have any impact on HRQL at 8 months (Paper IV). This treatment there fore appears justified despite considerable toxicity in view of possible life prolongation.
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| 9. |
- Isacson, Daniel
(författare)
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Treatment of Acute Uncomplicated Colonic Diverticulitis
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to evaluate the clinical management of AUD with regard to the no-antibiotic policy and its long-term effect, treatment on an outpatient basis and the potential health-care cost savingsStudy I: a retrospective study at Västmanlands Hospital that evaluated and confirmed the adherence to the no-antibiotic policy in patients with AUD and its safety regarding complications and recurrences. A total of 246 patients with acute diverticulitis were identified, of which 195 had computed tomography (CT) confirmed AUD. In total, 91.3% of these patients did not receive any antibiotics and only two developed complications.Study II: a retrospective study with the aim to conduct a long-term follow-up of all Swedish patients who participated in the AVOD trial in terms of recurrences, complications, surgery and quality of life. The medical records of 96% of the patients were reviewed with a mean follow up of 11 years. Quality of life questionnaires were sent out to all patients. There were no differences regarding the rates of recurrence, complications or surgery for diverticulitis. There were no differences in the quality of life between groups according to the EQ-5D questionnaire.Study III: a prospective study where 155 patients with CT-verified AUD as were treated as outpatients without antibiotics. On day 3, patients reported an average pain score of 1.8 of 10 on the VAS scale and only 30% of patients were using analgesia. Four patients returned to hospital because of treatment failure.Study IV: a retrospective cohort study at Västmanland’s Hospital evaluated the impact on admissions, complication rates and health-care costs of the policy of outpatient treatment without using antibiotics. Medical records of all patients diagnosed with AUD in the year before (2011) and after (2014) the implementation of outpatient management without antibiotics were reviewed. Overall 494 episodes of AUD were identified: 254 in 2011 and 240 in 2014. Three patients developed complications in 2011 and four in 2014. The proportion of patients managed as outpatients was 20% in 2011 compared with 61% in 2014. The hospital admissions, total length of stay of and total health-care costs were almost halved.In conclusion, these studies confirm the low complication and recurrence rates of AUD and strengthens findings that antibiotics have no benefit in the treatment of this disease. The no-antibiotic policy had no impact on short- or long-term outcomes regarding the rates of recurrence, complications, surgery or quality of life. Outpatient management was found to be feasible and safe, and significantly reduced admissions, which led to large health-care cost savings.
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| 10. |
- Jóhannsson, Helgi Örn, 1954-
(författare)
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Haemorrhoids : Aspects of Symptoms and Results after Surgery
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One hundred haemorrhoid patients were compared with 300 matched control persons. Haemorrhoid symptoms and bowel symptoms were studied. Most common symptom of the patients was bleeding (44%), followed by prolapse (24%), hygiene problem (14%), pain (12%) and itching (5%). Bowel symptoms, as bloating and evacuation difficulties, possibly related to IBS, were frequent among the patients.556 patients were operated upon with Milligan-Morgan haemorrhoidectomy. 418 (81%) answered a questionnaire on results, and on disturbances in anal continence. Totally140 (33%) reported recurrence, and 139 (33%) patients reported anal incontinence. Forty of the 139 patients associated this to the surgical procedure. Female gender was associated to increased risk of incontinence.The 40 patients who reported incontinence, were invited to undergo ano-rectal manometry, saline infusion test, endo-anal ultrasound, proctoscopy and clinical examination. Altogether 19 patients approved to participate. Matched control subjects and 15 persons previously operated for haemorrhoids, but without symptoms of incontinence, served as two reference groups. Incontinence score and saline infusion test showed significantly poorer continence in the patient group. Endo-anal ultrasound showed injury to the external sphincter in 20% of the patients. Anal pressure was slightly lower in the patient group, but the difference was not significant. Totally 225 patients were randomised to Milligan-Morgan or Ferguson haemorrhoidectomy. Primary aim was to study changes in anal continence. Other aims were to study postoperative pain, wound healing, complications, patient satisfaction and recurrence and changes in bowel function. Patients in the Ferguson group reported, slightly quicker wound healing (P=0.06). Postoperative pain was equal, as was rate of complications. After one year the Ferguson group reported lower incontinence score, and more satisfied patients. Recurrence rate was equal, 15-17%. Most bowel symptoms were reduced one year after surgery.In conclusion, functional bowel symptoms are common in haemorrhoid patients. Haemorrhoidectomy is associated with risk for incontinence in 5-10% of patients and females are at greater risk. A proportion of the patients who claim postoperative incontinence have physiological signs of sphincter incompetence, and external sphincter injuries are observed in those patients. Ferguson haemorrhoidectomy results in better anal continence and more satisfied patients.
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