DOI: 10.31038/CST.2018313

Abstract

In children and adolescents, primary osteosarcoma is one of the most common malignant bone tumors. It principally affects the long bones, especially in the distal femur, proximal tibia and proximal humerus. Osteosarcoma rarely arises from flat bone, and as in this patient’s case, osteosarcoma of the rib is very infrequent.  To the best of our knowledge, this is the first reported case of rib osteosarcoma in our country. Here we report a case of conventional rib osteosarcoma presenting as chest pain and mass that successfully had complete pathologic response with clear margins after four cycles of neoadjuvant therapy.

Introduction

Osteosarcomas principally originate in the metaphysis of the long bones. Approximately 10% of osteosarcomas originate in the flat bones, with the pelvis being the main site. Roughly 1 – 2% of osteosarcoma occur in the thoracic bones inclusive of the ribs, sternum, and clavicle [1].  The prevalence of osteosarcoma is in the second decade of life with another spike in older individuals after radiation or Paget’s disease [2]. Osteosarcoma of the rib have been reported in older children ranging from 7 to 13 years of age [3].  Diagnosis of osteosarcoma of the rib is a challenge for most physicians since the commonest presentation is pain and a palpable chest wall mass. The lesion is usually observed on a chest radiograph as a soft tissue mass. Limiting factors for its diagnosis is the difficulty visualizing typical periosteal reaction, rib destruction and calcifications within the mass in a chest radiograph compared to the site of the tumour if it were in a long bone. We present rare location of an osteosarcoma which posed a diagnostic challenge to both the pathologist and the physician in a young male.

Case Report

This is a case of an 18 year old Filipino male, apparently well until two months before consult, noted intermittent right upper quadrant pain. He later palpated a pea sized firm, movable, non-tender mass at the right upper quadrant area. Neither medications nor consult done until two months later noted gradual progression of the mass. It was approximately 3 x 3 cm in size with intermittent pain and occasional dyspnea. Consult done to a local hospital where chest radiograph was done revealing right pleural effusion. Underwent chest thoracostomy tube insertion was cytology negative for malignancy. Chest Computed tomography (Figure 1) done June 2016 revealed lobulated heterogenously enhancing mass lesion in antero-inferior aspect of right hemithorax measuring 5.3x 5.4 x 5.01 cm. Right paratracheal subcentimeter lymph nodes. Abdominal CT scan was unremarkable. Patient underwent excision biopsy of the mass at eighth rib revealed conventional osteosarcoma, osteoblastic type high grade
(Figures 2 and 3). Tumor size of 3.5 cm, no definite vascular invasion with tumor invasion into extra-osseous soft tissues and present in inked tissue edges. Diaphragmatic tumor was also noted to be high grade osteosarcoma.

Figure 1. lobulated heterogeneously-enhancing mass lesion in the antero-inferior aspect of the right hemithorax measuring 5.3 × 5.4 × 5.01 cm   in cranio-caudad, transverse and antero-posterior diameters. Mass cannot be separated from the expanded and lytic change anterior aspect of the right 8th rib with associated overlying soft tissue swelling and indentation into the superior-anterior margin of right hepatic lobe

Figure 2. Low power field magnification

Figure 3. High power field magnification several highly atypical spindle cells producing tumor osteoid. The cells have enlarged, hyperchromatic nuclei with prominent nucleoli. Brisk mitotic activity is seen.

He was referred to a Medical Oncologist where he underwent four sessions of neoadjauvant chemotherapy from June 23-August 29, 2016 with Doxorubucin (25mg/m²) and Cisplatin (50mg/m²) days 1-3 every 21 days. He tolerated the therapy well, no adverse events. Re-evaluation scans done September 27, 2016 showed Interval resolution of right sided pleural effusion. Right 7th anterior rib is surgically absent with stable post interventional change in right serratus anterior muscle. He was then referred to Thoracic Surgeon for surgery. Pre-operative pulmonary function test was unremarkable. He underwent video-assisted thoracic surgery, right converted to thoracostomy with chest wall reconstruction using bone cement for four hours and 26 minutes. Post-operative findings were dense pleural adhesions from apex down to diaphragm, no gross tumor noted along chest wall, diaphragm and pleura. Resection extended one rib above and one rib below (6th and 8th ribs). Specimen was sent to histopathology laboratory with later findings of fibrosis, haemorrhage and negative for tumor of pleural nodule and right lateral chest wall (Figures 4, 5 & 6).  No residual tumor and negative lines of resection for the 6th and 8th ribs.

Figure 4. Pleural Nodule, Right, Lateral Chest Wall, Diaphragm: Fibrosis, Old haemorrhage. No tumor present

Figure 5. Ribs 6-8^th, chest wall resection: No residual tumor, fibrosis, granulation tissue

Figure 6. Pleural Nodule, Diaphragm, Right, Parietal Pleura: fibrosis and granulation tissue formation. Negative for tumor

Surveillance studies done on the 3^rd, 6^th and 9^th month post-surgery were unremarkable. Chest CT scan (Figure 7) done did not show discrete enhancing mass in the anterolateral chest wall to suggest tumor recurrence and enlarged lymph nodes. Latest CT scan done July 21, 2017. Patient is back to school with no symptoms.

Figure 7. Surveillance chest CT scan: The RIGHT antero-lateral 6th to 8th ribs are surgically absent. No pulmonary mass or nodule.

Discussion

Chest computerized tomography examination is useful for identification and characterisation of the mass. Invasion to deeper structures like the muscles, pleura and lungs can also be accurately assessed with the aid of a CT scan as compared to plain radiograph. CT would be a more cost effective modality for evaluating the tumour since a magnetic resonance imaging (MRI) may not offer any additional information.³  Therefore, accurate diagnosis is an essential component in survival of these patients. Histopathological diagnosis is imperative in instituting a definite therapy. The classic feature of a ramifying osteoid matrix laid down by the neoplastic cells clinches the diagnosis and enables one to exclude all the other possible differentials.

Conventional osteosarcomas are the most aggressive osseous neoplasms. The overall prognosis of osteosarcoma in flat bones remains poor because of the difficulty of complete excision. The guidelines for management and the prognosis and survival rates in rib primary OS is not clear due to the small number of cases studied. However, there is documentation of better survival in patients who have had a complete resection of their tumor at the time of surgery [4]. A local wide excision with removal of the involved ribs and subsequent reconstruction using a mesh followed by adjuvant chemotherapy and radiotherapy may improve survival in these patients. Although osteosarcoma of flat bones is rarely associated with metastasis, it is still advised to include a CT scan of the thorax, chest x-rays, and bone scans as part of the diagnostic tool in order to look for metastasis.

The treatment of osteosarcoma generally consists of local excision with a wide margin [5]. It still remains to be unresolved exactly what size of margin is optimal. Palliative chemotherapy or radiotherapy may also be considered for those who undergo a palliative surgery since >80% of patients, local recurrence appears in the absence of a wide resection.

Conclusion

This case highlights the importance of including the diagnosis of osteosarcoma, although rare, as a differential diagnosis of primary malignant neoplasm of the rib. Point tenderness in the young also warrants further investigation for it may just be the sole manifestation of a treatable case as morbid as malignancy.

References

1. Mirra JM, Gold RH, Picci P (1989) Osseous tumors of intramedullary origin. In: Mirra JM, editor. Bone Tumors: Clinical, Radiological, and Pathological Correlations. Philadelphia: Lea and Febiger; 143–438.
2. Burt M,  Fulton M, Wessner-Dunlap S, Karpeh M, Huvos AG, et al. (1992) Primary bony and cartilaginous sarcomas of chest wall: results of therapy. Ann Thorac Surg 54: 226–232. [crossref]
3. Deitch J,  Crawford AH, Choudhury S (2003) Osteogenic sarcoma of the rib: a case presentation and literature review. Spine (Phila Pa 1976) 28: E74–77. [crossref]
4. Xu, J. and Yao, Q. and Hou, Y. and Xu, M. and Liu, S. and Yang, L. and Zhang, L. and Xu, H (2013) MiR-223/Ect2/p21 signaling regulates osteosarcoma cell cycle progression and proliferation. Biomedicine and Pharmacotherapy. 67: 381–386
5. Funovics PT, Bucher F, Toma CD, Kotz RI, Dominkus M (2011) Treatment and outcome of parosteal osteosarcoma: biological versus endoprosthetic reconstruction. J Surg Oncol 103:782–9.

DOI: 10.31038/CST.2018312

Abstract

An overlap clinical and biochemical can occur between dogs with sudden acquired retinal degeneration syndrome (SARDS) and those with blindness by hyperadrenocorticism (HAC). A 13-year-old, cross-breed female dog showing recent signs of polyphagia, swollen abdomen and sudden blindness was examined. The flat electroretinography was consistent with bilateral retinal damage. The biochemical tests for the diagnosis of HAC were inconclusive when the blindness was established. However, HAC was confirmed two months after through the urine cortisol: creatinine ratio (UCCR: 69.4 × 10^-6, RV: <10), plasmatic cortisol 1-hour post-ACTH (21.7 µg/dl, RV: <17) and 8-hour post-low dose dexamethasone suppression test (LDDST: 2.9 µg/dL, RV: <1.5). A basophilic microadenoma of the adenohypophysis (2.3 x 1.3 mm) with immunopositivity for ACTH was identified by histopathology. The final diagnosis was pituitary-dependent hyperadrenocorticism (PDH). This report, demonstrates through histopathology the association between a corticotropinoma and the sudden blindness by retinal damage in a dog with Cushing’s syndrome. In addition, it highlights the importance of timely use of the various hormonal tests for the correct diagnosis of HAC.

Keywords

ACTH, electroretinography, hyperadrenocorticism, pituitary, SARDS

Introduction

Sudden blindness with normal ophthalmoscopy and absence of electroretinography (ERG) response may be seen in dogs with PDH, but also with SARDS [1-4]. Likewise, dogs with SARDS may display systemic signs of HAC such as polyphagia (PF), polyuria (PU), polydipsia (PD), weight gain and biochemical changes (e.g., increase in serum alkaline phosphatase [SAP], total cholesterol [TChol]) in more than 80% of cases [3,4]. In the light of these arguments, there is a clear clinical and biochemical overlap between these two entities where blindness is irreversible [4]. In PDH cases, non-treatment may lead to the onset of numerous comorbidities (e.g., diabetes mellitus, hypertension, dyslipidemia) that can dramatically decrease survival [3, 5]. The confirmation or exclusion of its diagnosis is therefore essential.

This case offers the first histopathological evidence of the connection between a functional corticotropinoma (micro-adenoma) and sudden blindness caused by retinopathy.

Case report

A 13-year-old, cross-breed, neutered female dog weighing 12.5 Kg was referred for evaluation for sudden blindness. Additionally, it suffered from PF (two weeks before blindness), muscle atrophy in limbs, swollen abdomen and excessive panting (Figure 1). Negative response to threat test, slightly mydriatic pupils, photomotor reflex negative response, normal fundus with intraocular normotension and a flat ERG were consistent with retinal injury (Figure 2). Increased SAP (450 UI/ml, RV: < 250), TChol (250 mg/dl, RV: < 220) and decreased urine density (1022, RV: > 1030) were the only changes in the biochemistry and the hemogram (Table 1). Slightly increased UCCR with plasmatic cortisol suppression 8 hours post LDDST and normal adrenal glands in the ultrasonography ruled out HAC on the first examination (Table 1).

Table 1. Biochemical diagnosis and follow-up of Cushing disease

UCCR: urine cortisol/creatinine ratio (x10^-6); Co: plasma cortisol (µg/dl); Co4h-LDDST: Co at 4 hours post LDDST; Co8h-LDDST: Co at 8 hours post LDDST; Co1h-ACTH: Co at 1 hours post ACTH; pACTH: plasma adrenocorticotropic hormone (pg/ml); SAP: seric alkaline phosphatase (UI/l); BAW: bilateral adrenal width (mm); TChol: total colesterol (mg/dl); Tg: triglycerides (mg/dl); G: glucose (mg/dl); SP/DP: systolic and diastolic pressure (mmHg); W: weight (Kg); UPC: urinary protein creatinine; a: chemiluminescence; b: spectrophotometry; *: under treatment with Cabergoline and ketoconazole (0.07 mg/Kg PO q72h and 10 mg/kg PO q24h, respectively).

Two months later, in view of the development of PU, PD, compounded with weight gain, a second examination on the adrenal axis was performed, and the plasmatic cortisol 1-hour post-ACTH and 8-hour post-LDDST was found to be consistent with HAC (Table 1). Plasmatic ACTH (pACTH: 48 pg/ml, RV: 5-60) was found to be improperly high vis-a-vis the UCCR (69.4×10^-6, RV: <10). Unlike the findings of the first examination, an increase in triglycerides (Tg), systolic pressure, diastolic pressure and the urine protein: creatinine ratio became evident (Table 1).

Based on the previous findings, PDH was deduced and cabergoline was then administered as treatment (0.07mg/Kg PO q72h) [6] and Ketoconazol (10 mg/kg PO q12h, tolerated dose) [3]. The biochemical and clinical follow-up performed two months later revealed a reduction of clinical signs (PU, PD and PF), the normalization of TChol, Tg, blood pressure, and a reduction of SAP and UCCR (Table 1). Likewise, hyperplasia of both adrenal glands was observed in the ultrasonography. Shortly afterwards, an accidental fall, favored by the blindness, resulted in a hip fractured that precipitated the humanitarian euthanasia of the animal. The owners authorized a transsphenoidal extraction of the pituitary and both adrenal glands by celiotomy. The extracted pituitary showed normal appearance and a whitish nodule on its outer edge (Figure 3), and both adrenal glands evidenced a size increase.

 Normal adenohypophysis, in histological sections stained with hematoxylin-eosin (HE), consisted of a chain of globose-polyhedric cells arranged on a delicate fibrovascular stroma (Figure 4). In the periphery of the adenohypophysis, a proliferation of polyhedral cells organized in three to four rows of dense trabeculae of delicate fibrovascular stroma was found, which presented low pleomorphism, broad basophilic cytoplasm and a nucleus rounded with an evident nucleolus (Figure 5). These cells were organized in a larger, well-circumscribed, unencapsulated lobe, corresponding to an adenoma (2.34 x 1.3 mm) (Figure 6). The cells that make up the adenoma demonstrated intense positive cytoplasmic staining with the anti-ACTH antibody (mouse monoclonal, sc-52.980, Santa Cruz Biotechnology, Santa Cruz, CA, USA [1: 400 in PBS]) (Figure 7). Hiperplasia of the fascicular and reticular zones was found in both adrenal glands (Figure 8).

Figure 1. External aspect, bitch with pituitary-dependent hyperadrenocorticism and sudden blindness.

Figure 2. Electroretinography record showing flat waves in both eyes.

Figures 3-7. Pituitary, dog.

Figure 3. Macroscopic aspect of the pituitary and micro adenoma (arrows) after being fixed in 10% formaldehyde. n: neurohypophysis. a: adenohypophysis.

Figure 4. Microphotography normal adenohypophysis. A chain of globose-polyhedral cells, arranged in a delicate fibrovascular stroma. Hematoxylin-Eosin (H-E).

Figure 5. Microphotography basophilic adenoma composed of polyhedric cells with ample basophilic cytoplasm, arranged in thick trabeculae. H-E.

Figure 6. Microphotography pituitary with a basophilic adenoma of 2.3 x 1.3-mm (arrows) in adenohypophysis (a). ih: intermediate hypophysis. n: neurohypophysis. H-E.

Figure 7. Microphotography corticotropinoma cells with intense positive cytoplasmic staining with anti-ACTH antibody. Immunohistochemistry, Avidin-Biotin-peroxidase complex.

Figure 8. Microphotography adrenal cortex, diffuse hyperplasia fascicular zone (fz) and reticular zone (rz) with normal glomerular zone (gz). m: adrenal medulla (H-E).

Discussion

In this case, the sudden blindness, the absence of structural damage in both eyes, the integrity of optic chiasma (necropsy), the abolished ERG, the presence of systemic clinical signs (PF, PU, PD, weight gain) and the changes in biochemistry (SAP and TChol) were findings consistent with PDH, but also with SARDS [1,7]. The confirmation of PDH two months later the first evaluation using the same endocrine tests (LDDST and UCCR) was a peculiar finding. This fact highlights the advisability of performing a second endocrine evaluation in dogs with HAC signs and sudden blindness with inconcluse tests diagnostic, where a stimulation test should also be performed with ACTH [7], prior to reaching to any incorrect diagnosis of SARDS.

Images of the pitutary gland through computed tomography or magnetic resonance were no realizated; but the pituitary origin was deduced in view of plasma ACTH levels in connection with the increased UCCR and the absence of neoplastic injury to the adrenal glands. Additionally, it must be noted that even when using the CT and the MRI, pituitary tumors may not be detected in 28% to 37% of dogs with PDH [8,9]. Subsequently in the histopathology was confirmed the corticotropinoma. The basophilic staining characteristics obtained with the hematoxylin-eosin in the adenoma were compatible with the thyrotropic, gonadotropic or corticotropic cells, but the only cells ones of these that are immunopositive to anti-ACTH antibody are the corticotropic [10,11].

Like the blind dogs with PDH reported by Blatter [1], hypertriglyceridemia and hypercholesterolemia were found in this bitch in the second biochemical evaluation, but not at time of the onset of blindness. Other metabolic alterations mentioned in the retinopathy of dogs with Cushing’s disease are the increase in concentration of insulin, interleukin 6, and decrease in nitric oxide and adiponectin [2]; all of these except for insulinemia are not routinely used in the daily clinic, so their contribution to the development of blindness in this case could not be proven.

A limitation of this report is the retinal histopathological examination that could not be done due to conditions established by the owners in light of the need to extract both eyes.

Although the mechanism by which HAC induces sudden blindness in the dog is not well clarified, it is important to emphasize that its correct diagnosis and management of various comorbidities is fundamental to improve the survival of those dogs.

Finally, in dogs with sudden blindness, hypertension and dyslipidemia but with inconclusive diagnostic tests for HAC, it is recommended to carry out a timely medical and pharmacological management of each of the comorbidities, as well as a subsequent reevaluation of the adrenal axis.

References

1. Cabrera Blatter MF, Del Prado B, Gallelli MF, D´Anna E, et al. (2012) Blindness in dogs with pituitary dependent hyperadrenocorticism: relationship with glucose, cortisol and triglyceride concentration and with ophthalmic blood flow. Res Vet Sci 387–392.
2. Cabrera Blatter MF, Del Prado B, Miceli DD, Gomez N, et al. (2012) Interleukin-6 and insulin incrase and nitric oxide and adiponectin decrease in blind dogs with pituitary-dependent hyperadrenocorticism. Res Vet Sci 1195–1202.
3. Feldman EC. Canine Hyperadrenocorticism (2015) In: Feldman EC, Nelson RW, Reusch CE, Scott-Moncrieff JCR, Behrend E. Canine & Feline Endocrinology, 4th ed. St. Louise, Missouri, USA: Elsevier, 377–451.
4. Komáromy AM, Abrams KL, Heckenlively JR, Lundy SK, et al. (2016) Sudden acquired retinal degeneration syndrome (SARDS)–a review and proposed strategies toward a better understanding of pathogenesis, early diagnosis, and therapy. Vet Ophthalmol 19 : 319–31.
5. Miceli DD, Pignataro OP, Castillo VA (2017) Concurrent hyperadrenocorticism and diabetes mellitus in dogs. Res Vet Sci 115: 425–431. [crossref]
6. Castillo VA, Gómez NV, Lalia JC, Cabrera Blatter MF, García JD (2008) Cushing’s disease in dogs: cabergoline treatment. Res Vet Sci 85: 26–34. [crossref]
7. Carter RT, Oliver JW, Stepien RL, Bentley E (2009) Elevations in sex hormones in dogs with sudden acquired retinal degeneration syndrome (SARDS). J Am Anim Hosp Assoc 45 : 207–14.
8. Wood FD, Pollard RE, Uerling, Feldman EC (2007) Diagnostic imaging findings and endocrine test results in dogs with pituitary- dependent hyperadrenocorticism that did or did not have neurologic abnormalities: 157 cases (1989–2005). J Am Vet Med Assoc 231: 1081–1085.
9. Auriemma E, Barthez PY, Van der Vlugt-Meijer RH, Voorhout G (2006) Computed tomography and low-field magnetic resonance imaging of the pituitary gland in dogs with pituitary-dependent hyperadrenocorticism: 11 cases (2001–2003). J Am Vet Med Assoc 235: 409–414.
10. Jaime MN, López FIA, Cabrera GP (2003) Patología de los adenomas hipofisarios. Rev Esp Patol 36: 357–372.
11. Thomas JR, Gröne A (2016) Pituitary glands. In: Jubb KBF, Kennedy PC, Palmer NC. Pathology of domestic animals, 6th ed. St. Louise, Missouri, USA: Elsevier 276–290.

DOI: 10.31038/CST.2018311

Abstract

Background: Thanks to the increased effectiveness of the three pillars of cancer therapy i.e. early diagnosis, targeted surgery and chemotherapy, physician are now aiming at a now goal: improve quality of live of patients during and after cancer therapy

Objectives: This review article aims to identify clinical evidence of the effectiveness that MI and IP6 might have on QoL in cancer patients.

Methods: literature search was performed on MEDLINE, EMBASE, PubMed, Research Gate and Google scholar for studies published in English up to November 2017. We used the following combination of medical subject headings, terms and free text words: ‘inositol’, ‘quality of life’, ‘cancer’.

Conclusions: In conclusion, literature data seams to demonstrate that IP6 and MI are effective in improving QoL of patients undergoing chemotherapy due to breast cancer.

Keywords

Breast cancer, Quality of live, inositol, IP6, phytic acid

Introduction

Nowadays taking advantage of the three main tools that physicians are using to fight cancer, i.e. early diagnosis, targeted surgery and medical treatments (chemotherapy, hormonotherapy, immunotherapy) survival rate has reached a remarkable goal of roughly 65% (ranging from 25% for lung cancer to 87% for prostate cancer) [1, 2].

Such success rate has, with time, forced physicians to face a new challenge: how to improve patients’ quality of life (QoL) without reducing survival rate. Indeed, it has been demonstrated that QoL is an independent predictor with respect to life expectancy [3].

What is for sure is that we cannot simply ask for a reduction in chemo-radiotherapy so to improve QoL, indeed Bonadonna and coworkers demonstrated that as soon as patients receive less than 85% of the planned dose intensity the survival rate significantly decrease [3].

It is worth noting that the relative dose reduction might refer to both an actual reduction in the dosage of the drug used or to a delay in the therapy [4].

Having this in mind, several research groups worldwide are committed in improving patients QoL and therefore, eventually increase cancer treatment effectiveness too.

In this scenario, a major role has been played for several years by inositol(s), mainly myo-inositol (MI) and inositol hexakisphosphate (IP6) [4-6].

In this systematic review, we aim to identify clinical evidence of the effectiveness that MI and IP6 might have on QoL in cancer patients.

M&M Search strategy and data sources

We performed a literature search of MEDLINE, EMBASE, PubMed, Research Gate and Google scholar for studies published in English up to November 2017. We used the following combination of medical subject headings, terms and free text words: ‘inositol’, ‘quality of life’, ‘cancer’. Only clinical trials evaluating the effects of IP6 or IP6+MI as study group in women undergoing radio/chemotherapy for breast cancer were considered eligible.

In addition, reference lists of additional manuscript published were reviewed in order to identify additional eligible studies.

We followed the PRISMA checklist for meta-analysis [7].

Inclusion and exclusion criteria

Articles were critically reviewed for their eligibility in the meta-analysis. Among all the collected articles, clinical trials were identified by reading titles, abstracts and study design to select relevant studies according to inclusion/exclusion criteria.

Inclusion criteria restricted the search to: (a) the population of interest was made of women undergoing radio/chemotherapy due to breast cancer, (b) the intervention was IP6 with or without MI, (c) clear quantitative assessment of both quality of life (QoL) and blood counts. Exclusion criteria were: (a) duplicate publications, and duplicates on different database, (c) review papers and (d) animal studies.

Outcomes of interest

Primary outcomes: Quality of life, Functional status and Symptomatic scale based on the EORTIC questioner. Secondary outcomes: white blood cell and platelet counts.

Data extraction and quality evaluation

The following data were extracted from the selected studies and independently cross-checked by two investigators: general characteristics of the study (first author’s name, country where the study was conducted, study design, number of cases and controls, inclusion/exclusion criteria, type and duration of treatment) and results (means and S.D. for each outcome after intervention from treatment vs control). The quality of reports was evaluated according to the methods recommended by the Cochrane Handbook 5.0.2 [8]. including assessments of the randomization process, allocation concealment, blinding, selection criteria, baseline characters and withdrawal/dropouts.

Statistical analysis

The effect size was measured as the mean difference (MD) between the two treatment groups. A MD less than 0 was considered as a positive size effect for symptomatic scales; MD greater than 0 was considered as a positive size effect for Quality of life, Functional status, with blood cell counts and platelet counts. The heterogeneity analysis of intervention was performed by the Cochran’s Q test and the I² statistic, using a P value = 0.10. In order to account for heterogeneity across studies, the Der Simonian and Laird random effect model was used to obtain the pooled estimates and their 95% confidence intervals (CIs). Forrest plots were used to visually show the results of the analyses performed.

Meta-analysis was performed by means of OpenMeta [Analyst] software developed by The School of Public Health at Brown University USA. Results were considered statistically significant when the two-sided P value was <0.05.

Results

The flow diagram of the meta-analysis is presented in Figure 1 [7]. Based on the search 11 records were identified. After the screening 6 articles were assessed for eligibility. Following the screening 2 out of 4 papers were included in the analysis.

Figure 1.

A brief description of the manuscript matching the inclusion criteria is reported in Table 1.

Table 1.

Studies were conducted in Croatia [9] or Italy [10] and were published between 2010 and 2017.Treatments administered were IP6 +MI per OS at the dosage of 1.4g twice a day[9] or 5g of a 4% IP6 gel twice a day [10]. Noteworthy both treatments result in the same pharmacokinetic profile [11, 12].The duration of the treatment was 6 months for both studies.

The overall methodological study quality is summarized in Table 2.

Table 2.

Evaluation according to the methods recommended by the Cochrane Handbook 5.0.2.

M, the method was mentioned, but there was not detailed description;

N, the method was not used in the study;

Unclear, no relevant information was found in the study;

Y, the method was reported with detailed description.

The meta-analysis

In the two selected studies, a total of 17 women received IP6 alone or in combination with MI, and 17 women received control treatments (i.e. Vit-C, Hyaluronic acid gel).

The overall MD estimated from two studies showed a significant improvement for the patients treated with IP6 (+MI) after chemotherapy of the QoL (MD=36.167; 95%CI: 22.047 to 50.288 P= < 0.001) (Figure 2).

Additional improvements were highlighted for the Functional status (MD=33.261; 95%CI: 22.727 to 43.795 P= < 0.001) (Figure 3) and Symptoms Scale (MD= -28.577; -95%CI: 41.476 to -15.678; P= < 0.001) (Figure 4).

In addition to the data obtained from the EORTIC QLQ-C30 and QLQ-BR23 the blood counts results showed that IP6, eventually in association with MI, was able to reduce WBC drop after chemotherapy (MD= 3.579; -95%CI: 2.083 to 5.074 P= < 0.001) (Figure 5).

Figure 2. Forest plot showing effect sizes (mean difference (MD), 95% confidence interval (CI)) for QoL in women undergoing chemotheraphy for breast cancer treated with IP6 (+MI).

Figure 3. Forrest plot showing effect sizes (mean difference (MD), 95% confidence interval (CI)) for Functional Status in women undergoing chemotheraphy for breast cancer treated with IP6 (+MI).

Figure 4. Forest plot showing effect sizes (mean difference (MD), 95% confidence interval (CI)) for Smptoms Scale in women undergoing chemotheraphy for breast cancer treated with IP6 (+MI).

Figure 5. Forrest plot showing effect sizes (mean difference (MD), 95% confidence interval (CI)) for WBC in women undergoing chemotheraphy for breast cancer treated with IP6 (+MI).

Regarding platelet counts the analysis revealed considerable heterogeneity (Q(df=1)=7.870; Het. p-Value=0.005; I²=87.294). Nevertheless, it is worth to mention that in both studies, authors demonstrated that both treatments (either IP6 or IP6+MI) were able to prevent the drop of the platelet count.

Discussion

In the present review, we tried to highlight both new issues in the management of the oncological patient and new approaches in improving quality of life of patients undergoing chemotherapy.

In particular, literature data point at inositol(s), namely IP6 and MI, as an effective treatment able to improve patients QoL.

Indeed, literature data suggest that to improve cancer cure physicians have to improve cancer therapy effectives also by improving patients QoL, both during chemotherapy and afterwards.

MI as reaffirmed in a recent meta-analysis, is a well-known insulin sensitizer [13] nowadays hyperinsulinemia is considered a risk factor in cancer development. Indeed, in the majority of the tumors insulin regulated pathways are increased at both gene expression and activity of PI3K and Akt [14]. Evidence suggesting a positive role of Inositol (s) in cancer have been recently reviewed [4, 5, 15, 16]. Notably several authors have demonstrated that inositol phosphates and MI, in cancer cells, are able reduces PI3K expression (at both mRNA and protein level) [17] and Akt activation by inhibiting its phosphorylation [15, 18]. IP6 induce the impairment of the activity several signaling proteins such as: PI3K; PI3K-dependent activation of the tumor promoter induced AP-1; the phosphorylation-dependent activation of ERK [18]. Inhibition of PI3K activity, the protein kinase C (PKC) and the mitogen activated kinases (MAPK) have been documented by several studies both in vitro, [18-21] as well as in vivo, in particular, the in vivo studies were studies aiming to investigate inositol(s) chemo-preventive properties [22, 23].

In addition to the above described evidence that IP6 alone inhibits the growth of breast cancer cells, data by Tantivejkul et al., showed that IP6 synergistically acts with adriamycin or tamoxifen [24]. Noteworthy authors also manage to demonstrate that IP6 particularly effective when co-administerd with adriamycin or tamoxifen in ERα -negative cells and adriamycin resistant cell lines [24].

The clinical use of IP6+MI has been hampered by two main factors: bioavailability and palatability.

Human studies have demonstrated that dietary phytate is dephosphorylated during the digestion process by both plant phytases and phytases produced by human microbiota [25, 26].

Furthermore, several studies, aiming to investigate inositol phosphates solubility, have demonstrated that solubility in the stomach chyme negative correlates with the phosphorylation grade, i.e. the more phosphate group are attached to the inositol ring the less soluble and therefore bioavailable [27].

To solve this issue a transdermal gel has been used in the study by Proietti et al., indeed, instead of administering 1,4g of IP6 in powder, [9] researchers used a 5g of a 4% IP6 gel (200mg of IP6) [10].

In conclusion, literature data seams to demonstrate that IP6 and MI are effective in improving QoL of patients undergoing chemotherapy due to breast cancer.

References

1. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics. CA Cancer J Clin 65: 5–29.
2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, et al. (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136: E359–386. [crossref]
3. Bonadonna G, Valagussa P, Moliterni A, Zambetti M, et al. (1995) Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 332: 901–6.
4. Bizzarri M, Dinicola S, Bevilacqua A, Cucina A (2016) Broad Spectrum Anticancer Activity of Myo-Inositol and Inositol Hexakisphosphate. Int J Endocrinol 5616807.
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DOI: 10.31038/CST.2017283

Abstract

Objective: Analyse outcome and detect prognostic factors in surgical candidates with T4 non-small cell lung cancer (NSCLC).

Methods: All T4 NSCLC patients operated between 2001 and 2014 were included. Charts were retrospectively reviewed and data analyzed. Survival was calculated from the date of surgery until last follow-up. The impact of the following variables on overall survival was assessed: type of induction/adjuvant therapy, use of cardiopulmonary bypass (CPB), R-resection type, T4 site, histology, radiologic response to induction and post-induction pathologic T and N stages.

Results: Eighty-three patients were included. In 58 patients (70%), T4 was defined by a single structure involvement including mediastinum (n = 18, 31%), left atrium/pulmonary vein (n = 13, 23%), superior vena cava/right atrium (n = 8, 14%), aorta (n = 6, 10%), pulmonary artery (n = 5, 9%), trachea/carina (n = 3, 5%), spine (n = 3, 5%) or recurrent laryngeal nerve (n = 2, 3%). Induction therapy was administered in 49 patients (59%) consisting in chemotherapy (n = 38, 78%), radiation (n = 1, 2%) or chemoradiation (n = 10, 20%). Lung resections were lobar (n = 15), sublobar (n = 2) or pneumonectomy (n = 52). One isolated carinal resection was performed. Thirteen patients (15%) had unresectable tumors. Cardiopulmonary bypass (CPB) was used in 13 patients (16%). Post-operative mortality was 7%. Overall survivals at 3 and 5 years were 35% and 31%, respectively. In the multivariate analysis, pathologic tumor downstaging (ypT) and CPB use were positive and negative prognostic factors, respectively.

Conclusions: T4 NSCLC can be safely resected in selected patients and within a multimodality therapy approach. Responders to induction therapy with T-downstaging carry a survival benefit compared to non-responders.

Key words

lung cancer, T4, surgery, induction therapy, cardio-pulmonary bypass

Introduction

Treatment for T4 non-small cell lung cancer (NSCLC) invading the mediastinum, heart, great vessels, trachea/carina and vertebral body tend not to be surgical. Indeed, in a cohort study from 1992 to 2002 from the Surveillance, Epidemiology, and End-Results (SEER) Medicare data, only 1177 among 13077 patients (9%) underwent resection [1]. However, selected T4 NSCLC can be treated surgically within a multidisciplinary approach with survivals overwhelming the non-surgical cohort [2-4].

Here, we report a single-center experience of patients who underwent T4 NSCLC resection, with the aim of identifying clinical factors influencing long-term survival. These factors will help better selecting patients who may benefit from this challenging type of surgery.

Material and methods

Patients with a cytology/histology-proven NSCLC and invading the mediastinum, heart, great vessels, trachea/carina, recurrent laryngeal nerve, esophagus or vertebral body on radiologic imaging and referred to our institution for surgery from 2001 to 2014 were included. Patients’ data were retrospectively retrieved from our institutional database and completed with data from patients’ electronic charts. Patient informed consent was obtained prior to surgery.

Staging was routinely performed with computed tomography (CT) of the chest and upper abdomen as well as whole-body positron emission tomography integrated in CT (PET/CT). FDG-avid mediastinal lymph nodes were assessed either by cervical mediastinoscopy or endobronchial ultrasound-guided fine-needle aspiration (EBUS-FNA). Brain CT and/or magnetic resonance imaging (MRI) was performed routinely both for staging and restaging purposes. Response to induction therapy was assessed radiologically by CT of the chest and upper abdomen, and/or PET/CT. Imaging was reviewed for the purpose of the study by one author (H.G.) and tumor response classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD).

Patients who deemed technically completely resectable on imaging were planned for surgery and consisted in the patient cohort of the study. The appropriate surgical approach was planned according to imaging, mainly an anterolateral thoracotomy in the fifth intercostal space. If the tumor was deemed resectable after exploring the chest, the tumor and its surrounding invaded structures were removed en bloc. An anatomic lung resection was planned in all cases. Intraoperative lymph node staging was done according to the ESTS guidelines [5].

Indication and type of regimen for induction and adjuvant treatments were discussed on a case-by-case basis during our multidisciplinary tumorboard conference. Generally, three cycles of a platin-based doublet chemotherapy (with or without 45 Gy radiation) was administered preoperatively for cN2-disease or to decrease the local extension of the primary tumor. Adjuvant treatment was administered for persisting or unexpected N2-disease, or as part of a postoperative consolidation therapy.

NSCLC tumors were classified and staged according to the 7^th edition of the TNM classification of malignant tumors [6].

Statistical analysis was performed using SPSS 20.0 for Windows software (SPSS Inc, Chicago, IL.). Overall survival was estimated from the date of surgery until death or last follow-up, using the Kaplan-Meier survival analysis method. The impact on survival of 9 discrete variables—type of induction/adjuvant therapy, use of cardiopulmonary bypass (CPB), R-resection type, site of T4, histology, radiologic response to induction and post-induction pathologic T and N stages —was assessed by log-rank test and quantified by univariate Cox regression analysis. Variables with statistical significance were further analyzed in a multiple Cox regression model (backward). A p-value less than 0.05 was considered significant.

Results

Eighty-three surgical candidates (23 females, 28%) with T4 NSCLC were included. Median age was 64 (from 41 to 87). Median preoperative FEV1 and DLCO were 75% (from 34 to 120) and 67% (from 20 to 120) of the predicted, respectively.

Tumors were classified as T4 due to involvement of multiple (n = 25, 30%) or a single structures (n = 58, 70%). The most common single structure involved was the mediastinum (n = 18, 31%), followed by left atrium/pulmonary vein (n = 13, 23%), superior vena cava/right atrium (n = 8, 14%), aorta (n = 6, 10%), pulmonary artery (n = 5, 9%), trachea/carina (n = 3, 5%), spine (n = 3, 5%) and recurrent laryngeal nerve (n = 2, 3%).

Surgery was performed upfront in 34 patients (41%). Induction therapy was administered in 49 patients (59%) and consisted in chemotherapy alone (n = 38, 78%), radiation alone (n = 1, 2%) or chemoradiation (n = 10, 20%). A median of 3 cycles (from 1 to 7) of platin-based chemotherapy doublets were administered. Median radiation dose was 44 Gy (from 31 to 72 Gy). No radiologic complete response was seen after induction therapy. Radiologic tumor responses were PR (n = 35, 71%), SD (n = 12, 25%) and PD (n = 2, 4%).

Tumors and invaded structures were resected en bloc. Cardio-pulmonary bypass (CPB) was used in 13 patients (16% – Table 1). Lung resection included pneumonectomy (n = 52, left-sided in 30), lobectomy (n = 15) or sublobar resection (n = 2). One isolated carinal resection was performed. Thirteen patients (15%) had unresectable tumors at explorative thoracotomy.

Table 1. Patients characteristics who underwent T4 resection under cardio-pulmonary bypass

M = male, F = female, P = pneumonectomy, PA = pulmonary artery, SVC = superior vena cava, RA = right atrium, LA = left atrium, v. = vein, a. = artery, + = alive, * from anoxic brain injury, ** from respiratory failure

NSCLC subtypes were squamous cell carcinoma (n = 48, 58%), adenocarcinoma (n = 25, 30%), large cell carcinoma (n = 6, 7%) and other (n = 4, 5%). Downstaging of pathologic tumor stage after induction therapy (ypT) occurred in 16 patients (33%), including ypT3 (n = 1, 6%), ypT2 (n = 7, 44%), ypT1 (n = 5, 31%) and ypT0 (n = 3, 19%). Thirty-three (67%) patients had persisting ypT4 on pathologic examination after induction therapy. Complete resection was achieved in 45 patients (55%). Twenty-two patients (27%) had microscopic incomplete resection (R1) while 16 (20%) presented with unresectable tumor or macroscopic incomplete resections (R2).

Thirty-day or in-hospital mortality was 7%. Cause of death was pneumonia/adult respiratory distress syndrome (n = 2), cerebral vascular insult (n = 2), pulmonary embolism (n = 1) and sepsis/multi-organ failure (n = 1).

Overall 3- and 5-year survivals for the whole cohort was 35% (Standard Error – SE = 6%) and 31% (SE = 5%), respectively (Figure 1). Median survival was 18 months (95% confidence interval – CI = 11-25). Median follow-up was 17 months (from 0 to 127). Although not significantly (p = 0.19), 3- and 5-year survivals increased to 37% (SE = 6%) and 34% (SE = 6%) when patients with exploratory thoracotomy were excluded.

Figure 1. Overall survival for surgical candidates with T4 non-small cell lung cancer.

Patients at risk:

Univariate analysis showed that CPB use, type of radiologic response to induction therapy and pathologic T stage after induction (ypT) had a statistically significant impact on survival. In the multivariate analysis, only CPB use and ypT stage remained significant (Table 2). Corresponding survival curves are illustrated in Figures 2 and 3.

Figure 2. Survival depending on cardiopulmonary bypass (CPB) use. P-value from log rank test = 0.002.

Patients at risk:

Figure 3. Survival depending on post-induction pathologic tumor stage (ypT). P-value from log rank test = 0.001.

Patients at risk:

At the end of follow-up, 57 patients (69%) had a tumor recurrence. Median delay from surgery to first recurrence was 9 months (95%CI = 2-16). Recurrences were local intrathoracic (n = 28, 34%), distant (n = 17, 21%) or local and distant (n = 12, 14%). Disease-free survivals at 3 and 5 years was 29% (SE = 6%) and 23% (SE = 5%), respectively.

Table 2. Uni- and multivariate analysis of clinical variables with potential impact on survival. HR=hazard ratios, CI=confidence interval

⁺p-value derived from cox regression analysis

Discussion

Surgical treatment of T4 lung cancer is still debated. Analysis of the SEER Medicare database showed that only 9% of T4 NSCLC were offered surgery [1]. This is in part because of the potential for significant morbidity and mortality related to T4 surgery [7]. However, perioperative risk has diminished over time, with mortality ranging from 0% to 12.5% in more recent studies [7]. In our patient cohort, 30-day or in-hospital mortality was 7%.

Survival for patients with T4 NSCLC who cannot undergo complete resection is poor, ranging from 3% to 17% at five years [8-10]. In our cohort, 5-year survival reached 34% for resected T4 NSCLC. This is in line with results from the literature, where 5-year survival ranged from 19% to 38% [11-4].

Therefore, surgery for T4 NSCLC should be considered in relation to multidisciplinary care [7]. Patient selection plays a major role in decreasing perioperative mortality and increasing survival. From the literature, it has been demonstrated that completeness of resection as well as nodal status were factors significantly influencing survival [13,14]. In a large retrospective study including 271 patients with T4 NSCLC, five-year survivals for N0/N1 was 43% compared to 18% for N2/N3/M1, while 5-year survivals were 40% and 16% for R0 and R1 resections, respectively [13]. For both of these factors, only trends without significance were seen in our study.

We found in the multivariate analysis a significant impact on survival for histopathologic tumor response to induction therapy. Patients with pathologic downstaging to ypT0-3 had far better survivals compared to patients without downstaging (ypT4), namely 86% vs. 19% at five years. These results are in line with results of a previous study on T4 NSCLC invading the spine after induction treatment consisting in 2 cycles of cisplatin-etoposide combined to concurrent 45 Gy of radiation [15]. Patients with complete or near complete pathologic response, defined as ≥ 95% tumor necrosis on pathologic examination, behaved significantly better than patients with a partial response. Five-year survivals were 80% compared to 35%. Similar findings were also found in the context of stage IIIA-N2 NSCLC. A trend in better survivals was seen in patients with mediastinal downstaging, compared to patients with persistent N2 disease, with 5-year survivals of 49% and 27%, respectively [16].

Patients requiring CPB in our study had a 5-year survival of 15%. This is lower than the 37% reported in a systematic literature review including 20 articles and pooling 72 patients who required CPB for resection of NSCLC. The superiority survival reported in this review is mainly due to strong publication bias inherent to systematic literature reviews including a large number (12/20, 60%) of case reports or small case series including not more than three patients [17]. Nevertheless, CPB use was highlighted as a negative prognostic factor in the multivariate analysis from our cohort. The reason is unclear. First, it is demonstrated that CPB induced a pro-inflammatory response as well as a transient immunosuppression [18, 19]. Both of these effects may favor tumor progression. Second, it is postulated that tumors invading the heart or other vascular structures (and therefore requiring CPB) have a more aggressive biology. Indeed, in a study including thoracic inlet tumors, it was shown in a multivariate analysis, that subclavian artery invasion negatively impacted on survival [13]. These results are however in contradiction with results of a recent study on T4 surgical candidates, where survival was not different between patients operated on CPB (n = 20) vs. without CPB (n = 354) [10]. In this context, avoiding CPB whenever possible is probably an adequate strategy. Recently, in cases of aortic wall invasion by tumors, the placement of a thoracic aortic endograft allowed complete tumor resection without any aortic clamping or shunts [20].

Our study has some limitations, mostly due to its retrospective nature and limited sample size. However, it emphasized an additional criteria, namely pathologic response to induction treatment for better selecting patients who may benefit from surgery within a multimodal strategy in this heterogeneous T4 patient population.

Funding: None

Conflict of interest: None declared.

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